Brain Research Bulletin, Vol. 50, No. 3, pp.

149 165, 1999

Copyright 1999 Elsevier Science Inc.
Printed in the USA. All rights reserved
0361-9230/99/$see front matter

PII S0361-9230(99)00095-7

REVIEW ARTICLE

How did the human brain evolve?

A proposal based on new evidence from in vivo
brain imaging during attention and ideation
Stanley I. Rapoport*
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
[Received 7 December 1999; Revised 24 June 1999; Accepted 29 June 1999]
ABSTRACT: It is proposed that brain evolution in nonhuman
primates and humans was facilitated by heritable differences in
neuroplasticity and in the number of neurons and synapses
available during childhood and adolescence, therefore, in differences in modifiability and elaboration of neuronal networks
in brains of immature primate genotypes. These differences
were exploited when a primate population was forced to adapt
to a new cognitively or behaviorally demanding milieu, to select
more cognitively and brain competent adults who could best
compete and reproduce in this new milieu, extending their
genes within the population. Two recently solidified concepts
suggest a mechanism for this evolutionary process: (1) Association neocortex can be activated by attention and ideation in
the absence of sensory or motor contributions, as demonstrated by in vivo imaging and direct brain recording. (2) Activation of the immature brain can promote and stabilize neuronal networks that would disappear or otherwise lose their
function by adulthood. Taking these two ideas together, it is
proposed that the thought processes of attention and ideation, when used by immature primates to adapt to new cognitive or behavioral stresses, led by the repeated selection of
genotype to more cognitively able, larger-brained species with
more extensive association cortex and related regions.
1999 Elsevier Science Inc.

Intellect or intelligence, defined as the power or faculty of knowing

as distinguished from the power to feel and to will, represents the
combined faculties of understanding, reasoning, cognition, apprehension, attention, and ideation [65]. Although common mechanisms likely subserve intellect in brains of all mammals, absence
of a common psychometric scale prevents quantitative comparisons of intellect among mammalian species. Nevertheless, it generally is recognized that at least qualitative differences exist among
primates in certain cognitive domains, particularly those related to
symbolic processing, syntax, language and self-awareness [56,
69,206], and that these differences correspond somehow to differences in brain size and organization.
Comparative anatomic studies among living primates and the
primate fossil record show that brain size, normalized to body
weight, increased during primate evolution. The increase was
accompanied by expansion of the neocortex, particularly its association regions (see below) [166]. Although larger brains likely
provided more extensive neural substrates for increased intellect
during primate evolution [90,114], it is not clear whether, or by
what mechanism, a reciprocal effect of intellect contributed to
larger brains (see quote above) [32].
In this paper, I present evidence from in vivo neuroimaging in
humans and direct brain recording in nonhuman primates that such
a reciprocal effect exists and that it operates by directly activating
brain. I propose that such activation, in immature primates learning
to adapt to a new cognitive, social, cultural, or behavioral environment, reduced the extent of synaptic pruning and thereby promoted elaboration of brain circuits subserving higher order cognitive processes. Within a heterogeneous primate population, adult
genotypes whose brains could most effectively be modified by
such activation were most competitive, thus able to produce more
offspring and extend their genes within the population. In some
cases, a larger-brained, more cognitively able primate species

KEY WORDS: Evolution, Primate, Cognition, Positron emission

tomography, Genetics, Synapse, Pruning, Brain, Dreaming,
Neurodevelopment, Neocortex, Chimpanzee, Humans, Imaging, Attention, Ideation, Schizophrenia, Fragile X, Magnetic
Resonance, Visuoconstruction.

INTRODUCTION
One tells us, and all scientific evidence tends to demonstrate this: the brain
secretes thought, there isnt any thought without brain. What one hasnt
discussed is whether there is a reciprocal effect.1
Christian De Duve [32]

* Address for correspondence: Dr. Stanley I. Rapoport, Laboratory of Neurosciences, Building 10, Room 6C103, National Institute on Aging, National
Institutes of Health, Bethesda, MD 20892, USA. Fax: 1-301-402-0074; E-mail: sir@helix.nih.gov
1
Translated from the French: On nous a dit, et toutes les donnees scientifiques tendent a` le demontrer: le cerveau secre`te la pensee, il ny a pas de pensee
sans cerveau. Ce dont on na pas parle, cest de savoir sil y a un effet de retour.

149

150

RAPOPORT
TABLE 1
ENDOCRANIAL VOLUME AND BODY WEIGHT IN HOMINIDS AND CHIMPANZEES

Family species

Pongids
Pan troglodytes
Pan paniscus
Hominids
Australopithecus afarensis
Australopithecus africanus
Homo habilis
Homo erectus javanicus
Homo erectus pekinensis
Homo sapiens (neanderthalis)
Modern Homo sapiens

Endocranial Volume
(cm3)

Body
Weight

Time of Appearance

Mean (Range)

(kg)

(Millions of Years Ago)

383 (282500)
343 (275381)

47
35

7.56.5
3.12.5

401
442 (428486)
644 (590687)
926 (8131059)
1043 (9151225)
1487 (12001750)
1365 (11561775)

24
36
42
49
53
83
69

42.5
3.22.2
2.51.5
1.80.6
0.70.5
0.22
0.2

Values are from fossil record except for modern Homo sapiens and Pan. Remaining values are from living
species.
Data from [16,17,34,81,125].

arose through this process of natural selection [30,31]. An abstract of part of this theory has been published [168].
CO-EVOLUTION OF INTELLECT AND BRAIN IN
PRIMATES
The Primate Evolutionary Tree
The order Primates emerged from archaic terrestrial and nocturnal insectivores (shrew-like animals) some 90 to 65 million
years ago [92]. To identify the subsequent steps in primate evolution, evolutionary trees have been reconstructed based on
immunological differences in amino acid sequences of homologous proteins, and on hybridization differences between DNA,
among living primate species [176,184]. These trees indicate
that Old World monkeys and hominoidea (apes and hominids)
diverged from New World monkeys about 30 to 35 million years
ago. Gibbons appeared about 10 million years ago, then orangutans. Hominids, chimpanzees and gorillas became distinct from
each other some 5 million years ago. Two distinct species of
chimpanzee, Pan troglodytes and Pan paniscus, appeared about 2
million years ago [92], and modern Homo sapiens, the only extant
hominid, appeared about 200,000 years ago.
Primate Intelligence
Cognitive and behavioral consequences of brain lesions in
living primates [9,59,134], correlations between rates of maturation of cognitive abilities and of brain networks in humans and
nonhuman primates [60,122,222], and correlations in Alzheimer
disease patients between regional brain metabolic reductions and
cognitive deficits [66,76,167], support a multifactorial model of
primate intelligence. This model asserts that specific cognitive
processes and behaviors are subserved by overlapping and spatially distributed brain networks [122,132,197]. It is consistent
with evidence from monkeys and humans that the ability to recall
stored information is localized partly to hippocampal and entorhinal cortex circuits, visuospatial function to right hemispheric circuits, language function to left hemispheric circuits, and attention
and planning to frontal cortical circuits [9,68,76,134].
Two higher-order domains of intellect, syntactic processing of
images or symbols and mirror self-recognition, are evident in

chimpanzees and in humans, suggesting continuity between the

two species of the brain networks underlying these domains. The
pygmy chimpanzee, Pan paniscus, if exposed to human language
and meaningful lexigrams early in life, can achieve the syntactic
competence of a 2-year-old child when manipulating visual symbols [178]. The immature common chimpanzee, Pan troglodytes,
can learn these processes but to a lesser extent. The presence of
these abilities in chimpanzees is consistent with evidence that
Brodmann areas 39 and 40, which form a large inferior parietal
lobule within Wernickes language area of the left human cortex,
are prominent in the chimpanzee brain; they barely protrude from
the orangutan brain [58,128,150].
Mirror self-recognition by naive subjects is considered by some to
imply awareness of self as distinct from other selves in tertiary social
settings. It also may indicate that the subject sees himself as a distinct
intentional psychological entity with a continuous past, present, and
future [56,149]. Mirror self-recognition appears in children during the
second year of life [7], and has been demonstrated in chimpanzees,
gorillas, and orangutans but not monkeys [154,155].
Brain Size and Organization
Evidence that brain weight (normalized to body weight) is
higher in living primates than in most other mammals has long
suggested that intellect in primates co-evolved with increasing
brain size or encephalization [81,82,91,217]. Fossil cranial casts
indicate that encephalization was accelerated during the past 5
million years of hominid evolution (Table 1), and that the process
was accompanied by expansion of frontal and parietal association cortex [205].
A holistic interpretation by K. Lashley of co-evolution of brain
size and intellect is that increasing size, simply by providing more
neurons, axons, and synaptic connections, enhanced intellect by
increasing the capacity to discover significant relations among the
elements of a situation and to adjust behavior in terms of a
maximum number of such relations [114]. An extension of Lashleys thesis is that changes in brain size and cognition were
accompanied by elaboration of overlapping and regionally distributed brain networks, namely that organization as well as quantity played a role. This is consistent with evidence that different
cognitive abilities mature in primates in relation to maturation of
specific underlying networks, and that lesions or neurodegenera-

BRAIN EVOLUTION IN PRIMATES

tive changes in certain networks produce the expected cognitive
and behavioral deficits (see above).
Encephalization involving selective changes in certain brain
networks also agrees with evidence that the primate brain can be
divided into phylogenically older motor and sensory (visual, auditory, somatosensory, olfactory, and gustatory) systems, and into
two association Systems, I and II. Association Systems I and II
are considered to have expanded and differentiated (progressed)
during primate evolution [13,43,164,166,177,195]. The systems
are bilaterally asymmetrical in some Old World monkeys, the great
apes and especially in humans, illustrating the principle of cerebral dominance [57,58,115,223].
At a higher level of brain organization, motor and sensory systems
and association Systems I and II are considered to be integrated
within functional hierarchies which subserve vision, audition, somatosensory sensation and motor movement [49,61,95,215]. The
visual hierarchy in the rat has 3 levels with 5 modules or functionally
specific regions [49], in the cat it has 8 levels with 62 connections
among 16 modules [198,202,203]. In the macaque, the visual hierarchy is more complex. It consists of 10 neocortical levels plus retina,
lateral geniculate nucleus, entorhinal cortex and hippocampus, and
parahippocampus, with more than 300 connections traversing only
one to two levels [49,171]. The visual hierarchy is divided into two
bilateral functional streams in humans and higher primates. The
occipitotemporal stream subserves object identification, the occipitoparietal stream, object localization [74,136].
Comparative studies in living primate species of regional brain
volumes, interregional connections, and brain ontogeny and regional
vulnerability to neurodegenerative disease, suggest that evolutionary
changes in subcortical regions within Systems I and II were driven by
their connections with the expanding neocortex [164 166,177]. Indeed, the neocortex, particularly its association areas, expanded and
differentiated more rapidly than other regions during primate evolution. This has been demonstrated by calculating progression indices, equal to the volume of a brain region normalized to body weight
in a living species, divided by the volume of that region in a notional insectivore of equal body weight [43,166,195,196]. The progression index of the neocortex is 58 in the chimpanzee and 156 in
modern Homo sapiens. Progression indices of other regions in Systems I and II in modern Homo sapiens do not exceed 22, whereas they
are less than 1.0 for certain olfactory regions which regressed
during primate evolution.

