Hemispheric asymmetry: contributions from brain imaging.

Overview

Hemispheric asymmetry: contributions from brain imaging Kenneth Hugdahl1,2∗ A series of studies using functional and structural magnetic resonance imaging, including diffusion tensor imaging measures also, to elucidate the aspects of hemispheric asymmetry are reviewed. It is suggested that laterality evolved as a response to the demands of language and the need for air-based communication which may have necessitated a division of labor between the hemispheres in order to avoid having duplicate copies in both the hemispheres that would increase processing redundancy. This would have put pressure on brain structures related to the evolution of language and speech, such as the left peri-Sylvian region. MRI data are provided showing structural and functional asymmetry in this region of the brain and how fibers connecting the right and left peri-Sylvian regions pass through the corpus callosum. It is further suggested that the so-called Yakeloviantorque, i.e., the twisting of the brain along the longitudinal axis, with the right frontal and left occipital poles protruding beyond the corresponding left and right sides, was necessary for the expansion of the left peri-Sylvian region and the right occipito-parietal regions subserving the processing of spatial relations. Functional magnetic resonance imaging data related to sex differences for visuo-spatial processing are presented showing enhanced right-sided activation in posterior parts of the brain in both sexes, and frontal activation including Broca’s area in the female group only, suggesting that males and females use different strategies when solving a cognitive task. The paper ends with a discussion of the role of the corpus callosum in laterality and the role played by structural asymmetry in understanding corresponding functional asymmetry.  2010 John Wiley & Sons, Ltd. WIREs Cogn Sci 2011 2 461–478 DOI: 10.1002/wcs.122

HEMISPHERIC ASYMMETRY—WHY AND FOR WHAT?

T

he study on hemispheric asymmetry and brain laterality has a long tradition in the neurosciences, and in psychology, biology, and medicine (see Refs 1 and 2 for overviews). The fact that the vertebrate nervous system is divided into two halves has attracted the attention and has sparkled the speculation of numerous scientists for generations, actually further back than typically recognized. Of particular significance in the history of research on hemispheric asymmetry was the once held presumption that ∗ Correspondence

to: [email protected]

1

Department of Biological and Medical Psychology, University of Bergen, N-5020 Bergen, Norway

2 Division

of Psychiatry, Haukeland University Hospital, 5053 Bergen, Norway DOI: 10.1002/wcs.122

Vo lu me 2, September/Octo ber 2011

functional asymmetry was a property of only human brains; since asymmetry is linked to higher cognitive functions, comparative research is however challenging such a view.3–5

THE PRICE PAID BY NOT WALKING UPRIGHT? The fact that planum temporale (PT) asymmetry is found also in the great apes6 poses an interesting challenge to the current position of hemispheric asymmetry as being driven by the need for processing speed when decoding the speech signal since great apes do not have language. On the one hand, it can be argued that this weakens such a position since it shows that the neuronal underpinning for language and speech processing is not uniquely human. An alternative view that has been suggested is that an upright body position7 is necessary for the

 2010 Jo h n Wiley & So n s, L td.

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Overview

development of language, because of the need for a critical length of the vocal tract for the production of the sounds necessary for speech. Primates have the head tilted forward compared to humans, with a corresponding shortening of the vocal tract, probably a consequence of the need for using both arms and legs when walking and climbing. An alternative explanation may therefore be that PT asymmetry developed for some other (unknown) purpose in both species, and that it took on a speech-related function in humans later, but not in the great apes. Thus, a quadropedal way of moving in the environment might have been an evolutionary advantage for our primate ancestors, sacrificing the development of language and speech ability. The primate ancestors might therefore have paid the prize of a less advanced way of communicating for the advantage of moving around (with increased protection) in the ecological niche they occupied. A similar mechanism may have been at play in humans when it comes to handedness and the unique human trait of doing manual activities with a preferred hand. The fact that approximately 90% of humans prefer the right hand when it comes to manual activities that demand both hands’ strength and fine-graded movements is still a puzzle that is closely associated with theories and models of hemispheric asymmetry.

DEFINING HEMISPHERIC ASYMMETRY Hemispheric asymmetry, or laterality, is typically defined as a characteristic of the brain where a cognitive and behavioral function has a relative processing advantage compared to the other hemisphere. In some instances this can also be categorical differences, with only one hemisphere participating in a particular function8 for the decoding of phonetic information in the left and right hemispheres, respectively.9 A typical example of lateralized localization of function is handedness which means a behavioral advantage to use one hand for manual work rather than the other. Since the left and right cerebral hemispheres control the right and left sides of the body, respectively, right-handed individuals are typically left-dominant in terms of hemispheric control of various motor functions. Another example is language localization to the left hemisphere, after the discovery by Broca in 186310,11 that the brain area for controlling speech production is localized to the left inferior frontal gyrus, an area which today is called also Broca’s area. Another example favoring the right hemisphere is the ability to mentally rotate objects and images 462

