Neuroanatomical asymmetries in nonhuman primates in the homologs to Broca's and Wernicke's areas: a mini-review

A fundamental feature of the human brain is lateralization, which is defined as left-right differences neuroanatomy and neurofunctions that underlie different sensory, motor and cognitive functions [1–4]. Asymmetries in the structure are often conceptualized and quantified in terms of unilateral differences between homologous brain regions following a set of operationally defined neuroanatomical landmarks. More recent advances in neuroimaging techniques and quantification methods that operate at the level of the voxel or vertices have allowed for expansive, whole brain analyses of asymmetry in gray matter, white matter, cortical thickness, surface area and in anatomical and functional connectivity [5–9]. In humans, these approaches have revealed more comprehensive results with respect to whole brain variation in lateralization in morphology and connectivity.

In the study of behavioral and brain lateralization, scientists typically distinguish between individual and population-level asymmetries. Specifically, at the individual level, left-right difference measures obtained from bilateral traits are computed for each subject. The sign and absolute value indicate the direction and magnitude of a given subjects laterality and these are often described as asymmetry quotient (AQ) scores.

Population-level asymmetry indicates whether the average AQ scores for a sample of subjects differs from zero or, relatedly, whether a significant proportion of subjects within a sample show the same directional bias based on the sign of the AQ value. Thus, like other types of research on asymmetry, different distributions of lateralization can be obtained within a population or sample including: (1) a normal distribution of AQs, (2) a bimodal distribution AQ scores and (3) a rightward or leftward skewed distribution of AQ scores. Normal and bimodal distributions of AQ scores will have mean values on or about zero and reflect no population-level bias but for different reasons. In contrast, skewed distributions reflect population-level biases (depending on sample size and consistently of the asymmetry within the sample).

In the context of brain and behavioral asymmetries in nonhuman primates, it has been known for quite some time that individual subjects show asymmetries in certain behaviors, such as hand preferences or on measures of neuroanatomical structures [10–13]. What has been less documented and, indeed a matter of much greater debate, is whether nonhuman primates exhibit population-level asymmetries and, if they do, whether they are comparable in direction to those observed in humans. Indeed, the question of homology in population-level behavioral asymmetries has received considerable attention as it pertains to handedness [14–20]. However, there has been less research and thereby less discussion on the existence of population-level asymmetries in neuroanatomy in nonhuman primates and their similarities (and differences) to those observed in humans [21].

In this review, I summarize recently published data on asymmetries in the nonhuman primate brain that have utilized more modern imaging technologies, with a specific emphasis on studies in chimpanzees. Notably, many early studies on brain asymmetries focused on linear measurements of the length of cortical sulci measured directly from postmortem brains [22–26], endocasts [27–29] or in a few cases magnetic resonance images [30–32]. In addition, several studies quantified asymmetries in the shape of the skull based on endocasts or related methods [33–35]. These collective findings have been summarized recently by Hopkins et al. [21]. In this mini-review, I will summarize more recent findings on brain asymmetries in nonhuman primates that have utilized region-of-interest methods. Furthermore, I will limit the review to studies that have quantified brain regions considered homologous to Broca's and Wernicke's areas in the human brain (see Figure 1). Specially, some of the first studies to describe lateralization in structure and function came from case studies of patients with unilateral damage to the left hemisphere inferior frontal gyrus (IFG) or posterior superior temporal gyrus (STG). In these cases, the patients exhibited deficits in language production and/or language comprehension whereas patients with damage to these same brain regions in the right hemisphere did not show any speech deficits. This led to the view that language functions are largely controlled by the left hemisphere, a finding largely confirmed over the next century in additional clinical cases and from experimental studies using a variety of neuropsychological test and measure employing functional imaging. Because many believe that language is uniquely humans, the historical and contemporary interest in brain asymmetries has largely focused on quantifying measures of brain regions or sulci that are homologous to Broca's and Wernicke's area.