151
unchanged from generation to generation, in the absence of an
environmental challenge. In the face of such a challenge, assuming
that allele A would provide a competitive phenotypic advantage
compared with allele a, genotypes carrying A will have more
offspring than those carrying a. The net effect will be directional
natural selection, tending to shift the population phenotype to
individuals carrying A.
Nucleotide sequences in nuclear DNA differ only by 0.4% to
1.6% between modern Homo sapiens and the common chimpanzee, Pan troglodytes [102,184]. Consequently, the marked phenotypic differences that distinguish these two species, including a
3.5-fold difference in brain size, are unlikely to be due to point
mutations. They reflect other genetic processes, particularly more
likely gene recombination [100,102,145,166,218]. Recombination
represents the random union of gametes in the sexual process and
the very frequent crossing-over during meiosis [52]. It thus can
provide an enormous range of variants among genotypes without
changing basic gene structure [130]. In so doing, it can unite
favorable mutations in the same genotype even if they first appear
in different individuals [21,29].
Additionally, gene duplication, which is especially frequent at
chromosomal sites of molecular instability [145], likely contributed to primate brain evolution. Gene duplication has been suggested to have promoted rapid progression of the neocortex [5],
and has been shown to have introduced three-color vision at the
time of speciation of Old World primates [207].
Consistent with the slight difference in DNA between modern
humans and chimpanzees (see above), point mutations must have
contributed less to brain evolution in primates than did gene recombination. Indeed, altered proteins resulting from such mutations would
most often have been lethal or caused disease in a complex and
optimally connected organ like the brain [101,138,208,218]. In some
cases, however, point mutations of genes, within multigene families,
that arose through duplication would have been better tolerated and
even helpful in producing new combinations of receptors, enzymes,
and ion channels [38,41,145]. Finally, chromosomal rearrangements
can create absolute interspecies barriers and promote rapid phenotypic
evolution; several such rearrangements distinguish the great apes from
modern humans [33,119].
Genetic Determinants of Brain Structure and Function
Compared with the approximately 100,000 genes in the human
genome, there are between 40 and 100 billion neurons and many more

HERITABLE VARIATIONS IN BRAIN PROVIDE A

BASIS FOR NATURAL SELECTION
Genetic Principles Applied to Primate Evolution
To avoid the criticism of Lamarkism, any theory regarding
brain evolution in primates should be consistent with Darwins two
main principles of natural selection: (1) heritable variation
among individuals in a population and (2) a struggle for existence
leading to offspring with the most successful traits [30,31]. Additional factors considered by Darwin to promote speciation are a
long span of time and environmental or social isolation. With the
rediscovery of Mendelian genetics at the turn of the last century,
Darwins two principles were reformulated by considering the
subject of selection the gene, for which the concept of gene
frequency is especially important. One consequence of this reformulation is the Hardy-Weinberg principle of gene recombination
[72,73,100,130].
Briefly, according to the Hardy-Weinberg principle, under random mating and Mendelian inheritance, if a pair of alleles A and
a occur within a population with relative frequencies p and q
(where p q 1), then the equilibrium genotypic frequencies
are: p 2 AA, 2pqAa and q 2 aa. These frequencies will remain

FIG. 1. Proportionality of life phases and gestation in primates in relation

to order of speciation. From [121].

152

RAPOPORT

FIG. 2. Synaptic density during brain maturation. (A) Synaptic density in prefrontal cortex of macaque at various ages.
Horizontal stripe denotes average synaptic density in adult animal. Age in days postconception is on a logarithmic scale.
From [161]. (B) Synaptic density in layer III of human middle frontal gyrus as a function of age. From [86].

synaptic connections (10,000 to 100,000 synapses per neuron) in the

adult human brain [11,24,28]. Clearly, specification of much of adult
brain structure and function is not genetically programmed. Nevertheless, genetics determine the six-layered structure and the afferent,
efferent, and interlaminar connections of the neocortex [139,160,199].
In humans, genetics even are speculated to influence brain structure
for realizing certain categories of thought and for establishing syntactic and semantic properties of language [20,35,112].
Genetics also regulate the temporal expression of local neurotrophic and adhesion factors that influence brain development
[50,71]. Genetics specify the segmental or regional organization of
the nervous system by regulatory genes which contain generally
conserved homeobox, paired-box or zink-finger motifs, some of
which are regionally expressed in brain [84,143,156]. Furthermore, information in the genetic code may program large multigene families coding for brain receptors, enzymes or ion channels
into original combinatorial arrangements [41,44,187].
Epigenetic Determinants of Brain Structure and Function
The basic structure of local brain circuits is not specified by
genetics but depends instead on epigenetic factors such as electrical activity and energy constraints [27]. The fact that cortical
columns innervate their neighbors in brain areas specialized for a
few stimulus attributes is considered more efficient than having
columns with common attributes linked across a larger cortical
surface. Certain features of cortical mapping, such as stripes and
patches within visual areas and larger functional units or hypercolumns, may promote even more efficient wiring by minimizing
cortical connections [85,94,137].
Functional modalities of developing neocortex also are not genetically specified. They largely are determined by epigenetic factors
such as input from thalamus and ipsilateral and contralateral cortical
fields, and cholinergic stimulation [99,175]. For example, if visual
stimulation is absent in animals or humans blind since birth, auditory
and somatosensory cortical receptive fields will replace what otherwise would have been visual cortical territories [169,174].

Overproduction and Loss of Neural Elements During Gestation

and Maturation
Among living primates, differences in brain size correlate with
differences in the duration of gestation [36,63,121,146]. Prolongation of gestation during primate evolution, shown in Fig. 1,
likely contributed to these size differences by allowing more time
for neurogenesis in more recent species. It is estimated that a single
extra round of mitotic division at the stage of formation of proliferative units at the ventricular surface of the neural tube (before
stage E40 in the human fetus) would double the number of available cortical neurons formed from these units [159].
The duration of postnatal maturation of brain increased during
primate evolution pari passu with prolongation of gestation (Fig.
1). After birth, the primate brain continues to enlarge through
proliferation of glial cells, elaboration of synapses and axons, and
myelination. The rhesus monkey achieves 65% of its adult cranial
capacity by birth, chimpanzees 41%, and humans only 23%. Chimpanzees and gorillas reach 70% of adult cranial capacity early in
the first year of life, whereas modern humans do not attain adult
cranial capacity until 5 years of age [89,151]. Prolongation of
maturation in relation to primate evolution provided more time for
the brain to remain susceptible to structural and functional modification by thought involved in adaptive learning (see below).
During gestation, the mammalian brain produces many more
neurons than survive to adulthood. The extent of this overproduction is largely heritable, whereas subsequent neuronal loss or
apoptosis can be modulated by activity, competition, and trophic
substances through neuroplastic mechanisms [204,226].2 In rodents and monkeys, neurogenesis continues long after birth; 15%
and 30% of cortical neurons, respectively, are lost by adulthood
[79,144]. In contrast, in humans neurogenesis largely disappears
before birth and postnatal neuronal loss is short-lived, terminating
by 6 months of age [87,88,116]. Recently, however, limited neurogenesis has been demonstrated in the dentate gyrus of the adult
rat, and to a much lesser extent in the dentate gyrus of adult
monkeys and humans [46,55,104].

2
Neuroplasticity depends on a number of intrinsic proteins and peptides, including neurotrophins (NTs) such as nerve growth factor (NGF); brain-derived
neurotrophic factor (BDNF), NT-3, and NT-4, all of which act via tyrosine kinase (Trk) receptors on neuronal membranes; gp140, gp145trkB and gp145trkC;
and insulin-like growth factor-I (IGF-I) [188]. Some neurotrophins are regionally expressed and regulate development of the septum-basal forebrain
complex, limbic system or other brain networks [113,152]; others determine critical periods of susceptibility to electrical activity (see text). Certain
neurotrophins such as IGF-I may be effective only after birth, making the organism sensitive to learning [71]. Neurotrophins are reported to be absent from
the invertebrate nervous system [62], although homologues of the Trk receptor have been identified there [211]. The introduction of neurotrophins in
vertebrates provided new opportunities for brain-environment interactions.

BRAIN EVOLUTION IN PRIMATES

153

FIG. 3. Arrangement of vibrissae on face and their central representation in guinea pig. (a) Organization of vibrissal
sensory pathway. Neurons in trigeminal sensory ganglion V receive input from vibrissal follicles via the infraorbital
nerve. Their central processes synapse isomorphically in four subnuclei of the ipsilateral brainstem trigeminal
complex: pars principalis (nVp), pars oralis (nVo), pars interpolaris (nVi), and pars caudalis (nVc). Second-order
neurons in these nuclei project isomorphically to the contralateral ventrobasal complex of the thalamus, from which
third-order neurons project to whisker barrels in somatosensory cortex Sm1. (b) Arrangement of whiskers on the left
snout. Six rows of whiskers are designated AF in a dorsal to ventral direction; each row contains four whiskers,
except for B which has three and for F which has five. Whisker B-3 is indicated by asterisk, whisker F-3 by diamond.
Dorsal is up and rostral is to the left. (c) Pattern of whisker representation in the left pars interpolaris (nVi). The
arrangement is homeomorphic to that on snout. Representation of B-3 is marked by asterisk, of F-3 by diamond. (d)
Vibrissal representation in right primary somatosensory cortex. B-3 representation is marked by asterisk, F-3 by
diamond. From [185].

Synaptic proliferation followed by synaptic pruning characterizes maturation of the primate brain through adolescence. In the
macaque, neocortical synapses start to proliferate in the middle of
gestation, increase rapidly in number in the first two postnatal
months of life, then decline by some 40% between 3 and 5 years
of age (Fig. 2, left) [161,162]. In humans, the phases of synaptic
proliferation and pruning are both extended through 16 years of
age. For example, in layer III of human middle frontal gyrus,
synaptic density increases in the first two years of life, remains at
a plateau between 1 and 8 years, then declines by some 50%
through adolescence (Fig. 2, right) [86 88].
By virtue of its excess synapses and high regional expression
levels of neurotrophic factors, the immature primate brain is particularly sensitive to modification by the intensity and pattern of
electrical activity and of neurotransmitter release [99,183,204].
Termed neuroplasticity,2 much but not all of this sensitivity is lost
by adulthood. Neuroplasticity may be most evident during certain
critical periods, whose appearance and duration in the immature
brain depend on expression of factors such as N-methyl-D-aspartate (NMDA)-selective glutamate receptor proteins, growth associated protein (GAP-43) and other phosphoproteins and surface
adhesion molecules [15,103,204]. Failing to activate a network
during its critical period can lead to permanent functional and

structural deficits, whereas unusually intense activation may expand its functional and structural capabilities [83].
In Pan troglodytes, the critical period for learning to use stones
as hammer and anvil to open nuts is before 8 years of age [126]. This
learning is thought to represent cultural variation, as it occurs in
some colonies but not others [216]. Likewise, Pan paniscus can learn
syntactic processing by using lexigrams when young but not when
adult [173,178]. In humans, the critical period for acquiring language
exists prior to 16 years of age in both hemispheres, but it usually is
exploited only by the left hemisphere [140]. However, if the left
cerebral cortex is removed early in life, the right hemisphere can
assume virtually normal language function [6].
BOTTOM-UP EVOLUTION OF PRIMARY MOTOR
AND SENSORY SYSTEMS
Observed correlations between whisker sense organs and their
central representation in small mammals led Van der Loos to
propose that the periphery imposes its spatial organization on
sensory cortex, not the other way around, and brain maps and
periphery do not originate independently from one another [209].
This bottom-up principle implies that evolution of motor and
sensory systems in mammals was somehow driven by and coevolved with heritable changes in peripheral sense organs and

154

RAPOPORT

FIG. 4. Cortical sensory representation in species with different sensory specializations. In echo-locating ghost bat, more than
half of cortex processes auditory information (black Aud). In platypus, two thirds of cortex (including SI, PV, R, and M)
receives input from electrosensory or mechanosensory receptors on bill (hatched). In star-nosed mole, visual cortex (V,
dotted) is very small compared with large cortical area devoted to representation of nose. Scale bars 1 mm. Abbreviations:
A, primary auditory area; M, motor cortex or manipulation area; PV, parietal ventral area; R, rostral auditory area; SI, primary
somatosensory area 3b; SII, secondary somatosensory area; V, primary visual area. From [108].