in three-dimensional (3D) space which is localized to right parietal lobe areas.12 The underlying causes of hemispheric asymmetry still remain unanswered, although there has been advances in recent years with the introduction of functional brain-imaging techniques, such as functional magnetic resonance imaging (fMRI) and new methods to quantify anatomical differences in shape and volume of regions in the right and left hemispheres through voxel-based magnetic resonance (MR) morphometry measures. Yet another imaging modality is the tracking of white matter fibers, called diffusion tensor imaging (DTI). Taken together, the introduction of the neuroimaging techniques has opened the possibility for closer examinations of whether asymmetry for cognitive and behavioral functions has anatomical correlates. Providing brain anatomical correlates of cognitive and behavioral functions will also contribute to unravel the evolutionary paths that may have shaped functional asymmetry. A consequence of hemodynamic imaging studies of hemispheric asymmetry is the emphasis on functional segregation, rather than integration. The concept of functional segregation13 assumes that anatomically distinct brain areas have different functional properties. Frith14 provides several arguments as to why segregation, rather than integration, is the guiding principle behind the functional organization of the brain, taking arguments from evolution, economy, and the complexity of the design of the brain. Thus, the finding of structural asymmetry in homologous areas in the left and right hemispheres would strengthen the validity of a corresponding functional asymmetry where the function in question is functionally related to the area in question.

EQUIPOTENTIALITY AND NEURONAL CONNECTIVITY WITHIN AND BETWEEN THE HEMISPHERES The introduction of the functional brain imaging techniques also ended the view held by many neuroscientists of what could be called the ‘equipotentiality’ and ‘mass action’ principles originally introduced by Lashley in 1940–1950.15 The equipotentiality principle stated that all cortical areas can substitute for each other as far as higher cognitive functions are concerned. The principle of mass action similarly stated that the reduction in performance for a given cognitive function, e.g., the ability to learn, is proportional to the amount of brain tissue destroyed, and the more complex the cognitive task, the more disruptive the brain lesions would be. Lashley never made



WIREs Cognitive Science

Hemispheric asymmetry

a distinction within versus between the hemispheres, thus it is not clear whether equipotentiality would be greater within compared to between hemispheres. Modern views on specialization of the hemispheres is not only focused on finding specific areas or regions within or between the hemispheres that may show functional specificity, but also to understand the functional relationships, or connectivity, between different areas and regions in a network perspective. In this regard, the terms functional versus effective connectivity have been used16 where functional connectivity means the statistical correlation between two areas in the brain with regard to observed signal strength to a common cognitive task, while effective connectivity means that a given brain region may have a causal influence on another region or regions. It is suggested here that the principle of neuronal connectivity also applies to hemispheric asymmetry, such that areas and regions within a hemisphere show greater connectivity than areas and regions between the hemispheres, particularly for temporo-frontal and temporo-parietal interhemispheric regions. It could in addition be argued that the breakthrough research by Geschwind17,18 and Sperry19 showing that the disconnection between brain regions and the cerebral hemispheres would reveal not only functional disorders but also the functioning of the cerebral hemispheres (see Ref 20 for an excellent review of the rise and fall of disconnection theories). Another important development in the recent years was the finding by Sun et al.21 of a possible link to a specific gene (LMO4) which is differentially expressed on the right and left sides of the brain in the peri-Sylvian region covering the superior temporal gyrus and sulcus. This region of the brain is overlapping with both Wernicke’s functional area for speech sound perception and the PT structural area in the brain.22 This raises the question of the uniqueness of human asymmetry and asymmetry for language as the dominant principle of organization of the two cerebral hemispheres.

EVOLUTIONARY ORIGIN—NOT DUPLICATING THE MESSAGE What is not known, however, is what evolutionary advantage would have been gained through a division of labor between the two cerebral hemispheres. A pervasive theory is that of the advantage of not having a competition for processing of two identical messages.23,24 This implies that there would be an advantage having a single information-processing system which facilitates communication at high speed, and to avoid having identical forms of Vo lu me 2, September/Octo ber 2011

cortical representations. The simultaneous activation of homologous areas in each hemisphere would run the risk of attenuating and blurring information, thus slowing down sensory processing and subsequent motor output. A variant of this is to say that evolution of higher cognitive functions pushed for a division of labor between the hemispheres, forcing the development of the two hemispheres as the result of a demand for processing speed and efficiency.25 The development of two cerebral hemispheres as a response to a push for better adaption to the demands of the environment should also have been accompanied by an increase in neural capacity, since specializing one hemisphere for a particular function leaves the other hemisphere free to perform other functions. Thus, lateralization may have been a way to increase brain capacity to carry out simultaneous, parallel processing24 without the mutual inhibition and information loss as may have been the case in a situation where information would have been duplicated. An extension of this argument is that it would also have been advantageous to avoid shuffling information across long distances in the brain, which would mean the loss of processing speed. It would therefore be better that information is processed in a single hemisphere with the involvement of spatially restricted neural networks.