Brodmann's area 22 (BA22) or Wernicke's area is found in the posterior STG [36,37]. The most reliable landmark to quantify this region is referred to as the planum temporale (PT), which is the bank of tissue that lies posterior the Heschl's gyrus (see Figure 1). Historically, scientists have quantified either the surface area or the gray matter volume of the PT in humans and consistently reported a significant leftward asymmetry (PT) (see Figure 2a and Table 1). With respect to nonhuman primates, in one of the first systematic comparative studies of PT asymmetry in chimpanzees, Gannon et al. [38] measured the surface area from a sample of 18 postmortem brains and reported a leftward asymmetry in 17 of the apes. In three subsequent studies, the PT surface area was measured either directly from MRI scans or from 3D reconstructions of the sulci in samples of chimpanzees and all three studies reported a significant population-level leftward asymmetry [39–42]. More recently, Marie et al. [43] quantified the PT in a sample of 96 adult baboons and reported a population-level leftward asymmetry. Following on from this report, Becker et al. [44] measured the PT in a sample of 35 newborn baboons (<3 months of age) and similarly found a leftward asymmetry. Lastly, in rhesus monkeys, no population-level bias has been found, a somewhat interesting result in light of the results reported in baboons, another Old World primate species.

In addition to the surface area, several authors have also measured the gray matter volume of the PT in nonhuman primates. Not surprisingly, the results for PT gray matter asymmetries are largely consistent with the surface area measures. This is because, assuming that cortical thickness in gray matter remains relatively consistent throughout the region, then the larger surface area will produce a larger gray matter volume. Thus, the leftward asymmetries observed for surface area in chimpanzees [41] and baboons [45] are similarly observed for gray matter volume (see Figure 2b and Table 1). In contrast, neither rhesus monkeys, bonnet monkeys or vervet monkeys show a population-level bias in gray matter volume for the PT [46] (see Figure 2b).

There are remarkably few studies documenting asymmetries at the cellular level in BA22 in human and nonhuman primates (Table 1). In one of the only reported studies in humans, Galaburda et al. [47] reported a larger volume of BA22 in the left hemisphere of four postmortem brains. In chimpanzees, Spocter et al. [48] measured the volume, neuron number and neuron density of BA22 in 12 postmortem adult brains and reported a significant leftward asymmetry for each measure (see Table 1). In a follow up study, Spocter et al. [49] further quantified microstructural asymmetries in BA22 by measuring neuropil space and found no population-level bias. Finally, Gannon et al. [50] measured the volume of BA22 in 6 rhesus monkeys and found the 5 of the 6 individuals showed a leftward asymmetry.

Comparative studies of the IFG in nonhuman primates are challenging because of differences in the sulcal landmarks the define the region (see Figure 3). Specifically, in humans, the IFG is broadly classified into the Pars opercularis (Op) and the Pars triangularis (Tr). The Pars opercularis is bordered superiorly by the inferior frontal sulcus (ifs), anteriorly by the anterior ascending ramus of the lateral fissure (aalf) and posteriorly by the inferior precentral sulcus (iprs). The Tr is bordered inferiorly by the horizonal ramus of the lateral fissure (half) and posteriorly by the ascending ramus, and together these rami form a ‘triangle’ shaped gyrus [51–53]. In chimpanzees, the sulci landmarks that define the Op are homologous; however, chimpanzees lack a horizontal ramus of the lateral fissure which precludes being able to define the Tr using sulci landmarks. In more distantly related Old and New World monkeys, the cortical folds are even less similar further complicating the measurement. Cytoarchitectonic studies in macaques and baboons have shown that BA44 and BA45, the constituent cellular components that derive the Op and Tr, respectively, are buried in the central portion of the arcuate sulcus [54,55]. Thus, some have suggested that measurement of the entire or portions of arcuate sulcus can be used as approximations to the measurement of Broca's area, at least in Old World monkeys (discussed below).