muscle effectors, advantageous adaptations to new physically

demanding milieus.
Figure 3 illustrates the somatosensory system that subserves
whisker sensation in the guinea pig. This system includes, starting
from the periphery: (1) sensory receptors at the base of the whiskers, innervated by the maxillary branch of the trigeminal nerve
(V), (2) axons of the fifth cranial nerve, (3) cell bodies within the
ipsilateral interpolar and caudal nuclei of the trigeminal complex,
(4) neurons within the bilateral brain stem nuclei, (5) contralateral
ventrobasal and posterior thalamic nuclei, whose neurons respond
to vibrissae movement with precise somatotopic representation,
and (6) contralateral barrel field in the somatic sensory cortex
[185]. The barrel field, a cylindrical structure demarcated by
perikarya, is oriented perpendicularly to the surface of the sensory
cortex in layer IV. Its posteriomedial part forms a subfield of
barrels of greater size, each of which is related topographically to
one single vibrissa on the contralateral snout.
In different rodent strains, the number of whisker barrels in
somatosensory cortex corresponds to the number of whiskers on
the opposite snout [209,213,220,221]. Removal or deafferentation
of whiskers before birth prevents the appearance of whisker barrels
in the expected locations [185]. Further, whisker barrel size can be
modulated by local neurotrophic factors,2 potential targets for
recombination (see above). For example, transgenic mice that
overexpress insulin-like growth factor I (IGF-I) have larger whisker barrels with more and larger neurons and more neuropil,
whereas transgenic mice that express IGF-binding protein-1
(IGFBP-1) have smaller whisker barrels [71].
Correlations between the extent of use of the hand (or paw) and its
central representation further reflect bottom-up evolution. The hand,
which is critical for adapting to an arboreal environment [92], is
disproportionately represented in the somatosensory cortex of many
primates [18]. It also is widely represented in the somatosensory
cortex of different species of otters, in proportion to their tactile
sensitivity [157]. Fine motor movement in raccoons also corresponds
to extensive somatosensory representation of the hand [214].
Stereoscopy and three-color vision (trichromacy) are peripheral
modifications that helped primates adapt to an arboreal habitat [92,
207]. They appear to have co-evolved with important central nervous
system changes: (1) an occipital neocortex with a larger percentage of
association neocortex (33.6% of occipital cortex in gibbons, 60.4% in
orangutans, and 74.6% in humans) [11] and more association modules mediating form, color, movement and depth (see above)

[49,75,120,136,171,224]; (2) two bilateral visual pathways, an

occipitotemporal pathway mediating object identification and
an occipitoparietal pathway mediating object localization (see
above); and (3) in trichromatic Old World monkeys, apes, and
humans, a six-layered lateral geniculate body with two subdivisions: four dorsal small-cell (parvocellular) layers, and two ventral
large-cell (magnocellular) layers; each eye projects to three of the
six layers in an alternating fashion. The parvocellular visual system, which mediates color perception by combining and subtracting red, green, and blue cone inputs, also is elaborated in primary
striate cortex (V1), visual association cortex (V2) and higher
association cortical areas dedicated to color processing [70,120,
182].
Other examples of advantageous co-evolution of in peripheral
sense organs and brain have been noted in mammals [109,142].
The bill of the platypus is a mechanosensory and electrosensory
organ helping the animal to identify prey and enemies in muddy
Australian streams, the echo-locating bat uses its ears to identify
flying insects in mid-flight, and the star-nosed mole exploits specialized sense organs on its nose to survive in its underground
habitat. As illustrated in Fig. 4, each of these species has the
expected overrepresentation of its special sense organ in its
somatosensory cortex [108,109].
Figure 5A illustrates how bottom-up evolution of a primary
sensory system could arise. A mammalian population, displaying
heritable variations in brain synapses and neuroplasticity, and in
the surface expression of critical sense organs, is presented with a
new physically demanding milieu. Those immature genotypes
within a heterogeneous population, who best elaborate their sensory skills because of these heritable differences, will as adults
likely be most fecund. Their genes will extend within the population, in some cases leading to a new species.
TOP-DOWN EVOLUTION OF BRAIN ASSOCIATION
SYSTEMS
So the land, I said, must first exist as a concept in the mind? Then it
must be sung? Only then can it be said to exist.
Bruce Chatwin [19]

While the introduction of stereoscopic and trichromatic vision,

and the more effective use of the hands, promoted bottom-up
evolution of sensory systems in the primate brain, higher-order
thought processes involving attention, memory, complex commu-

BRAIN EVOLUTION IN PRIMATES

FIG. 5. Suggested flow charts for bottom-up evolution of primary sensory and motor systems in mammals in general (A), and for top-down
evolution of association systems in primates (B). The return arrow at the
bottom of (B) signifies that increasing social and behavioral demands
created by the appearance of a new primate species can in turn increase
pressure for a new cycle of evolution [217]. See text for discussion.

nication, syntactic manipulation of images and later of words,

visuospatial ability, planning, and self-awareness, likely promoted changes in brain association areas through a top-down
mechanism. The model of Fig. 5B illustrates the proposed steps of
this mechanism.

155
This model assumes that higher-order thought can directly activate and modify widespread brain regions in immature primates.
Such activation will reduce synaptic pruning and lead to the selection
of genotypes whose elaborated brain association networks allow
them to be most cognitively competent (see above). The selection
takes place, however, only when a genetically heterogeneous population is faced with a new cognitive, social, cultural or behavioral
stress. The genes of the successful adults spread within the population,
leading in some cases to a new cognitively more competent, largerbrain species. This process can be recursive (upward arrows at bottom
of Fig. 5B) and accelerated if the new species which appears creates
further cultural stresses, as was likely during evolution of the great
apes and hominids [216,217].
Several lines of evidence support the top-down mechanism
illustrated by Fig. 5B. First, in vivo neuroimaging and direct brain
recording demonstrate that ideation and attention, free of sensory or
motor components, can activate or modify activation of wide areas of
cortex in humans and nonhuman primates. Additionally, studies in a
wide number of species show that the intensity and pattern of neural
activity can permanently modify the structure and function of the
immature brain.
The environmental changes that promoted top-down brain evolution in hominids are reasonably well understood, and will be mentioned briefly in the context of Fig. 5B. Starting some 5 million years
ago, periods of drought in Africa led to replacement of large areas of
forest first by partially wooded, well-watered regions, followed after
about 2.5 million years by wide areas of arid grassland or savanna. It
is speculated that some chimpanzees first moved from their receding
arboreal habitat to the semi-arboreal environment, where upright
posture and bipedalism would provide a competitive advantage for
surveying the landscape, hunting and escaping predators. Skeletal
changes suggesting bipedalism, in the pelvis, bones of the foot, cranial
labyrinth and semicircular canals, are found in Australopithecus fossils. These changes are fully evident in Homo [10,23,193,194]. In
turn, upright posture is considered to have freed the arms and hands
for using weapons for fighting and hunting in Australopithecus and
later, during speciation of Homo habilis, for fashioning tools [64].
Hunting, in turn, permitted the fruit and leaf diet of the arboreal
habitat to be replaced by a diet of meat, and of fish and shellfish (in
the Rift valley). This diet was high in calories and polyunsaturated
fatty acids, necessary for evolving an enlarging brain [1,12]. Upright
posture also promoted descent of the larynx and extension of the
pharynx which, together with modifications in the position and freedom of movement of the tongue, introduced speech and rudimentary
language during speciation of Homo erectus [117].
Ideation Activates Wide Areas of Association Cortex in Human
Brain
The ability to create and manipulate visual images or symbols
contributes to a wide range of mental activities, from memory to
syntax to planning, whereas visuoconstruction promotes adaptation to the three-dimensional external world. In vivo neuroimaging
using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI),3 and in vivo recording in the
macaque brain, now indicate that cognitive processes, free of

3
PET with the use of short-lived positron emitting isotopes, such as 18F-fluoro-2-deoxy-D-glucose or H215O, can provide values for regional cerebral blood flow
(in a time frame of about 1 min), or for the regional cerebral metabolic rate for glucose (in a time frame of 30 45 min, respectively). Both of these in vivo
parameters reflect brain energy consumption arising largely from synaptic activity [158,170,190]. On the other hand, functional magnetic resonance imaging
(fMRI), which depends on differences in parametric properties between oxygenated and unoxygenated hemoglobin, allows noninvasive measurements of brain
blood flow with a temporal resolution of seconds and an anatomic resolution of mm [111].

156

RAPOPORT

FIG. 6. Brain blood flow measured with positron emission tomography in medial occipital cortex of subjects asked
to visualize small and large images (bell, telephone, clock, boat) with eyes closed, compared with flow in control
listening task. F, small images; , medium images; , large images. Activation for smallest images in right and
left visual areas 17 and 18, for medium images in area 17 right hemisphere, and for large images in areas 17 and
18 of right hemisphere. From [107].

direct motor or perceptual components, can activate widespread

association brain circuits. Such activation, according to Fig. 5B,
would help to select the most cognitively able genotypes in a
primate population varying in brain synaptic number and neuroplasticity, among other properties. In this section, we will examine
recent examples of activation by mental imagery.
Figure 6 illustrates cerebral blood flow activation in human
visual association cortex (Brodmann area 18) and primary
striate cortex (Brodmann area 17) during mental imagery. The
subjects were blindfolded while undergoing PET, and were asked
to visualize formerly presented objects, such as a boat or a ball.
The flow changes were compared with changes during a control
listening task that prevented free-running imagery [107]. They
were the same as found when the objects were actually presented.
In a later study, repetitive transcranial magnetic stimulation was
used to inhibit brain activation during presentation of patterns of
stripes. Such stimulation also interfered with task performance,
confirming that activation during visual perception and mental
visual imagery clearly identifies regions which participate in visual
processing [106].
In another PET study, subjects were asked to mentally construct three-dimensional cube assemblies that they had never before seen but were described to them verbally (Fig. 7A). Under
these conditions, brain blood flow rose bilaterally in superior
occipital and inferior parietal cortical areas contributing to object
localization, and in inferior temporal cortical areas contributing to
object identification (see above). Premotor frontal cortex also was
activated, but primary visual cortex was not (Fig. 7B) [131].
In a third experiment, subjects were asked to mentally rotate
figures composed of angular branching forms or human hands.
PET demonstrated that separate widespread circuits were activated
[105]. With rotation of the forms, blood flow was increased in the
parietal lobe and Brodmann association visual area 19. During
mental rotation of the hands, activation occurred in precentral
motor gyrus (M1), superior and inferior parietal lobes, primary
visual cortex, insula and frontal areas 6 and 9.
The issue of spoken language, so important in hominid evolution and likely corresponding to visual symbol manipulation in
nonhuman primates (see above), deserves mention. A recent fMRI
study demonstrated that the internal generation of learned words
in the absence of speech stimulated Brocas motor speech area
(Brodmann areas 44 and 45 in left dorsolateral cortex) (Fig. 8)
[80]. A later fMRI study also demonstrated activation of Brocas
area in subjects who were asked to silently generate words begin-

ning with particular letters, as well as activation of striate and

extrastriate visual cortex [53].
Evidence that primary striate visual cortex (V1, Brodmann area
17) can be activated by mental imagery (see above) [53,107] and
that its activation can be modulated by attention (see below) [191]
does not mean that functional activation actually is initiated in this
region. Striate cortex activation more likely reflects input from
Brodmann areas 18 and 19 higher up in the visual hierarchy (see
above), where mental images are considered to be stored and
initiated [107]. This interpretation is supported by the fact that
auditory cues also can engender striate activation (see above).
Clearly, cross-modal auditory input would have to enter polymodal association areas high up in the visual stream, then descend
the stream before activating primary striate cortex [49,147].
Attention Can Modulate Cortical Activation in Primate Brain
Attention is a cognitive editing process that de-emphasizes
irrelevant information while adding interpretations and inferences
about the meaning of targeted information. Attention thus biases
competition among brain networks so as to enhance activity in
those that subserve relevant compared with irrelevant stimuli [39,
127,153]. Areas in the frontal lobe, parietal cortex, anterior cingulate gyrus, basal ganglia, thalamus, midbrain, and cerebellum
are considered to constitute an attentional network in primates
[133].
Activation of widespread areas of brain can be enhanced by
attention. Rates of neuronal firing were increased by 50 to 100% in
frontal association cortex of macaques during an attention-demanding spatial task [40] and, as illustrated in Fig. 9, in area V4
neurons of visual association cortex [127]. In another study, an
elevated firing frequency of area V4 neurons in macaques during
an attentional task was accompanied by a decreased frequency
bandwidth and enhanced task performance [192].
Association cortex blood flow has been shown repeatedly in
human subjects to be increased by attention [26,77,172]. In one
study, performing a color-distractor task caused blood flow to
increase in the right prefrontal cortex in proportion to the attentional load or difficulty of the task [3]. Reaction time, a measure of
effort, was shown to be reduced by the anticholinesterase drug,
physostigmine, during a working memory-for-faces task, which
also activated the right prefrontal cortex. The reduction in reaction
time was accompanied by a proportional reduction in right prefrontal activation, confirming the role of this region in attention
and effort and suggesting its dependence on cholinergic transmis-