PLANUM TEMPORALE AND LANGUAGE ASYMMETRY The PT area is located in the horizontal plane in the upper posterior part of the temporal lobes in the peri-Sylvian region covering parts of the superior temporal gyrus and extending to the superior temporal sulcus. The PT is located just posterior to the Heschl’s gyrus and extends posteriorly to the descending ramus of Sylvian fissure.26,27 Interestingly, the PT area is about 30–35% larger on the left side, although it is not known what exactly is causing this anatomical asymmetry.26 Figure 1 shows the identification of the PT in MR images. Note the apparent lack of asymmetry in the dyslexic individual.22 It has been shown that the neuronal columns are more widely spaced on the left side which would favor greater connectivity per neuron, thus enhancing information-processing speed.28 It also has been shown that the axons in the left PT region are more heavily myelinated,29 which would favor increased impulse traveling speed, again enhancing informationprocessing speed. If it is further acknowledged that the left PT area is part of a functional neuronal network extending ventrally and anteriorly that is specialized for speech perception, the structural asymmetry would


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FIGURE 1 | Structural axial MRI image showing a slice through the planum temporale (PT) area about 8–10 mm above the AC-PC midline, with the PT area marked by manual tracings on the left and right sides. Note the prominent asymmetry with larger area in the left hemisphere. (Reprinted with permission from Ref 22. Copyright 2000 Elsevier Limited.)

be understandable as promoting the rapid decoding of the phonological information in a speech signal which is essential for fluency of speech understanding.30 This view is strengthened by the findings of Catani et al.31 who used DTI and subsequent fiber tractography to describe a language network in the left hemisphere connecting Brocas’s and Wernicke’s areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex. The network identified by Catani et al.31 thus includes the PT and adjacent areas in the left temporal lobe.

STRUCTURAL (ANATOMICAL) VERSUS FUNCTIONAL (BEHAVIORAL) ASYMMETRY The neuronal organization of the left PT area reveals an important overlap in structural, or anatomical, and functional, or cognitive, asymmetry. Although not a necessary prerequisite for the interpretation of functional asymmetries, the identification of an underlying structural asymmetry would strengthen any observation of a functional asymmetry. A prerequisite for such an argument would however be that there exist an a priori theoretical connection between a found structural asymmetry and a corresponding functional asymmetry. It would not be sufficient just to demonstrate that a certain region or area in the brain is asymmetrical with regard to gray matter volume, favoring one hemisphere, 464

if this region has not been linked to a specific function or set of functions. Such a relationship exists for asymmetry for speech perception, as seen in e.g., the right ear advantage to speech syllables in dichotic listening performance32 and the larger left compared to right hemisphere PT area.33,34 There is, for example, no corresponding structural asymmetry in the visual cortex that would provide a clue to the basis for effects of functional asymmetry found with visual stimuli, using e.g., the visual half-field technique.35 This is in stark contrast to the detailed specialization of the visual cortex within a hemisphere as evidenced from the excellent mapping of visual areas done by Van Essen.36 It should be pointed out, however, that not all studies in the auditory domain have reported a perfect relationship between structural and functional asymmetries, e.g., Dos Santos Sequeira et al.34 used dichotic listening to CV syllables together with MR volumetric measurements of gray matter concentration in the PT area. It was found that both handedness and sex of the subjects modulated asymmetry for structure and function, in a complex relationship with only right-handed males showing a tendency for a structure–function relationship involving the PT area (see also the work of Westerhausen et al.37 who found a structural leftward asymmetry in the corticospinal tract which was, however, not related to handedness). Another example of gross anatomical differences between the two hemispheres is the recent finding by Sandu et al.38 on increased cortical surface irregularities in the right hemisphere. Sandu et al.38 calculated the fractal dimension, which is a mathematical expression of regularity and selfsimilarity of an object or structure, of the cortical surface from segmented MR images and found a higher value for the cortical surface surrounding the right hemisphere. The same authors also reported that schizophrenia patients had altered cortical surface irregularities, particularly involving the right hemisphere. Measures such as fractal dimension analysis of MR data may therefore reveal subtle micro-architectural differences in the cortical surface between the hemispheres, not possible to detect with traditional MR measures. Thus, the issue of structural–functional asymmetry correspondence may be more subtle than previously thought. Not all studies have found a correlation between PT asymmetry and language asymmetry, and have consequently questioned the anatomical demarcation of the PT.27,39 However, more recent studies, using MR, data have found a clear correlation between the two factors,34 and that the PT is anatomically possible to outline.26





Anterior

Frontal petalia

F Left hemisphere

Right hemisphere

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FIGURE 2 | The asymmetries found in the gross anatomy of the two brain hemispheres are shown. Protrusions of the hemispheres, anteriorly and posteriorly, are observed, as well as differences in the widths of the frontal (F) and occipital (O) lobes. A twisting effect is also observed, known as Yakovlevian torque, in which structures surrounding the right Sylvian fissure are ‘torqued forward’ relative to their counterparts on the left. (Reprinted with permission from Ref 42. Copyright 2003 Nature Publishing Group.)