In three separate studies that have utilized region-of-interest methods, either no population-level or a slight rightward bias was reported in human subjects [56–58]. In a comparative study of the IFG gray matter volume in 30 human and 30 chimpanzees by Keller et al. [58], neither species showed a population-level bias (see Table 2). In one subsequent study measuring the total gray matter volume of the IFG in a much larger sample of chimpanzees (n = 189), Hopkins et al. [59] reported no population-level bias, consistent with the report by Keller et al. [58]. In contrast, studies by Cantalupo and Hopkins [60] reported a leftward asymmetry in the overall volume of the IFG in chimpanzees, bonobos and gorillas, albeit in much smaller samples of subjects.

More recently, Xiang et al. [61] compared surface area and cortical thickness asymmetries between humans and chimpanzees. In this study, chimpanzee brains were aligned to a human brain template in the software program Freesurfer. Subsequently, the Desikan–Killany atlas maps, developed for use in humans, were subsequently applied to a sample of 77 chimpanzee brain scans and 91 scans of humans. With respect to the Op, Tr, STG and transverse temporal (TT) gyrus, the magnitude and direction of asymmetry were influenced by the different morphological measures (see Figure 4). For surface area, population-level leftward asymmetries were found for both chimpanzees in the superior temporal and TT gyri while no group level bias was found for either the POP or Tr. These results are largely consistent with the previous finding that have used traditional region-of-interest measures. For cortical thickness, no population-level asymmetries were found for either humans or chimpanzees for the Tr and POP regions. In humans, significant rightward asymmetries were found for the superior temporal but not the TT gyrus. In the chimpanzee, significant rightward asymmetries were found for the transverse but not STG.

As noted above, early studies attempting to quantify brain asymmetries focused on measuring the length of select sulci in different primate species from either endocasts or directly from postmortem brains. In contrast with sulci length, recent studies incorporating MRI scans have quantified sulci surface area and the average depths by extracting cortical folds from the 3D scans using software programs such as Brainvisa (BV). To date, these approaches have been used to measure asymmetries in sulci within the temporal lobe including the sylvian fissure (SF) and superior temporal sulus (STS). Additional measures of asymmetry have been reported for frontal lobe sulci with the ventrolateral and inferior frontal gyri (see Figure 5).

With respect to the frontal lobe, Bogart et al. [62] measured the surface area and depth of the rectus (REC) and arcuate (ARC) in a sample of rhesus (n = 21) and bonnet (n = 28) macaque monkeys. Neither species showed a population bias for either folds (see Table 3). Becker et al. [63] measured the surface area and average depth of the ARC in 50 baboons and found no overall population-level bias (but see Discussion). The sulci that define the IFG include the fronto-orbital (FO), precentral inferior (PCI) and inferior frontal sulci (IFS). Using the software program BV, the surface areas and mean depth of the FO, PCI and IFS were quantified in the left and right hemispheres in 294 chimpanzees. For both surface area and depth, significant leftward asymmetries were found for the IFS and FO sulci but not PCI (see Table 3). In addition, the dorsal portion of the FO sulcus was reported to be significantly more often bifurcated in the left compared with the right hemisphere, a result consistent with a previous study describing the sulci patterns of the IFG in postmortem chimpanzee brains [64].

Regarding the temporal lobe sulci, chimpanzees showed a leftward asymmetry for the SF while neither the rhesus nor bonnet monkeys showed a population-level bias (see Table 3). For the STS, chimpanzees showed an overall rightward population-level bias as did the bonnet but not the rhesus monkeys. One interesting observation of the rightward STS asymmetry from the chimpanzee sample was the evidence that the rightward was particularly prominent in the area of the STS referred as the STAP (superior temporal asymmetric pit) [65]. In humans, significant and robust rightward asymmetries have been reported and it was hypothesized to be uniquely human (LeRoy et al. [66]). Contrary to this claim, chimpanzees showed a significant rightward asymmetry in the STAP region, though the magnitude of the bias was much smaller than data reported for human subjects (see Figure 6).