BRAIN EVOLUTION IN PRIMATES

157

B
FIG. 7. Functional anatomy of spatial visual imagery. (A) Three-dimensional cube assemblies that a subject was asked to visualize
during positron emission tomography to measure brain blood flow. Thirty seconds before injection of 15O-labeled water, subject
was asked to visualize a starting cube (gray) at the center of his field of view and to add cubes according to a list of 11 directional
words binaurally delivered by earphones. (B) Lateral image of significant increments in flow during construction of cube assemblies
versus listening to words without construction. Mental construction activated bilateral occipitoparietal-superior occipital cortex,
inferior parietal cortex and premotor cortex and right inferior temporal cortex but not primary visual areas. Results show that the
dorsal route known to process visuospatial features can be recruited by verbal cues without visual stimuli. Views of brain: left upper,
sagittal; right upper, coronal; left lower, transverse. Z scores indicating statistical significance given on color bar. From [131].

158

RAPOPORT

FIG. 8. Functional magnetic resonance showing selective activation of Brocas area during word generation by internal speech. Signal is
related to regional blood flow. White lines in upper left anatomic image of brain give position of axial slice analyzed. Upper right image
is axial anatomic image corresponding to the slice level of the activated signal in lower left (with each color level, from bottom to top,
representing a 0.5% in signal intensity). The lower right image is overlay of the activation image on the anatomic image, showing
activation primarily in Brocas area. The upper plot on the right is a time course of signal intensity from a region within Brocas area (the
more posterior box in the overlay image), showing task-related increase in signal intensity; the lower plot, from a neighboring area (more
anterior box), shows absence of task-related increase in signal intensity. Right side of figure is left side of brain. From [80].

sion [54,67]. The right prefrontal cortex belongs to a widespread

network, including left prefrontal cortex, which can be activated
by attention, memory and visual processing [129,133,141].
Attention can modulate activation of primary as well as association visual cortex during visual discrimination [191]. The modulation is spatially specific, enhancing responses to attended stimuli and suppressing responses when attention was directed
elsewhere. As discussed above, the effect on primary striate cortex
likely is mediated by feedback input from association areas higher
up along the visual hierarchy.
Dreaming May Consolidate Effects of Brain Activation During
Wakefulness
Evidence suggests that dreaming can reinforce daytime brain
activation, in which case, according to the model of Fig. 5B,
dreaming could enhance the brain evolutionary process. Dreaming
is said to consolidate what has been learned or experienced during
wakefulness, potentially helping to stabilize critical association
circuits within the immature brain [97,110]. Maturation of the
human sleep electroencephalogram correlates with the biphasic
maturational changes in both brain synaptic density (see above)
and brain glucose metabolism [22]. Thus, the duration of deep
sleep is longer in the child than in the adult and its delta waves,

summed postsynaptic potentials in assemblies of cortical neurons

and dendrites [45], rise in amplitude from 100 V to 250 V
between birth and 10 years of age, then fall to less than 100 V by
16 years.
These correlations with maturation argue that dreaming, like
daytime ideation, can influence and be influenced by synaptic
growth and pruning during childhood and adolescence [48]. A
direct influence on brain of mental imagery during dreaming has
been demonstrated by showing brain activation during rapid eye
movement sleep in the thalamus, amygdaloid complex, anterior
cingulate cortex, and right parietal operculum [14,123,124]. The
effect may be mediated by high-frequency thalamico-cortical oscillations accompanying rapid eye movement sleep [96,148].
Abnormal Activation and Mental Imagery in Human Psychiatric
Disorders
Whereas normal ideation and attention are considered to reduce
synaptic pruning and consolidate critical brain networks in immature primates according to Fig. 5B, abnormal ideation and attention
may be accompanied by abnormal synaptic pruning, leading to
diseases such as schizophrenia, obsessive-compulsive disorder,
and fragile X syndrome. Each of these diseases has an important

BRAIN EVOLUTION IN PRIMATES

159
verbal function. Brains of adults with fragile X syndrome are 12%
larger than normal, also suggesting abnormal synaptic growth or
pruning during maturation [180]. In agreement, abnormal dendritic
spines are found in mice in which the fragile X mental retardation
protein is knocked out [25]. In adult patients, PET demonstrates
elevated glucose metabolism in the lenticular nucleus, thalamus
and premotor regions, and abnormal hemispheric metabolic asymmetry in the superior parietal lobe.
DISCUSSION

FIG. 9. Modulation by attention of responses of a neuron in visual area V4

of macaque brain. Upper panel: Stimulus 1 was centered in the receptive
field of the neuron being recorded, stimulus 2 in the other half of the visual
field. The animal was instructed to attend to either one of these stimuli.
Lower panel: Neuron responses to both stimuli presented simultaneously
when animal was attending to stimulus 1 (left) or stimulus 2 (right). Each
histogram shows firing rate before and during (bar below X axis) stimulus
presentation. The average firing rate was 50% greater when the animal
attended to stimulus 1 in the neurons receptive field than to stimulus 2.
From [127].

genetic component, appears early in life, and is accompanied by

abnormal brain glucose metabolism or blood flow.
For example, the usual appearance of schizophrenia in the late
teens and early 20s has been ascribed to abnormal synaptic pruning
during adolescence, leading to widespread structural and functional disturbances in brain [47]. On PET, schizophrenic patients
with auditory-verbal hallucinations demonstrate brain blood flow
activation in orbitofrontal cortex, hippocampus, and subcortical
thalamic and striatal nuclei (Fig. 10) [186]. These observations
also are an example of widespread brain activation by ideation, in
this case abnormal hallucinations, in the absence of sensory or
motor input.
Obsessive-compulsive disorder appears commonly during
childhood or adolescence [51]. Patients with this disease perform
repeated stereotyped acts or have repeated stereotyped thoughts
which they unable to stop, although they recognize that their
behavior is inappropriate. In about 10% of patients, only stereotyped thoughts ever exist [163]. PET evidence of abnormal glucose
metabolism in orbitofrontal and prefrontal cortex, anterior cingulate gyrus, and caudate nucleus, suggests that disease symptoms
reflect disinhibition of System II corticostriatal networks [8,166,
201,219]. The serotonin-uptake inhibitors clomipramine and fluoxetine provide symptomatic improvement while also regularizing
corticostriatal metabolism on PET [200]. The fact that the symptoms and metabolic abnormalities can sometimes be relieved by
behavioral therapy involving repeated exposure to the obsessed-for
thoughts [181], is consistent with our proposition that ideas or
thoughts can act within brain, like drugs, to directly modify brain
activity, metabolism and function.
The mental retardation of fragile X syndrome is characterized
by worse deficits in visuospatial attention/short-term memory than

Imagining how primate brains but particularly our brains

evolved requires consideration of the brain in immature ability of
the primates to undergo permanent changes via synaptic modulation and other neuroplastic processes in response to activation by
ideation and attention, of the neo-Darwinian principles of heritable
variation among genotypes in a population, and of changes in the
environment leading to increased survival and procreation of the
most cognitively competent and brain capable genotypes.
In a prior paper [166], I suggested that regional brain differences among living primates species [195,196] are consistent with
selective progression during evolution of association neocortex and related subcortical regions within two systems of extended
networks. I termed this progression integrated phylogeny. System I includes association neocortex and connected areas of cingulate gyrus, basolateral nucleus of amygdaloid complex, posterior
hippocampal formation, entorhinal cortex, basal forebrain and
some catecholaminergic nuclei [210]. It subserves a wide variety
of cognitive processes, including speech and language, executive
functions, declarative and spatial memory, planning and attention,
and visuospatial function [9,60,68,76,132,134]. System I appears
affected in certain human neurodegenerative diseases, including
Picks disease, Alzheimers disease and the dementia of Down
syndrome [164,166].
System II, which can be subdivided into five parallel circuits,
consists of parts of frontal association cortex, of the basal ganglia
(caudate nucleus, globus pallidus, and putamen), thalamus (pulvinar and dorsomedial nucleus), parts of the substantia nigra (pars
compacta), related midbrain catecholaminergic nuclei and involves
the cerebellum [2,37,42,78,135,179]. In addition to subserving
motor performance and initiation of movement in the absence of
sensory guidance, System II contributes to memory and directed
attention. The frontal cortex in System II is thought to facilitate
learning new rules and rejecting older ones, the basal ganglia to
potentiate previously learned rules based on environmental context. It appears selectively vulnerable in humans with Parkinson or
Huntington disease [166].
In this paper, I now consider how attention and ideation could
have promoted the appearance of more cognitively able, largebrain primate species in which System I and II were selectively
expanded. I review the substantial and generally accepted evidence
that heritable changes in peripheral sense organs or motor effectors, adaptations to physically demanding environments, through
bottom-up activation and neuroplastic modulation reduced apoptosis and synaptic pruning within primary sensory and motor
brain systems. The result was extension within a genetically heterogeneous population, according to neo-Darwinian principles, of
the most sensory- or motor-adapted genotypes, and, in some cases,
a new species.
The model for top-down evolution in Fig. 5B, like that for
bottom-up evolution in Fig. 5A, assumes heritable variation due
to its synaptic and neuroplastic competence in the capacity of the
immature primate brain to respond to activation. The model also
assumes that activation of immature primate brain networks and
synapses in response to a new cognitively or behaviorally demand-

160

RAPOPORT

FIG. 10. Axial sections demonstrating brain areas with significantly increased cerebral blood flow during
auditory verbal hallucinations in schizophrenic subjects, as measured with positron emission tomography
(PET). Functional PET results (threshold Z 3.1, p 0.001) displayed in color, superimposed on magnetic
resonance scan in Talairach space. The left primary motor-sensory cortex, thalamus, striatum, hippocampus,
parahippocampal and cingulate gyri, and orbitofrontal cortex are activated, considered to be part of a
cortical-subcortical network. From [186].