THE YAKOVLEVIAN TORQUE AND ASYMMETRY OF HEMISPHERIC WIDTHS Another profound anatomical asymmetry is the socalled Yakovlevian torque,40,41 visible to the naked eye, in which the brain seems to have developed during phylogeny in a ‘twisted’ way around its longitudinal axis, with the right frontal pole protruding beyond the left, and the left occipital pole protruding beyond the right. This torque accompanies a relative widening of the right frontal and left occipital poles.42 The Yakovlevian torque42 is shown in Figure 2. The anatomical organization of the torque supports an assumption of structure–function correspondence for fast and efficient information processing. The widening and twisting of the posterior left hemisphere can be thought of as a consequence of a wider and larger left PT area which would push the posterior part of the left hemisphere backward with a protrusion at the occipital pole on the left side beyond the corresponding protrusion of the right occipital Vo lu me 2, September/Octo ber 2011

pole. Correspondingly, widening of the anterior parts of the right hemisphere such that the right frontal pole protrudes beyond the left frontal pole would be expected, if right parietal and frontal areas would be more involved than the corresponding left areas in visuo-spatial processing. A right-sided functional asymmetry for visuo-spatial processing, associative learning,43 and attentional functioning is typically reported in neuroimaging studies (see Ref 12 and also see Ref 44, in which an increased right-sided activation to visual attention tasks has been reported). Thus, it seems reasonable that functional advantages in the left and right hemispheres have structural equivalents as seen in the Yakovlevian torque effect. Moreover, Crow45,46 has consistently argued that the torque effect may be a prerequisite for asymmetry for language and that e.g., psychosis may be a consequence of deficits in structural asymmetry of the brain.47 A hypothesis can be forwarded based on the torque effect that the cortical mantle should be thinner at the left occipital and right frontal protruded poles. This could be looked at as when wrapping a thin cover (like a ‘pizza-dough’) around the tip of a post and pushing the post against the wrapping, which would extend the wrapping at the tip of the post, making the surface thinner. Figure 3 shows this principle from morphometric measures of MRI cortical thickness data. As can be seen in Figure 3, left hemisphere frontal areas are thicker than corresponding right hemisphere areas, while right hemisphere temporal lobe areas are thicker than corresponding left hemisphere areas. Thus, there is an inverse relationship between lateralized pole protrusions and thickness of the underlying cortical mantle which would be expected if the cortical mantle is extended anteriorly or posteriorly in one hemisphere relative the other. Anatomical asymmetries are, however, not only observed at the anterior and posterior cortical poles, but also in other areas when cortical thickness is measured. Luders et al.48 found significant leftward asymmetry in the precentral gyrus, middle frontal, anterior temporal, and superior parietal lobes, and a corresponding rightward asymmetry in the inferior posterior temporal lobe and inferior frontal lobe. Thus, when measured on a voxel-basis in the whole brain volume, structural asymmetry is found not only in the regions related to known functional asymmetries, such as speech and language, but also in widespread regions and areas. The use of MRbased measures, such as voxel-based morphometry (VBM), for the quantification of gray and white matter asymmetry between the hemispheres has qualified the classic statement that functional asymmetries are not accompanied by structural asymmetries. It


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FIGURE 3 | Significantly thicker voxels in the left hemisphere (yellow/red areas) and in the right hemisphere (blue/purple areas) visualized on the lateral surface. Unpublished data from Bradley Peterson, Columbia University, USA, Kerstin von Plessen and Kenneth Hugdahl, University of Bergen, Norway.

remains, however, still to be explained what the functional significance is (if any), on asymmetry in areas and regions not uniquely involved in a cognitive function. It is thus clear that the issue of structural asymmetry and the relationship to functional asymmetry are theoretically both important and interesting. In addition, Luders et al.48 reported a complex relationship between the sex of the subject and anatomical asymmetries, with either failure of significant sex differences, or complex relationships. Considering that sex typically is seen as one of the most important modulatory factors for functional asymmetry, these findings are interesting. The overall thicker left hemisphere in anterior regions and thicker right hemisphere in posterior regions support the hypothesis that the cortical hemispheres have evolved in a torque-like manner. Previous studies on brain volume and voxel-based gray matter density have shown right anterior and left posterior hemispheric protrusions.49–52