For the PT, IFG and sulci measures in the chimpanzees, the data were derived from two independent samples of captive apes. Specifically, one set of MRI data were obtained from chimpanzees housed at the National Center for Chimpanzee Care (NCCC) whereas the second cohort was collected in apes housed at the Yerkes National Primate Research Center (YNPRC). These two captive populations of apes were derived from distinct founder animals and there was no interbreeding that took place between individuals between the two populations. Thus, this arrangement provides an opportunity to compare the patterns of asymmetry between these two cohorts as a means of assessing their repeatability. As can be seen in Figure 7, patterns of asymmetry for the PT, IFG and the frontal and temporal lobe sulci were evident in both samples of chimpanzees suggesting the results are repeatable.

At the most basic level, and in contrast with many historical views, population-level asymmetries are evident in chimpanzees and, to a lesser extent, other nonhuman primate species. The most robust and consistent population-level asymmetry in chimpanzees and seemingly in baboons is the leftward bias evident in the PT. This finding has been reported in both species using multiple methods of analyses and at different levels of analysis including surface area and gray matter volume. Chimpanzees also show a leftward asymmetry in the volume and neuron density of the BA22 but there are no available data from baboons. It appears the rhesus monkeys may show a population-level leftward asymmetry at the cellular level for BA22 but this sample was relatively small and therefore the results should be interpreted cautiously, particularly in light of the lack of population-level bias in morphological measures from larger samples of subjects. Within the IFG, the evidence of population-level asymmetries seems less clear and appears to be high dependent on the type of measurement (i.e. sulci surface areas versus gray matter volume) and method of assessment. Performing comparative studies of brain asymmetry have several challenges and addressing them in future research would greatly benefit the field and theory. Three considerations for future research are discussed below.

As noted above, humans are predominantly and strongly right-handed whereas the evidence for population-level handedness in nonhuman primates is far less prevalent and, when evident, not nearly as strongly expressed [4,67,68]. For example, population-level right handedness has been reported in chimpanzees for multiple measures of hand use but the proportion of right-handed individuals approximates 65–70% compared with the 85–90% often reported in human subjects [18,19,69–71]. Because neuroanatomical asymmetries can be associated with handedness [72–77], the comparison of brain asymmetries between primate species is more complicated. Notably, in most studies of human subjects, the majority if not all of the subjects are right-handed whereas the handedness of subjects in many studies with nonhuman primates are either unknown or not reported. In instances where handedness was known in studies with nonhuman primates, significant brain-behavior associations have been reported in some but not all cases [78–84]. For instance, with respect to the ARC sulcus, Becker et al. [63] found that asymmetries in the depth of this fold were significantly more leftward in baboons that communicated gesturally more often with their right compared with the left hand. Similarly, Taglialatela et al. [85] found that chimpanzees that preferred to gesture with their right hand showed greater leftward asymmetries in the IFG compared with individuals that preferred their left hand or had no hand preference bias. In contrast, in both chimpanzees and baboons, hand preferences for bimanual actions were associated with asymmetries in the motor hand area of the precentral gyrus. These findings illustrate two important points. First, without considering or controlling for the handedness of subjects when comparing brain asymmetries between species, it is possible that the results might be biased due to an over representation of right- (or left-handed) individuals within one or more species. Second, at least in nonhuman primates, the type of measure of handedness appears to be associated with asymmetries in different cortical regions depending on their motor and communicative functions. This type of distinction in different dimensions of handedness is not typically considered when testing for association with brain asymmetries in humans.