ing environment can select out adult genotypes whose brain and
behavior allow them to better compete and reproduce. The topdown process differs from bottom-up evolution in several important ways: (1) The new environment involves cognitive, social
or behavioral stresses rather than physical stresses. (2) Brain
activation is from within rather than from the periphery; recent in
vivo neuroimaging and direct recording studies show that ideation
and attention, free of sensory or motor input, can act like whiskers
within the brain to stimulate widespread brain association areas.
(3) Selection among immature genotypes during prolonged maturation is due to reduced synaptic pruning with consolidation of
association circuitry rather than of sensory and motor circuitry.
Synaptic stabilization secondary to adaptive thought processes in
immature primates, although it has not been directly or perhaps
even indirectly demonstrated, is consistent with a reported relation
between early education in humans and reduced vulnerability to
Alzheimers disease in later life [4,189,225]. (4) New primate
species may create new cognitive, social or cultural stresses which
in turn can accelerate brain evolution [216,217].
Effects of environmental enrichment on brain structure and
function have been demonstrated in immature rodents. Although

not exactly comparable to what might have occurred in immature

primates because of the very significant postnatal neurogenesis and
apoptosis in rodents [79], the rodent studies do confirm susceptibility of immature neuroplastic brain to postnatal environmental
influences. Compared with littermates reared in a deprived environment, adult rats exposed when young to an enriched environment perform better on learning tasks and demonstrate a large
gamut of structural differences. They have a thicker neocortex,
more synapses and dendritic spines in the molecular and dentate
layers of the cerebellum and in basal ganglia, increased thickness,
dendritic arborization, more neurons in the dentate gyrus of the
hippocampus (due in part to post-natal neurogenesis), and more
dendritic spines in the visual cortex [93,98,212].
Charles Darwin [31] concluded that articulate language, by
connecting definite sounds with definite ideas, played a special
role in human evolution, and that it arose in concert with correlated modifications of brain and body parts, set into motion when
the first human ancestors assumed an upright posture. His conclusion is widely accepted [16,35,118]. Darwin nevertheless emphasized, as I do in this paper, the continuity of brain and behavior
between nonhuman primates and modern humans. He noted that

BRAIN EVOLUTION IN PRIMATES

these species have . . . the same senses, intuitions and sensations;
they feel wonder and curiosity; they possess the same faculties of
imitation, attention, memory, imagination and reason. This principle of continuity is incorporated in my thesis of integrated
phylogeny of Systems I and II, and is supported by evidence for
hemispheric asymmetries, symbolic and syntactic processing, and
mirror self-recognition in the great apes as well as in modern
Homo sapiens.
ACKNOWLEDGEMENTS

The author wishes to thank Drs. Steven P. Wise, Gene Alexander, Alan
Schechter, Judith L. Rapoport, and Duane M. Rumbaugh for their helpful
comments on this paper.

ABBREVIATIONS
BDNF, brain derived nerve growth factor; fMRI, functional magnetic resonance imaging; IGF-I, insulin-like growth factor-I; IGFBP-1, IGF-binding protein-1; GAP, growth associated protein;
NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NT,
neurotrophin; PET, positron emission tomography; Trk, tyrosine
kinase.
REFERENCES
1. Aiello, L. C.; Wheeler, P. The expensive-tissue hypothesis. The brain
and the digestive system in human and primate evolution. Curr.
Anthropol. 36:199 221; 1995.
2. Alexander, G. E.; DeLong, M. R.; Strick, P. L. Parallel organization
of functionally segregated circuits linking basal ganglia and cortex.
Annu. Rev. Neurosci. 9:357381; 1986.
3. Alexander, G. E.; Greenwood, P. M.; Parasuraman, R.; Pietrini, P.;
Furey, M. L.; Mentis, M. J.; Desmond, R. E.; Szczepanik, J.; Levine,
B.; Connolly, C.; Schapiro, M. B.; Rapoport, S. I. Use of target
relevant distractors to probe the visual attention system with functional neuroimaging: Potential applications for early diagnosis of
Alzheimers disease (AD). Abstr. Eur. Arch. Psychiatry Clin. Neurosci. 248(suppl. 1):S16; 1998.
4. Alexander, G. E.; Moeller, J. R.; Grady, C. L.; Pietrini, P.; Mentis,
M. J.; Schapiro, M. B. Association of premorbid intellectual function
with cerebral glucose metabolism in Alzheimer disease. Am. J.
Psychiatry 154:165172; 1997.
5. Allman, J. M.; Kaas, J. H. A representation of the visual field in the
caudal third of the middle temporal gyrus of the owl monkey (Aotus
trivigatus). Brain Res. 31:85105; 1971.
6. Ameli, N. O. Hemispherectomy for the treatment of epilepsy and
behavior disturbance. Can. J. Neurol. Sci. 7:3338; 1980.
7. Amsterdam, B. K. Mirror self-image reactions before age two. Dev.
Psychobiol. 5:297305; 1972.
8. Baxter, L. R. Jr. Positron emission tomography studies of cerebral
glucose metabolism in obsessive compulsive disorder. J. Clin. Psychiatry 55 (suppl. 10):54 59; 1994.
9. Benton, A. Visuoperceptual, visuospatial, and visuoconstructive disorders. In: Heilman, K. M.; Valenstein, E., eds. Clinical neuropsychology, 2nd ed. New York: Oxford University Press; 1985:151185.
10. Berge, C. Heterochronic processes in human evolution: An ontogenetic analysis of the hominid pelvis. Am. J. Phys. Anthropol. 105:
441 459; 1998.
11. Blinkov, S. M.; Glezer, I. I. The human brain in figures and tables. A
quantitative handbook. New York: Plenum; 1968.
12. Broadhurst, C. L.; Cunnane, S. C.; Crawford, M. A. Rift Valley lake
fish and shellfish provided brain-specific nutrition for early Homo.
Br. J. Nutr. 79:321; 1998.
13. Brodal, A. Neurological anatomy in relation to clinical medicine, 3rd
ed. Oxford: Oxford University Press; 1981.
14. Buchsbaum, M. S.; Gillin, J. C.; Wu, J.; Hazlett, E.; Sicotte, N.;
Dupont, R. M.; Bunney, W. E. Jr. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography.
Life Sci. 45:1349 1356; 1989.

161
15. Cabelli, R. J.; Hohn, A.; Shatz, C. J. Inhibition of ocular dominance
column formation by infusion of NT-4/5 or BDNF. Science 267:
16621666; 1995.
16. Campbell, B. G. Humankind emerging, 5th ed. Glenview: Scott,
Foresman and Co.; 1988.
17. Cann, R. L.; Stoneking, M.; Wilson, A. C. Mitochondrial DNA and
human evolution. Nature 325:3136; 1987.
18. Carlson, M. Significance of single or multiple cortical areas for tactile
discrimination in primates. Exp. Brain Res. Suppl. 10:116; 1985.
19. Chatwin, B. The songlines. New York: Penguin; 1987.
20. Chomsky, N. Rules and representations. Behav. Brain Sci. 3:1 61;
1980.
21. Christiansen, F. B.; Otto, S. P.; Bergman, A.; Feldman, M. W.
Waiting with and without recombinations: The time to production of
a double mutant. Theor. Popul. Biol. 53:199 215; 1998.
22. Chugani, H. T.; Phelps, M. E.; Mazziotta, J. C. Positron emission
tomography study of human brain functional development. Ann.
Neurol. 22:487 497; 1987.
23. Clarke, R. J.; Tobias, P. V. Sterkfontein member 2 foot bones of the
oldest South African hominid. Science. 269:521524; 1995.
24. Collonnier, M. The electron-microscopic analysis of the neuronal
organization of the cerebral cortex. In: Schmitt, F. O.; Worden, F. G.;
Adelman, G.; Dennis, S. G., eds. The organization of the cerebral
cortex. Cambridge: MIT Press; 1981:125152.
25. Comery, T. A.; Harris, J. B.; Willems, P. J.; Oostra, B. A.; Irwin,
S. A.; Weiler, I. J.; Greenough, W. T. Abnormal dendritic spines in
fragile X knockout mice: Maturation and pruning deficits. Proc. Natl.
Acad. Sci. USA 94:54015404; 1997.
26. Corbetta, M.; Miezin, F. M.; Dobmeyer, S.; Shulman, G. L.; Petersen,
S. E. Selective and divided attention during visual discriminations of
shape, color, and speed: Functional anatomy by positron emission
tomography. J. Neurosci. 11:23832402; 1991.
27. Cowey, A. Cortical maps and visual perception: The Grindley Memorial Lecture. Quant. J. Exp. Psychol. 31:117; 1979.
28. Cragg, B. G. The density of synapses and neurons in normal, mentally defective and ageing human brain. Brain 98:8190; 1975.
29. Crow, J. F. An advantage of sexual reproduction in a rapidly changing environment. J. Hered. 83:169 173; 1992.
30. Darwin, C. The origin of species by means of natural selection.
London: Penguin Books; 1859.
31. Darwin, C. The descent of man and selection in relation to sex, vol.
49. Princeton: Princeton University Press; 1871.
32. De Duve, C. Intervention de Christian De Duve et discussion avec
Dominique Lecourt. In: La Pensee est-elle le Produit de la Selection
Naturelle? Paris: Presses Universitaire de France; 1996:14.
33. De Grouchy, J. Chromosome phylogenies of man, great apes, and Old
World monkeys. Genetica 73:3752; 1987.
34. Deacon, T. W. The human brain. In: Jones, S.; Martin, R.; Pilbeam,
D., eds. The Cambridge encyclopedia of human evolution. Cambridge: Cambridge University Press; 1992:115123.
35. Deacon, T. W. The symbolic species. The co-evolution of language
and the brain. New York: W. W. Norton; 1997.
36. Dehay, C.; Giroud, P.; Berland, M.; Smart, I.; Kennedy, H. Modulation of the cell cycle contributes to the parcellation of the primate
visual cortex. Nature 366:464 466; 1993.
37. Delong, M. R.; Georgopoulos, A. P.; Crutcher, M. D. Cortico-basal
ganglia relations and coding of motor performance. Exp. Brain Res.
Suppl. 7:30 40; 1983.
38. Dennis, E. A. Diversity of group types, regulation, and function of
phospholipase A2. J. Biol. Chem. 269:1305713060; 1994.
39. Desimone, R.; Duncan, J. Neural mechanism of selection of visual
attention. Annu. Rev. Neurosci. 18:193222; 1995.
40. di Pellegrino, G.; Wise, S. P. Effects of attention on visuomotor
activity in the premotor and prefrontal cortex of a primate. Somatosens. Mot. Res. 10:245262; 1993.
41. Dreyer, W. J. The area code hypothesis revisited: Olfactory receptors
and other related transmembrane receptors may function as the last
digits in a cell surface code for assembling embryos. Proc. Natl.
Acad. Sci. USA 95:90729077; 1998.
42. Dubois, B.; Malapani, C.; Verin, M.; Rogelet, P.; Deweer, B.; Pillon,
B. Fonctions cognitives et noyaux gris centraux: Le mode`le de la
maladie de Parkinson. Rev. Neurol. (Paris). 150:763770; 1994.