CORPUS CALLOSUM AND INTERHEMISPHERIC CONNECTIVITY Avoiding duplicate messages is not the same as saying that there would be no advantage in hemispheric collaboration and information interaction between the two hemispheres to either share information or to coordinate ongoing processing. The neuronal basis for such interaction is provided by a brain structure located between the hemispheres, the corpus callosum, which is the major interhemispheric fiber tract. Thus, hemispheric asymmetry and the corpus callosum are closely interrelated, such that theories on the origin 466

of hemispheric asymmetry show an important role in the functional specificity of callosal fibers.25,53,54 One influential example is the hypothesis provided by Ringo et al.,25 according to which the development of hemispheric specialization is attributed to the existence of an interhemispheric conduction delay across the callosum (see also Refs 55 and 56). These authors propose that a symmetric or bihemispheric functional network would have to rely on the exchange of information to coordinate processing between its two parts. However, the efficacy of this communication would be restricted by the conduction time for the commissural fibers so that for larger brains an efficient interhemispheric cooperation would be hampered by information traveling long distances. A recent study by Adesnik and Scanziani57 showed that impulse propagation horizontally spread first within the activated home column and to the adjacent columns in the horizontal plane, which decays with increasing distance from the source dipole (see also Ref 58). As a result (short distance) asymmetric networks would be preferred over (long distance) symmetric networks, where functionally related cell assemblies would be forced to cluster in one hemisphere. This explanation would apply for phylogenetic development as well in which natural selection would select asymmetric species. The same would apply for ontogenetic development in which a redirection53 or elimination of callosal axons54 would allow for a certain plasticity in establishing efficient uni- or bilateral networks. From this it could be hypothesized that stronger asymmetry should be related to a weaker interhemispheric connection, and that the association between asymmetry and interhemispheric connection should depend on brain size. It has also been repeatedly shown that stronger anatomical asymmetry is related to reduced interhemispheric connectivity as indicated by a smaller corpus callosum.59,60 Such inverse correlation can even be found in specific functional networks, e.g., speech processing, with a larger (leftward) PT asymmetry in size61,62 or minicolumnar density63 which has been shown to be negatively correlated with size or the number of callosal projections in the isthmus or splenium of the corpus callosum. Thus, an association is found with the callosal regions that are supposed to contain the fibers interconnecting the temporal lobe speech processing areas see also.64 However, only indirect evidence exists for a predicted influence of brain size on this association. It could therefore be argued that hemispheric asymmetry may be necessary to avoid neuronal signal conduction decay and delay with increasing distances,





i.e., when having to cross the brain midline that would result from symmetric networks. Bilateral, symmetric functional networks differ from unilateral, asymmetric networks not only in the strength of the signal but also in the type of the callosal connections. The cytoarchitecture of the corpus callosum reveals that it is the primary sensory or motor areas that are interconnected via fast conduction and strongly myelinated axons. In contrast, highly specialized areas and regions, like the PT or in the frontal lobes, which show strong functional asymmetry, are linked to the contralateral hemisphere via slow, weakly myelinated axons. As a result, it is frequently argued that the differences in callosal connectivity represent different ‘channels’ within the corpus callosum that would support different kinds of interhemispheric interactions.65 The ‘fast channel’ seems to provide the exchange of information that is important for the integration of information from the two sides of the sensory field, e.g., the midline fusion of the visual field. The ‘slow channel’, however, may instead support a modulatory function, in which one hemisphere exerts influence on the ongoing processing in the homolog area in the opposite hemisphere, e.g., by means of contralateral inhibition. Evidence for both the information transfer function8,66 as well as for the modulatory function67,68 can be found supporting a ‘dual role’ of the corpus callosum. Thus, it is suggested that the development of hemispheric asymmetry not only caused a reduction in callosal projections (as would be predicted by Ringo et al.25 ), but it also coincided with a change of the functional role of the callosal fibers. In other words, with increasing asymmetry, the callosal connections changed from an ‘integrating’ information transfer system to a ‘separating’ modulatory system. Figure 4 shows the

fiber tracts connecting the right and left PT areas in the posterior temporal lobe.69

THEORIES OF HEMISPHERIC INTERACTION Moscovitch70 advanced a callosal relay model of hemispheric function and interaction. A callosal relay model holds that only one hemisphere can perform a certain task or process a certain type of stimuli. This means that when information is presented to the less dominant hemisphere, it is not processed in that hemisphere but transferred across the corpus callosum to the more dominant hemisphere. A direct access model claims, on the other hand, that both hemispheres can perform the task, but that one would normally take over performing the task because of a processing superiority, or simply speaking, it does the job better. In the visual domain there is evidence for both a callosal relay and a direct access model71,72 when applying a face recognition task. However, using a complex task like recognizing a face will load on a variety of sensory and cognitive processes, of which some may be lateralized and others not, thus not unequivocally providing evidence for either a relay and direct access model. The data by Pollmann et al.8 provide unambiguous evidence for a callosal relay model using the data from patients with circumscribed lesions in specific regions of the corpus callosum. Pollmann et al.8 studied patients with lesions affecting either the anterior or posterior sections of the corpus callosum, with the assumption that the auditory pathways cross the callosum at posterior locations (isthmus/splenium). The results showed that patients with more posterior lesions completely failed to report any syllable from the left ear, while the right ear

FIGURE 4 | Diffusion tensor imaging (DTI) of white matter tractography outlining neural pathways in the transverse (red color), longitudinal (green color), and vertical (blue color) axes. (Reprinted with permission from Ref 69. Copyright 2009 Oxford University Press.)