Among primates, the human brain is ∼28% of its total volume at birth, which is much smaller compared with other primate species [86]. Additionally, compared with other primates, humans have a particularly long period of infant and juvenile periods of development. The relatively immature brain coupled with the longer period of infancy makes the human brain more susceptible to the influence of early social and environmental input on cortical development, including asymmetry [87–89]. Specifically, human and nonhuman primate newborns are not born into a symmetrical world. From birth (and arguably prior to birth), infants experience asymmetrical sensory and motor experiences, such as head orientation and nipple preferences by the infant and cradling biases by the primary caregiver which arguably can impact the development of both directional and absolute behavioral and brain asymmetries [90–100]. This is important for two reasons. First, depending on their consistency across individuals, the long-term impact of early asymmetrical input on the brain may result in more consistent and robust asymmetries in humans compared with other primate species. Thus, all other factors being equal, estimated effect sizes for the detection of population-level asymmetries will be greater in humans compared with other primate species. This, in turn, would be mean fewer subjects would be needed to detect population-level biases in humans compared with other primates. Samples sizes are already relatively small in many studies on asymmetries in nonhuman primates; therefore, it is possible that population-level asymmetries may be evident in nonhuman primate species for some measures but these studies are underpowered given the estimated smaller effect size.

Lastly, though not reviewed here, it is clear that voxel and surface-based whole brain approaches to the study of brain asymmetry in nonhuman primates are becoming increasingly evident in the literature [61,101–104]. There are many advantages to these approaches in the context of comparative studies of asymmetry in human and nonhuman primates. Notably, it allows for comparison in broadly defined brain regions between species without reliance on common sulci or related landmarks. That stated, there are some potential pitfalls that merit discussion. Notably, in whole brain approaches, the individual MRI scans through many registration steps are warped into a common stereotaxic space which is normally an ‘average’ or template brain for the species. The challenge is that inherent asymmetries in the template brain can exists which can potentially introduce biases in image registration and the measurement of individual asymmetries. Save the recent study by Xiang et al. [61], previous studies using voxel- or surfaced-based whole brain measures of asymmetries in nonhuman primates have not adopted preprocessing or analytic methods that assure that the template brains are indeed symmetrical.

In sum, in many ways, the study of brain asymmetries in nonhuman primates is still in its infancy. Modern imaging technologies have allowed for scientists to increase the scope and complexity in the study of brain asymmetries at multiple levels of analysis. Compared with studies focused on postmortem tissue, modern imaging also allows for increased samples sizes which has historically and continues to be a significant limitation, particularly in light of the fact that the effect sizes may be smaller in the smaller brained nonhuman primates. At the same time, there remains a need for additional studies examining brain asymmetries at the cellular level of analysis, including in human brains. Lastly, like other aspects of cortical function in relation to complex behavior and cognition, lateralization in function likely operates through a series of connected nodes rather than discrete, isolated brain regions [105–110]. Thus, it is possible (and likely) that specific functions might be governed by a series of lateralized nodes that may be connected within and between hemispheres. Thus, studies may benefit by considering a comparative analysis of functional or anatomical connectivity rather than the whole brain or region-of-interest analyses.

• Chimpanzees are an excellent model species for comparison to humans in the evolution of brain asymmetries.

• Individual and population-level leftward asymmetries are evident in the PT of chimpanzees at multiple levels of analysis. Similar leftward asymmetries appear evident in baboons but it less consistent in other Old World monkey species.

• Despite initial reports of leftward volumetric asymmetries in the homolog of Broca's area, evidence of population-level asymmetries is less clear cut in chimpanzees and humans.

The author declares that there are no competing interests associated with this manuscript.

This work was supported, in part, by NIH grants AG-067419, NS-073134, NS-42867 and NS-092988.

Open access for this article was enabled by the participation of University of Texas M.D. Anderson Cancer Centre in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society.

AQ

asymmetry quotient

ARC

arcuate

BA22

Brodmann's area 22

BV

Brainvisa

FO

fronto-orbital

IFG

inferior frontal gyrus

Ifs

inferior frontal sulcus

PCI

precentral inferior

PT

planum temporale

REC

rectus

SF

sylvian fissure

STAP

superior temporal asymmetric pit

STG

superior temporal gyrus

STS

superior temporal sulus