162
43. Eccles, J. C. Evolution of the brain: Creation of the self. London:
Routledge; 1989.
44. Eizinger, A.; Jungblut, B.; Sommer, R. J. Evolutionary change in the
functional specificity of genes. Trends Genet. 15:197202; 1999.
45. Elul, R. The genesis of the EEG. Int. Rev. Neurobiol. 15:227272;
1972.
46. Eriksson, P. S.; Perfilieva, E.; Bjork-Eriksson, T.; Alborn, A. M.;
Nordberg, C.; Peterson, D. A.; Gage, F. H. Neurogenesis in the adult
human hippocampus. Nat. Med. 4:13131317; 1998.
47. Feinberg, I. Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence. J. Psychiatr. Res. 17:319 334;
1983.
48. Feinberg, I.; Thode, H. C. Jr.; Chugani, H. T.; March, J. D. Gamma
distribution model describes maturational curves for delta wave amplitude, cortical metabolic rate and synaptic density. J. Theor. Biol.
142:149 161; 1990.
49. Felleman, D. J.; Van Essen, D. C. Distributed hierarchical processing
in primate cerebral cortex. Cereb. Cortex. 1:1 47; 1991.
50. Finlay, B. L.; Darlington, R. B. Linked regularities in the development and evolution of mammalian brains. Science 268:1578 1584;
1995.
51. Flament, M.; Whitaker, A.; Rapoport, J. L.; Davies, M.; Berg, C. Z.;
Shaffer, D. An epidemiological study of obsessive-compulsive disorder in adolescence. In: Rapoport, J. L., ed. Obsessive-compulsive
disorder in children and adolescents. Washington, DC: American
Psychiatric Press, Inc.; 1989:253267.
52. Fraser Roberts, J. A.; Pembrey, M. E. An introduction to medical
genetics, 8th ed. Oxford: Oxford University Press; 1985.
53. Friedman, L.; Kenny, J. T.; Wise, A. L.; Wu, D.; Stuve, T. A.; Miller,
D. A.; Jesberger, J. A.; Lewin, J. S. Brain activation during silent
word generation evaluated with functional MRI. Brain Lang. 64:231
256; 1998.
54. Furey, M. L.; Pietrini, P.; Haxby, J. V.; Alexander, G. E.; Lee, H. C.;
Van Meter, J.; Grady, C. L.; Shetty, U.; Rapoport, S. I.; Schapiro,
M. B.; Freo, U. Cholinergic stimulation alters performance and task
specific regional cerebral blood flow during working memory. Proc.
Natl. Acad. Sci. USA 94:6512 6516; 1997.
55. Gage, F. H.; Kempermann, G.; Palmer, T. D.; Peterson, D. A.; Ray,
J. Multipotent progenitor cells in the adult dentate gyrus. J. Neurobiol. 36:249 266; 1998.
56. Gallup, G. G. Jr. Self-recognition in primates. A comparative approach to the bidirectional properties of consciousness. Am. Psychol.
32:329 338; 1977.
57. Gannon, P. J.; Holloway, R. L.; Broadfield, D. C.; Braun, A. R.
Asymmetry of chimpanzee planum temporale: Humanlike pattern of
Wernickes brain language area homolog. Science. 279:220 222;
1998.
58. Geschwind, N.; Levitsky, W. Human brain: Left-right asymmetries in
temporal speech region. Science 161:186 187; 1968.
59. Goldman, P. S.; Galkin, T. W. Prenatal removal of frontal association
cortex in the fetal rhesus monkey: Anatomical and functional consequence in postnatal life. Brain Res. 152:451 485; 1978.
60. Goldman-Rakic, P. S. Development of cortical circuitry and cognitive function. Child Dev. 58:601 622; 1987.
61. Goldman-Rakic, P. S. Changing concepts of cortical connectivity:
Parallel distributed cortical networks. In: Rakic, P.; Singer, W., eds.
Neurobiology of neocortex. New York: John Wiley and Sons; 1988:
177202.
62. Gotz, R.; Schartl, M. The conservation of neurotrophic factors during
vertebrate evolution. Comp. Biochem. Physiol. 108C:110; 1994.
63. Gould, S. J. Ontogeny and phylogeny. Boston: Harvard University
Press; 1977.
64. Gould, S. J. The pandas thumb. More reflections in natural history.
New York: W. W. Norton; 1980.
65. Gove, P. B. Websters third new international dictionary of the
English language unabridged. Springfield: G. and C. Merriam Co.;
1966.
66. Grady, C. L.; Haxby, J. V.; Horwitz, B.; Sundaram, M.; Berg, G.;
Schapiro, M.; Friedland, R. P.; Rapoport, S. I. Longitudinal study of
the early neuropsychological and cerebral metabolic changes in dementia of the Alzheimer type. J. Clin. Exp. Neuropsychol. 10:576
596; 1988.

RAPOPORT
67. Grady, C. L.; Maisog, J. M.; Horwitz, B.; Ungerleider, L. G.; Mentis,
M. J.; Salerno, J. A.; Pietrini, P.; Wagner, E.; Haxby, J. V. Agerelated changes in cortical blood flow activation during visual processing of faces and location. J. Neurosci. 14:1450 1462; 1994.
68. Grady, C. L.; McIntosh, A. R.; Horwitz, B.; Maisog, J. M.; Ungerleider, L. G.; Mentis, M. J.; Pietrini, P.; Schapiro, M. B.; Haxby, J. V.
Age-related reductions in human recognition memory due to impaired encoding. Science 269:218 221; 1995.
69. Griffin, D. R. Animal minds. Chicago: University of Chicago Press;
1994.
70. Guillery, R. W. A speculative essay on geniculate lamination and its
development. Prog. Brain Res. 51:403 418; 1979.
71. Gutierrez-Ospina, G.; Calikoglu, A. S.; Ye, P.; DErcole, A. J. In vivo
effects of insulin-like growth factor-I on the development of sensory
pathways: Analysis of the primary somatic sensory cortex (S1) of
transgenic mice. Endocrinology 137:5484 5492; 1996.
72. Hamilton, W. D. The genetic evolution of social behaviour. J. Theor.
Biol. 7:152; 1964.
73. Hardy, G. H. Mendelian proportions in a mixed population. Science
28:49 50; 1908.
74. Haxby, J. V.; Grady, C. L.; Horwitz, B. Two visual processing
pathways in human extrastriate cortex mapped with positron emission
tomography. In: Lassen, N. A.; Ingvar, D. H.; Raichle, M. E.; Friberg,
L., eds. Brain work and mental activity (Alfred Benzon Symposium
31). Copenhagen: Munksgaard; 1991:324 333.
75. Haxby, J. V.; Grady, C. L.; Horwitz, B.; Ungerleider, L. G.; Mishkin,
M.; Carson, R. E.; Herscovitch, P.; Schapiro, M. B.; Rapoport, S. I.
Dissociation of object and spatial visual processing pathways in
human extrastriate cortex. Proc. Natl. Acad. Sci. USA 88:16211625;
1991.
76. Haxby, J. V.; Grady, C. L.; Koss, E.; Horwitz, B.; Schapiro, M.;
Friedland, R. P.; Rapoport, S. I. Heterogeneous anterior-posterior
metabolic patterns in dementia of the Alzheimer type. Neurology
38:18531863; 1988.
77. Haxby, J. V.; Horwitz, B.; Ungerleider, L. G.; Maisog, J. M.; Pietrini,
P.; Grady, C. L. The functional organization of human extrastriate
cortex: A PET-rCBF study of selective attention to faces and locations. J. Neurosci. 14:6336 6353; 1994.
78. Heindel, W. C.; Salmon, D. P.; Shults, C. W.; Walicke, P. A.; Butters,
N. Neuropsychological evidence of multiple implicit memory systems: A comparison of Alzheimers, Huntingtons and Parkinsons
disease patients. J. Neurosci. 9:582587; 1989.
79. Heumann, D.; Leuba, G. Neuronal death in the development and
aging of the cerebral cortex of the mouse. Neuropathol. Appl. Neurobiol. 9:297311; 1983.
80. Hinke, R. M.; Hu, X.; Stillman, A. E.; Kim, S. G.; Merkle, H.; Salmi,
R.; Ugurbil, K. Functional magnetic resonance imaging of Brocas
area during internal speech. NeuroReport 6:675 678; 1993.
81. Hofman, M. A. Encephalization in hominids: Evidence for the model
of punctuationalism. Brain Behav. Evol. 22:102117; 1983.
82. Hofman, M. A. On the evolution and geometry of the brain in
mammals. Prog. Neurobiol. 32:137158; 1989.
83. Holden, C. Overstimulated by early brain research? Science 278:
1569 1571; 1997.
84. Holland, P. W. H. Pursuing the functions of vertebrate homeobox
genes: Progress and prospects. TINS 12:206 210; 1989.
85. Hubel, D. H.; Wiesel, T. N. Uniformity of monkey striate cortex: A
parallel relationship between field size, scatter and magnification
factor. J. Comp. Neurol. 158:295305; 1974.
86. Huttenlocher, P. R. Synaptic density in human frontal cortex
Developmental changes and effects of aging. Brain Res. 163:195
205; 1979.
87. Huttenlocher, P. R. Morphometric study of human cerebral cortex
development. Neuropsychologia 28:517527; 1990.
88. Huttenlocher, P. R.; Dabholkar, A. S. Developmental anatomy of
prefrontal cortex. In: Krasnegor, N. A.; Lyon, G. R.; Goldman-Rakic,
P. S., eds. Development of the prefrontal cortex: Evolution, neurobiology and behavior. Baltimore: Paul H. Brookes; 1997:69 83.
89. Jacobson, M. Development of specific neuronal connections. Science
163:543547; 1969.
90. Jerison, H. J. Paleoneurology and the evolution of mind. Sci. Am.
234:90 101; 1976.

BRAIN EVOLUTION IN PRIMATES

91. Jerison, H. J. Allometry, brain sizes, cortical surface, and convolutedness. In: Armstrong, E.; Falk, D., eds. Primate brain evolution.
Methods and concepts. New York: Plenum; 1982:77 84.
92. Jones, S.; Martin, R.; Pilbeam, D. The Cambridge encyclopedia of
human evolution. Cambridge: Cambridge University Press; 1992.
93. Jones, T. A.; Klintsova, A. Y.; Kilman, V. L.; Sirevaag, A. M.;
Greenough, W. T. Induction of multiple synapses by experience in
the visual cortex of adult rats. Neurobiol. Learn. Mem. 68:1320;
1997.
94. Kaas, J. H. The segregation of function in the nervous system: Why
do sensory systems have so many subdivisions? Contrib. Sensory
Physiol. 7:201240; 1982.
95. Kaas, J. H. Why does the brain have so many visual areas? J. Cogn.
Neurosci. 1:121135; 1989.
96. Kahn, D.; Pace-Schott, E. F.; Hobson, J. A. Consciousness in waking
and dreaming: The roles of neuronal oscillation and neuromodulation
in determining similarities and differences. Neuroscience 78:1338;
1997.
97. Kavanau, J. L. Memory, sleep, and dynamic stabilization of neural
circuitry: evolutionary perspectives. Neurosci. Biobehav. Rev. 20:
289 311; 1996.
98. Kempermann, G.; Kuhn, H. G.; Gage, F. H. More hippocampal
neurons in adult mice living in an enriched environment. Nature
386:493 495; 1997.
99. Kilgard, M. P.; Merzenich, M. M. Cortical map reorganization enabled by nucleus basalis activity. Science 279:1714 1718; 1998.
100. Kimura, M. The neutral theory of molecular evolution. Cambridge:
Cambridge University Press; 1983.
101. King, A. J.; Moore, D. R. Plasticity of auditory maps in the brain.
Trends Neurosci. 14:3137; 1991.
102. King, M.-C.; Wilson, A. C. Evolution at two levels in humans and
chimpanzees. Science 188:107116; 1975.
103. Knipper, M.; Kopschall, I.; Rohbock, K.; Kopke, A. K. E.; Bonk, I.;
Zimmermann, U.; Zenner, H.-P. Transient expression of NMDA
receptors during rearrangement of AMPA-receptor-expressing fibers
in the developing inner ear. Cell Tissue Res. 287:23 41; 1997.
104. Kornack, D. R.; Rakic, P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc. Natl. Acad. Sci. USA
96:5768 5773; 1999.
105. Kosslyn, S. M.; DiGirolamo, G. J.; Thompson, W. L.; Alpert, N. M.
Mental rotation of objects versus hands: Neural mechanisms revealed
by positron emission tomography. Psychophysiology 35:151161;
1998.
106. Kosslyn, S. M.; Pascual-Leone, A.; Felican, O.; Camposano, S.;
Keenan, J. P.; Thompson, W. L.; Ganis, G.; Sukel, K. E.; Alpert,
N. M. The role of area 17 in visual imagery: Convergent evidence
from PET and rTMS. Science 284:167170; 1999.
107. Kosslyn, S. M.; Thompson, W. L.; Kim, I. J.; Alpert, N. M. Topographical representations of mental images in primary visual cortex.
Nature 378:496 498; 1995.
108. Krubitzer, L. The organization of neocortex in mammals: Are species
differences really so different? Trends Neurosci. 18:408 417; 1995.
109. Krubitzer, L.; Manger, P.; Pettigrew, J.; Calford, M. Organization of
somatosensory cortex in monotremes: In search of the prototypical
plan. J. Comp. Neurol. 351:261306; 1995.
110. Krueger, J. M.; Obal, F. Jr.; Kapas, L.; Fang, J. Brain organization
and sleep function. Behav. Brain Res. 69:177185; 1995.
111. Kwong, K. K.; Belliveau, J. W.; Chesler, D. A.; Goldberg, I. E.;
Weisskoff, R. M.; Poncelet, B. P.; Kennedy, D. N.; Hoppel, B. E.;
Cohen, M. S.; Turner, R.; Cheng, H.-M.; Brady, T. J.; Rosen, B. R.
Dynamic magnetic resonance imaging of human brain activity during
primary sensory stimulation. Proc. Natl. Acad. Sci. USA 89:5675
5679; 1992.
112. Lakoff, G. Women, fire, and dangerous things. What categories
reveal about the mind. Chicago: University of Chicago Press; 1987.
113. Large, T. H.; Bodary, S. C.; Clegg, D. O.; Weskamp, G.; Otten, U.;
Reichardt, L. F. Nerve growth factor expression in the developing rat
brain. Science 234:352355; 1986.
114. Lashley, K. S. Persistent problems in the evolution of mind. Q. Rev.
Biol. 24:28 42; 1949.
115. LeMay, M.; Billig, M. S.; Geschwind, N. Asymmetries of the brains
and skulls of nonhuman primates. In: Armstrong, E.; Falk, D., eds.