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correct reports approached 100%, yielding a more or less complete right ear advantage. Lesion data provide excellent first-hand evidence with regard to causality and whether a region or function is necessary, while behavioral and imaging data only provide evidence that a certain area or region is involved in a particular function. A similar conclusion is reached when looking at what Heilman and Valenstein73 called ‘auditory neglect’, i.e., neglectlike symptoms to simultaneous presentations of nonverbal stimuli in patients with fronto-parietal lesions. Hugdahl et al.74 found a similar pattern of responding in a patient with unilateral frontal and thalamic lesions when tested with the consonant–vowel dichotic listening paradigm. This patient was unable to report anything from the left ear while at the same time reporting almost 100% from the right ear. Thus, at least when it comes to auditory speech sound stimuli, a callosal relay model receives stronger support than does a direct access hemispheric asymmetry model. The data for the auditory modality are also in general stronger than the data for the visual modality since lesion data provide clear-cut evidence regarding the causal influence of a brain region on performance, while functional neuroimaging and neuropsychological data on healthy individuals at best can inform that a certain brain region is involved in a function, without further specification about whether the region is causal or necessary for the function in question.

MIRROR SYMMETRY AND INTERHEMISPHERIC TRANSFER An interesting variant of the dependence of interhemispheric transfer across the corpus callosum is the theory of mirror symmetry suggested by Corballis and Beale75 in which a visual stimulus initially projected to one hemisphere (e.g., through visual half-field presentations) gets a mirror image copied to the other hemisphere as a memory trace. Such a principle would establish and maintain coherence between across the hemispheres.76 Because the fibers through the corpus callosum project to homologous areas in the hemispheres, with a one-to-one mapping, e.g., the presentation of the letter ‘b’ to the left hemisphere would be transferred and stored in the right hemisphere as its mirror image, i.e., the letter ‘d’. Dehane76 has an interesting discussion on how the mirror symmetry theory of Corballis and Beale75 can be used to understand how a child learns to read and to discriminate between letters like ‘b’ and ‘d’ in the learning process. An extension of Dehane’s76 discussion would therefore be that 468

hemispheric asymmetry is necessary for the process of learning to read to be successful.

WHITE MATTER TRACTOGRAPHY—A NEW PATHWAY TO HEMISPHERIC ASYMMETRY With the application of DTI in MRI studies of the brain, it has become possible to also visualize and track asymmetry of white matter and neural fiber tracts.77,78 DTI measures diffusion of water molecules within the brain parenchyma following the principle of Brownian motion. As water molecules interact with cellular barriers when freely diffusing through brain tissue, the measured diffusion properties carry information about the micro-structural tissue organization (see Ref 78 for review). Brain structures containing fat, e.g., the myelin sheaths or cell membranes provide obstacles for passage of the water molecules.79 Thus, perfusion of water molecules is easier perpendicular to, than parallel to, the longitudinal axis of white matter fiber bundles. This results in a directional bias of the diffusion process that can be seen as an indicator of the main fiber orientation, and this can thus be used to calculate fiber bundle thickness in a 3D fashion in the whole brain volume (for review see Ref 80). Thus, DTI and corresponding DTI-guided tractography provide a unique non-invasive approach to study different functional subregions within the brain, and to determine a new aspect of structural asymmetry. Catani et al.82 recently reviewed the literature on white matter asymmetry, focusing on DTI studies, and made the important observation that efforts to study white matter asymmetry have been hampered by the absence of reliable methods to trace connections in the human brain. With the recent developments in DTI technology and application to the study of the intact human brain was in this respect a breakthrough development.78,81 Catani et al.82 conclude that the numerous studies now being published is likely to fill the gap on our anatomical knowledge of human brain connections and will reinvigorate models of cognition based on asymmetrical distribution of large-scale networks. Thus, studies of the asymmetry of white matter tracts will provide a new avenue to understanding hemispheric asymmetry by allowing for the study on how asymmetry of specific brain regions is supplemented by asymmetry of how the areas are connected both within and between the hemispheres. Catani et al.82 point to the importance of using DTI in e.g., visualizing the asymmetry of fiber tracts connecting brain areas involved in lateralized cognitive functions. An example of such connectivity





is the role played by asymmetry of the arcuate fasciculus fiber tract to connect speech perception and speech production areas. The arcuate fasciculus is a large association tract connecting the speech perception areas in the peri-Sylvian and PT regions with corresponding language production areas in the frontal lobes. The arcuate fasciculus seems moreover to be involved in many other functional asymmetries involving also visuo-spatial functions. The use of VBM and DTI measures have revealed that the white matter regions containing fibers of the arcuate fasciculus are larger in the left compared to the right hemisphere.83,84 This would enhance languageprocessing speed and efficiency in the left hemisphere by direct and parallel white matter connections within the left hemisphere as opposed to indirect and serial connections of the right hemisphere, connecting language areas in the left hemisphere. Another intriguing hypothesis was put forward by JohansenBerg et al.85 that variability in brain structure may reflect variation in functional properties of specific brain systems. Structural variation may therefore reflect variation in behavioral performance. JohansenBerg et al. used DTI to show that variation in interhemispheric connectivity through the corpus callosum motor pathways correlated with manual skills on a motor co-ordination task. Similarly, Putnam et al.86 used DTI to track interconnecting areas in the visual cortex through the posterior,