163

116.

117.
118.
119.
120.

121.
122.
123.

124.

125.
126.

127.
128.
129.

130.
131.

132.

133.

134.
135.
136.

137.
138.
139.

140.
141.
142.
143.

Primate brain evolution. Methods and concepts. New York: Plenum;

1982:263278.
Leuba, G.; Garey, L. J. Evolution of neuronal numerical density in
the developing and aging human visual cortex. Hum. Neurobiol.
6:1118; 1987.
Lieberman, P. Interactive models for evolution: Neural mechanisms,
anatomy, and behavior. Ann. N. Y. Acad. Sci. 280:660 672; 1976.
Lieberman, P. Uniquely human. The evolution of speech, thought,
and selfless behavior. Cambridge: Harvard University Press; 1991.
Lima-De-Faria, A. Molecular evolution and organization of the chromosome. Amsterdam: Elsevier; 1983.
Livingstone, M.; Hubel, D. Segregation of form, color, movement,
and depth: anatomy, physiology, and perception. Science 240:740
749; 1988.
Lovejoy, C. O. The origin of man. Science 211:341350; 1981.
Luria, A. R. The working brain. An introduction to neuropsychology.
New York: Basic Books; 1973.
Madsen, P. L.; Holm, S.; Vorstrup, S.; Friberg, L.; Lassen, N. A.;
Wildschiodtz, G. Human regional cerebral blood flow during rapideye-movement sleep. J. Cereb. Blood Flow Metab. 11:502507;
1991.
Maquet, P.; Peters, J.; Aerts, J.; Delfiore, G.; Degueldre, C.; Luxen,
A.; Franck, G. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 383:163166; 1996.
Martin, R. D. Primate origins and evolution: A phylogenetic reconstruction. Princeton: Princeton University Press; 1990.
Matsuzawa, T. Field experiments on use of stone tools by chimpanzees in the wild. In: Wrangham, R. W.; McGrew, W. C.; De Waal,
F. B. M.; Heltne, P. G., eds. Chimpanzee cultures. Cambridge:
Harvard University Press; 1994:351370.
Maunsell, J. H. R. The brains visual world: Representation of visual
targets in cerebral cortex. Science 270:764 769; 1995.
Mauss, T. Die faserarchitektonische Gliederung des Cortex cerebri
der anthropomorphen affen. J. Psychol. Neurol. 18:410 467; 1911.
McIntosh, A. R.; Rajah, M. N.; Lobaugh, N. J. Interactions of
prefrontal cortex in relation to awareness in sensory learning. Science
284:15311533; 1999.
Medawar, P. B.; Medawar, J. S. Aristotle to zoos. A philosophical
dictionary of biology. Cambridge: Harvard University Press; 1983.
Mellet, E.; Tzourio, N.; Crivello, F.; Joliot, M.; Denis, M.; Mazoyer,
B. Functional anatomy of spatial mental imagery generated from
verbal instructions. J. Neurosci. 16:6504 6512; 1996.
Mesulam, M.-M. Patterns in behavioral neuroanatomy: Association
areas, the limbic system, and hemispheric specialization. In: Mesulam, M.-M., ed. Principles of behavioral neurology. Philadelphia:
F. A. Davis; 1985:170.
Mesulam, M.-M. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann. Neurol.
28:597 613; 1990.
Milner, B. Visual recognition and recall after right temporal lobe
excision in man. Neuropsychologia 6:191209; 1968.
Mishkin, M.; Appenzeller, T. The anatomy of memory. Sci. Am.
256:80 89; 1987.
Mishkin, M.; Ungerleider, L. G.; Macko, K. A. Object vision and
spatial vision: Two cortical pathways. Trends Neurosci. 6:414 417;
1983.
Mitchison, G. Neuronal branching patterns and the economy of
cortical wiring. Proc. R. Soc. Lond. [Biol.]. 245:151158; 1991.
Monod, J. Le hasard et la necessite. Essai sur la philosophie naturelle
de la biologie moderne. Paris: Editions du Seuil; 1970.
Mountcastle, V. B. An organizing principle for cerebral function: The
unit module and the distributed system. In: Schmitt, F. O.; Worden,
F. G., eds. The neurosciences. Fourth study program. Cambridge:
MIT Press; 1979:21 42.
Newport, E. L. Maturational constraints on language learning. Cogn.
Sci. 14:1128; 1990.
Nichelli, P.; Grafman, J.; Pietrini, P.; Alway, D.; Carton, J. C.;
Miletich, R. Brain activity in chess playing. Nature 369:191; 1994.
Northcutt, R. G.; Kaas, J. H. The emergence and evolution of mammalian neocortex. Trends Neurosci. 18:373379; 1995.
OKane, C. J.; Gehring, W. J. Homeobox and nervous system devel-

164

144.

145.
146.
147.
148.
149.
150.
151.
152.

153.
154.
155.
156.
157.
158.

159.
160.
161.
162.
163.
164.
165.

166.
167.

168.
169.
170.
171.

RAPOPORT
opment. In: Adelman, G., ed. Neuroscience year. Supplement 1 to the
encyclopedia of neuroscience. Boston: Birkhauser; 1989:7577.
OKusky, J.; Colonnier, M. Postnatal changes in the number of
neurons and synapses in the visual cortex (area 17) of the macaque
monkey: A stereological analysis in normal and monocularly deprived animals. J. Comp. Neurol. 210:291306; 1982.
Ohno, S. Evolution by gene duplication. Berlin: Springer Verlag;
1970.
Pagel, M. D.; Harvey, P. H. How mammals produce large brained
offspring. Evolution 42:948 957; 1988.
Pandya, D. N.; Seltzer, B. Association areas of the cerebral cortex.
Trends Neurosci. 5:386 390; 1982.
Pare, D.; Llinas, R. Conscious and pre-conscious processes as seen
from the standpoint of sleep-waking cycle neurophysiology. Neuropsychologia 33:11551168; 1995.
Parfit, D. Reasons and persons. Oxford: Clarendon Press; 1984.
Passingham, R. E. Anatomical differences between the neocortex of
man and other primates. Brain Behav. Evol. 7:337359; 1973.
Pianka, E. R. On r and K selection. Am. Nat. 104:592597; 1970.
Pimenta, A. F.; Zhukareva, V.; Barbe, M. F.; Reinoso, B. S.; Grimley,
C.; Henzel, W.; Fischer, I.; Levitt, P. The limbic system-associated
membrane protein is an Ig superfamily member that mediates selective neuronal growth and axon targeting. Neuron 15:287297; 1995.
Posner, M. I.; Dehaene, S. Attentional networks. Trends Neurosci.
17:7579; 1994.
Povinelli, D. J.; Eddy, T. J. Chimpanzees: Joint visual attention.
Psychol. Sci. 7:129 135; 1996.
Povinelli, D. J.; Preuss, T. M. Theory of mind: Evolutionary history
of a cognitive specialization. Trends Neurosci. 18:418 424; 1995.
Price, M. Members of the Dlx- and Nkx2-gene families are regionally
expressed in the developing forebrain. J. Neurobiol. 24:13851399;
1993.
Radinsky, L. B. Evolution of somatic sensory specialization in otter
brains. J. Comp. Neurol. 134:495505; 1969.
Raichle, M. E.; Grubb, R. L. Jr.; Gado, M. H.; Eichling, J. O.;
Ter-Pogossian, M. M. Correlation between regional cerebral blood
flow and oxidative metabolism: In vivo studies in man. Arch. Neurol.
33:523526; 1976.
Rakic, P. Specification of cerebral cortical areas. Science 241:170
176; 1988.
Rakic, P. A small step for the cell, a giant leap for mankind: A
hypothesis of neocortical expansion during evolution. Trends Neurosci. 18:383388; 1995.
Rakic, P.; Bourgeois, J.-P.; Eckenhoff, M. F.; Zecevic, N.; GoldmanRakic, P. S. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232:232235; 1986.
Rakic, P.; Bourgeois, J.-P.; Goldman-Rakic, P. S. Synaptic development of the cerebral cortex: Implications for learning, memory, and
mental illness. Prog. Brain Res. 102:227243; 1994.
Rapoport, J. L. Personal communication; 1999.
Rapoport, S. I. Brain evolution and Alzheimers disease. Rev. Neurol.
(Paris) 144:79 90; 1988.
Rapoport, S. I. A phylogenetic hypothesis for Alzheimers disease.
In: Sinet, P. M.; Lamour, Y.; Christen, Y., eds. Genetics and Alzheimers disease. Research and perspectives on Alzheimers disease.
Fondation Ipsen pour la Recherche Therapeutique. Berlin: SpringerVerlag; 1988:62 88.
Rapoport, S. I. Integrated phylogeny of the primate brain, with
special reference to humans and their diseases. Brain Res. Rev.
15:267294; 1990.
Rapoport, S. I. Anatomic and functional brain imaging in Alzheimers disease. In: Bloom, F. E.; Kupfer, D. J., eds. Psychopharmacology: The fourth generation of progress. New York: Raven; 1994:
14011415.
Rapoport, S. I. Were attention and ideation natural selection factors
that promoted evolution of the primate brain? Soc. Neurosci. Abstr.
23:221; 1997.
Rauschecker, J. P. Compensatory plasticity and sensory substitution
in the cerebral cortex. Trends Neurosci. 18:36 43; 1995.
Reivich, M. Blood flow metabolism couple in brain. Res. Publ.
Assoc. Res. Nerv. Ment. Dis. 53:125140; 1974.
Rockland, K. S.; Pandya, D. N. Laminar origins and terminations of

172.
173.

174.
175.

176.
177.
178.
179.
180.

181.

182.
183.
184.

185.
186.

187.
188.
189.

190.
191.

192.

cortical connections of the occipital lobe of the rhesus monkey. Brain

Res. 179:320; 1979.
Roland, P. E. Cortical regulation of selective attention in man. A
regional cerebral blood flow study. J. Neurophysiol. 48:1059 1078;
1982.
Rumbaugh, D. M. Competence, cortex, and primate models. A comparative primate perspective. In: Krasnegor, N. A.; Lyon, R.; Goldman-Rakic, P. S., eds. Development of the prefrontal cortex: Evolution, neurobiology, and behavior. Baltimore: Paul H. Brookes; 1997:
117139.
Sadato, N.; Pascual-Leone, A.; Grafman, J.; Ibanez, V.; Deiber,
M. P.; Dold, G.; Hallett, M. Activation of the primary visual cortex
by Braille reading in blind subjects. Nature 380:526 528; 1996.
Sanes, J. N.; Donoghue, J. P. Organization and adaptability of muscle
representations in primary motor cortex. In: Caminiti, R.; Johnson,
P. B.; Burnod, Y., eds. Control of arm movement in space: Neurophysiological and computational approaches. Berlin: Springer-Verlag; 1993:103127.
Sarich, V. Immunological evidence on primates. In: Jones, S.; Martin,
R.; Pilbeam, D., eds. The Cambridge encyclopedia of human evolution. Cambridge: Cambridge University Press; 1992:303306.
Sarnat, H. B.; Netsky, M. G. Evolution of the nervous system, 2nd ed.
Oxford: Oxford University Press; 1981.
Savage-Rumbaugh, E. S.; Murphy, J.; Sevcik, R. A.; Brakke, K. E.;
Williams, S. L.; Rumbaugh, D. M. Language comprehension in ape
and child. Monogr. Soc. Res. Child Dev. 58:1254; 1993.
Schacter, D. L. Implicit memory: History and current status. J. Exp.
Psychol. Learn. Mem. Cogn. 13:501518; 1987.
Schapiro, M. B.; Murphy, D. G. M.; Hagerman, R. J.; Azari, N. P.;
Alexander, G. E.; Miezejeski, C. M.; Hinton, V. J.; Horwitz, B.;
Haxby, J. V.; Kumar, A.; White, B.; Grady, C. L. Adult Fragile X
syndrome: Neuropsychology, brain anatomy, and metabolism. Am. J.
Med. Genet. 60:480 493; 1995.
Schwartz, J. M.; Stoessel, P. W.; Baxter, L. R. Jr.; Martin, K. M.;
Phelps, M. E. Systematic changes in cerebral glucose metabolic rate
after successful behavior modification treatment of obsessive-compulsive disorder. Arch. Gen. Psychiatry 53:109 113; 1996.
Sherman, S. M. Functional organization of w-, x- and y-cell pathways
in the cat: A review and hypothesis. Prog. Psychobiol. Physiol.
Psychol. 11:233314; 1985.
Shuman, E. Growth factors sculpt the synapse. Science 275:1277
1278; 1997.
Sibley, C. G. DNA-DNA hybridisation in the study of primate
evolution. In: Jones, S.; Martin, R.; Pilbeam, D., eds. The Cambridge
encyclopedia of human evolution. Cambridge: Cambridge University
Press; 1992:313315.
Sikich, L.; Woolsey, T. A.; Johnson, E. M. Jr. Effect of a uniform
partial denervation of the periphery on the peripheral and central
vibrissal system in guinea pigs. J. Neurosci. 6:12271240; 1986.
Silbersweig, D. A.; Stern, E.; Frith, C.; Cahill, C.; Holmes, A.;
Grootoonk, S.; Seaward, J.; McKenna, P.; Chua, S. E.; Schnorr, L.;
Jones, T.; Frackowiak, R. S. J. A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176 179; 1995.
Simeone, A. Otx1 and Otx2 in the development and evolution of the
mammalian brain. EMBO J. 17:6790 6798; 1998.
Snider, W. D. Functions of the neurotrophins during nervous system
development: What the knockouts are teaching us. Cell 77:627 638;
1994.
Snowdon, D. A.; Kemper, S. J.; Mortimer, J. A.; Greiner, L. H.;
Wekstein, D. R.; Markesbery, W. R. Linguistic ability in early life
and cognitive function and Alzheimers disease in late life. Findings
from the Nun study. JAMA 275:528 532; 1996.
Sokoloff, L. Energy metabolism and effects of energy depletion or
exposure to glutamate. Can. J. Physiol. Pharmacol. 70:S107S112;
1992.
Somers, D. C.; Dale, A. M.; Seiffert, A. E.; Tootell, R. B. H.
Functional MRI reveals spatially specific attentional modulation in
human primary visual cortex. Proc. Natl. Acad. Sci. USA 96:1663
1668; 1999.
Spitzer, H.; Richmond, B. J. Task difficulty: Ignoring, attending to,
and discriminating a visual stimulus yield progressively more activity
in inferior temporal neurons. Exp. Brain Res. 83:340 348; 1991.

BRAIN EVOLUTION IN PRIMATES

193. Spoor, F.; Wood, B.; Zonneveld, F. Implications of early hominid
labyrinthine morphology for evolution of human bipedal locomotion.
Nature 369:645 648; 1994.
194. Stanley, S. M. An ecological theory for the origin of Homo. Paleobiology 18:237257; 1992.
195. Stephan, H.; Andy, O. J. Quantitative comparative neuroanatomy of
primates: An attempt at a phylogenetic interpretation. Ann. N. Y.
Acad. Sci. 167:370 387; 1969.
196. Stephan, H.; Frahm, H.; Baron, G. New and revised data on volumes
of brain structures in insectivores and primates. Folia Primatol. 35:
129; 1981.
197. Sternberg, R. J. General intellectual ability. In: Sternberg, R. J., ed.
Human abilities: An information-processing approach. New York:
W. H. Freeman; 1985:530.
198. Stone, J.; Dreher, B.; Leventhal, A. Hierarchical and parallel mechanisms in the organization of visual cortex. Brain Res. 180:345394;
1979.
199. Sur, M.; Pallas, S. L.; Roe, A. W. Cross-modal plasticity in cortical
development: Differentiation and specification of sensory neocortex.
Trends Neurosci. 13:227233; 1990.
200. Swedo, S. E.; Pietrini, P.; Leonard, H. L.; Schapiro, M. B.; Rettew,
D. C.; Goldberger, E. L.; Rapoport, S. I.; Rapoport, J. L.; Grady, C. L.
Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Revisualization during pharmacotherapy. Arch. Gen.
Psychiatry. 49:690 694; 1992.
201. Swedo, S. E.; Schapiro, M. B.; Grady, C. L.; Cheslow, D. L.;
Leonard, H. L.; Kumar, A.; Friedland, R.; Rapoport, S. I.; Rapoport,
J. L. Cerebral glucose metabolism in childhood-onset obsessivecompulsive disorder. Arch. Gen. Psychiatry 46:518 523; 1989.
202. Symonds, L. L.; Rosenquist, A. C. Corticocortical connections
among visual areas in the cat. J. Comp. Neurol. 229:138; 1984.
203. Symonds, L. L.; Rosenquist, A. C. Laminar origins of visual corticocortico connections in the cat. J. Comp. Neurol. 229:39 47; 1984.
204. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270:
593598; 1995.
205. Tobias, P. V. The brain of Homo habilis: A new level of organization
of cerebral evolution. J. Hum. Evol. 16:741761; 1988.
206. Tomasello, M.; Call, J. Primate cognition. Oxford: Oxford University
Press; 1997.
207. Tovee, M. J. The molecular genetics and evolution of primate colour
vision. Trends Neurosci. 17:30 37; 1994.
208. Van Broeckhoven, C. L. Molecular genetics of Alzheimer disease:
Identification of genes and gene mutations. Eur. Neurol. 35:8 19;
1995.
209. Van der Loos, H. The development of topological equivalences in the
brain. In: Meisami, E.; Brazier, M. A. B., eds. Neural growth and
differentiation. New York: Raven; 1979:331336.
210. Van Hoesen, G. W. The parahippocampal gyrus. New observations
regarding its cortical connections in the monkey. Trends Neurosci.
5:345350; 1982.

165
211. Van Kesteren, R. E.; Fainzilber, M.; Hauser, G.; van Minnen, J.;
Vreugdenhil, E.; Smit, A. B.; Ibanez, C. F.; Geraerts, W. P. M.;
Bulloch, A. G. M. Early evolutionary origin of the neurotrophin
receptor family. EMBO J. 17:2534 2542; 1998.
212. Weiler, I. J.; Hawrylak, N.; Greenough, W. T. Morphogenesis in
memory formation: Synaptic and cellular mechanisms. Behav. Brain
Res. 66:1 6; 1995.
213. Welker, E.; Van der Loos, H. Quantitative correlation between barrelfield size and the sensory innervation of the whiskerpad: A comparative study in six strains of mice bred for different patterns of
mystacial vibrissae. J. Neurosci. 6:33553373; 1986.
214. Welker, W. I.; Seidenstein, S. Somatic sensory representation in the
cerebral cortex of the raccoon (Procyon lotor). Am. Zool. 4:7594;
1959.
215. White, E. L.; Keller, A. An integrative view of cortical circuitry. In:
White, E. L., ed. Cortical circuits. Synaptic organization of the
cerebral cortex. Structure, function and theory. Boston: Birkhauser;
1989:179 215.
216. Whiten, A.; Goodall, J.; McGrew, W. C.; Nishida, T.; Reynolds, V.;
Sugiyama, Y.; Tutin, C. E. G.; Wrangham, R. W.; Boesch, C.
Cultures in chimpanzees. Nature 399:682 685; 1999.
217. Wilson, A. C. The molecular basis of evolution. Sci. Am. 253:164
173; 1985.
218. Wilson, A. C.; Carlson, S. S.; White, T. J. Biochemical evolution.
Annu. Rev. Biochem. 46:573 639; 1977.
219. Wise, S. P.; Rapoport, J. L. Obsessive-compulsive disorder: Is it a
basal ganglia dysfunction? In: Rapoport, J. L., ed. Obsessive-compulsive disorder in children and adolescents. Washington, DC: American Psychiatric Press; 1989:327344.
220. Woolsey, T. A. Barrels, vibrissae, and topographic representations.
In: Adelman, G., ed. Encyclopedia of neuroscience, vol. 1. Boston:
Birkhauser; 1987:111113.
221. Woolsey, T. A.; Welker, C.; Schwartz, R. H. Comparative anatomical
studies of the SmI face cortex with special reference to the occurrence
of barrels in layer IV. J. Comp. Neurol. 164:79 94; 1975.
222. Yakovlev, P. I.; Lecours, A. R. The myelogenetic cycles of regional
maturation of the brain. In: Minkowski, A., ed. Regional development of the brain in early life. Philadelphia: F. A. Davis; 1967:370.
223. Yeni-Komishian, G. H.; Benson, D. A. Anatomical study of cerebral
asymmetry in the temporal lobe of humans, chimpanzees and rhesus
monkeys. Science 192:387389; 1976.
224. Young, M. P. Objective analysis of the topological organization of
the primate cortical visual system. Nature 358:152155; 1992.
225. Zhang, M. Y.; Katzman, R.; Salmon, D.; Jin, H.; Cai, G. J.; Wang,
Z. Y.; Qu, G. Y.; Grant, I.; Yu, E.; Levy, P.; Klauber, M. R.; Liu,
W. T. The prevalence of dementia and Alzheimers disease in Shanghai, China: Impact of age, gender, and education. Ann. Neurol.
27:428 437; 1990.
226. Zilles, K. Neuronal plasticity as an adaptive property of the central
nervous system. Ann. Anat. 174:383391; 1992.