(a)

Group1 strong left lateralization (62.5%)

splenium, part of the corpus callosum and about 30% of the subjects revealed homotopic connections between the primary visual cortices, again suggesting interindividual differences in callsosal connectivity, but now in the posterior part of the corpus callosum. Putnam et al.86 also reported more frequent connection for the right hemisphere, which would expand the findings of Johansen-Berg85 by indicating the asymmetry of callosal connectivity. Catani et al.31 used cluster analysis on DTI data outlining the language pathways connecting Broca’s and Wernicke’s areas and obtained three distinct subject groups (Figure 5), with the largest group showing extreme leftward asymmetry, and another smaller group with bilateral pathways, although stronger connections on the left side, and a third small group with bilaterally symmetrical pathways. This would indicate individual differences in lateralization of white matter organization that have functional consequences. One such consequence is shown in Figure 5 which reveals that individuals with a more bilateral brain organization of white matter performed better on a verbal memory test (CVLT).31 Thus, as suggested by the authors,31 ‘the degree of lateralization of peri-Sylvian pathways is heterogeneous in the normal population and, paradoxically, bilateral representation, not extreme lateralization, might ultimately be advantageous for specific cognitive functions’ (Abstract).

Group2 bilateral, left lateralization (20%) 80 CVLT (words recalled)

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FIGURE 5 | Lateralization of language pathways and behavioral correlates. (a) Distribution of the lateralization pattern of the direct long segment (red). (b) Significant correlation between the lateralization index (streamlines) of the direct segment and (c) performances on the CVLT (number of words correctly recalled). (Reprinted with permission from Ref 31. Copyright 2007 PNAS.)



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Females

Males

FIGURE 6 | Clusters of significant MR signal increases in the 3D mental rotation condition after subtraction of the 2D control stimulus condition. The images were height thresholded at a significance level of p < 0.001. See text and corresponding table for further details. (Reprinted with permission from Ref 12. Copyright 2006 Elsevier Publishing.)

SEX DIFFERENCES IN THE BRAIN AND IN COGNITIVE PERFORMANCE A critical, and also controversial, question with regard to an evolutionary origin of hemispheric asymmetry is the question of sex differences in cognitive and behavioral functions that have been shown to be asymmetrically distributed in the brain, such as language and spatial orientation and visual processing. In a series of studies, Hausmann et al.87,88 have demonstrated that functional asymmetries in women strongly depend on the menstruation cycle. In the progesterone phase there is less interhemispheric communication possibly because of increased interhemispheric inhibition. Interestingly, Hausmann et al. have shown that females vary in their ability for spatial processing across the menstrual cycle, considered to be a male advantage. It should also be mentioned that some studies have shown that sex differences in hemispheric asymmetry is dependent on the sample size. For example, Voyer89 demonstrated rather weak effect sizes for gender differences in various functional asymmetry measures, and Figure 6 shows fMRI brain imaging data from the study by Hugdahl et al.12 in females (left panel) and males (right panel) when solving a mental rotation task based on Shepard and Metzler’s90 well-known geometric object stimuli being rotated in 3D space. As can be seen in Figure 6, females bilaterally activated areas in the inferior frontal cortex, including Broca’s area, while males activated only parietal lobe areas. Thus, 470

it seems that males and females would utilize different processing strategies when approaching the same task, females using a verbal, or language-guided approach, while males using a spatial, or perceptual-guided approach. Performance data in the Hugdahl et al.12 study did not reveal significant differences between the sexes. Thus, the fMRI results showed that even in the absence of a behavioral difference in performance, males and females still showed biological differences in the strategy they apply when solving a cognitive (even when the net result is equally good). The issue of sex differences in language processing still is a controversial issue; with contradicting results, e.g., Shaywitz et al.91 found reduced asymmetry in BOLD fMRI activation in females during language processing. However, Frost et al.92 did not replicate this finding, also when using a larger sample size. These results may contribute to a discussion of the origin of sex differences and hemispheric asymmetry in an evolutionary perspective. Perhaps the different brain activations in males and females are ‘modern’ variants of a functional division of labor made necessary from the need to socialize the next generation of offspring into a language-guided culture versus the need to orient in 3D space to localize the prey and to find the way back home to feed the members of the culture. Such a division of labor not only between the hemispheres but also between the sexes would follow from a need not to duplicate the message to be processed and to unnecessary slow down processing speed, as discussed above.





DICHOTIC LISTENING—A MEASURE OF AUDITORY ASYMMETRY Although the majority of functional asymmetry studies have been conducted in the visual modality (see Ref 93 for overview of visual asymmetry studies), the auditory modality provides a better fit between functional and structural asymmetry. This is possibly related to the strong relationship between left hemisphere speech perception and language, and PT structural asymmetry. Functional asymmetry in the auditory modality has been most consistently studied with the dichotic listening paradigm (see Ref 32 for a description of dichotic listening in asymmetry research; see also Ref 1,2). In a typical dichotic listening situation, two different speech sounds, like isolated consonant–vowel (CV) syllables, are presented simultaneously, one in each ear. In its most straightforward use, the subject is simply asked to report what he/she perceives on each trial, restricting the response to a single syllable. Normal adult subjects report more correct items for the right ear stimulus, also when controlling for intensity differences between the two stimuli, and eventual hearing threshold differences between the ears. The favored explanation for the right ear advantage (see Ref 94) is that although auditory input is transmitted to both auditory cortices in the temporal lobes, the contralateral projections are stronger and more preponderant, interfering with the ipsilateral projections. The advantage for the contralateral auditory projections in dichotic listening means that the language-dominant left hemisphere receives a stronger signal from the right ear. The contralateral signal from the left ear to the right hemisphere must first pass the corpus callosum to be processed in the speech processing specialized left hemisphere. This was nicely demonstrated in a dichotic listening study by Pollmann et al.8 in patients with circumscribed lesions to different subregions in the corpus callosum. Patients with lesion in the posterior third of the callosum, including the isthmus and parts of the splenium, failed to report anything from the left ear stimuli. The right ear advantage observed in performance studies was validated in an O15 -positron emission tomography (PET) study94 ; using a monitoring variant of the classic dichotic listening paradigm, brain activation was compared to CV syllables and musical stimuli (cf. also Refs 95, 96 using different dichotic listening paradigms). The CV syllables and musical stimuli showed opposite activation asymmetries in the PT area in the temporal lobe. More intense activation was observed in the left superior temporal gyrus to the CV-syllable stimuli, while greater activation to the musical stimuli was observed in corresponding right Vo lu me 2, September/Octo ber 2011

temporal lobe areas. Interestingly, both extent and intensity of activation were greater to the CV-syllable stimuli compared to the musical instrument stimuli. The PET results by Hugdahl et al.94 to CV syllables have later been validated by fMRI97 thus revealing the stability of the functional neuroimaging results. Figure 7 shows left hemisphere fMRI activation when presenting consonant–vowel syllables in the dichotic listening situation. The observed increase in the right hemisphere activation in the same areas for the perception of brief musical chords, used as control stimuli to the asymmetry produced by the CV syllables in the study by Hugdahl et al.94 (cf. Ref 98), may point to a role for the right peri-Sylvian region to also decode non-phonological information, like prosody, in the speech signal (cf. e.g., Ref 43 for other aspects of right hemisphere functioning).

DYNAMIC MODULATION OF BOTTOM-UP ASYMMETRY EFFECTS Thomsen et al.99 reported that an extended temporofrontal network is activated during processing of dichotically presented CV-syllable stimuli when contrasted with binaural stimulus presentations, in a group of young adults. Similar results have been reported also in other imaging studies with CV syllables.100,101 The results by Thomsen et al.99 showed that the prefrontal network was particularly involved under conditions requiring active deployment of attention in auditory space as when instructing subjects to pay attention to and report the right or left ear stimulus. This then points to the importance of also taking cognitive topdown effects into consideration when addressing hemispheric asymmetry, and has a long history of such studies, however, beyond the scope of the current review (see the pioneering studies and theories by Kinsbourne102 ; see also Ref 103) The fact that stimulus-driven functional asymmetry effects can be modulated by top-down cognitive effects like attention shifts in auditory space is important for understanding the brain dynamics of hemispheric asymmetry. In a follow-up study, Thomsen et al.104 further found that the ability to cognitively modulate the right ear advantage in the dichotic listening situation was reduced in a group of older subjects compared to the younger adult subjects. This also corresponded with a reduction in neuronal activation in the anterior cingulate and prefrontal areas in the older group, an area shown to be critical for higher cognitive processes like attention and executive functions.105 A second finding in the Thomsen et al. study99 was that gray


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FIGURE 7 | Brain imaging data by functional magnetic resonance imaging (fMRI), showing asymmetrical neuronal activation favoring the left side in the peri-Sylvian region to dichotic presentations of CV syllables. (Reprinted with permission from Ref 97. Copyright 2008 Elsevier Publishing.)

matter density, as measured with a VBM approach, was reduced in frontal areas in the older subjects compared with the younger ones. These results thus point to a correspondence when it comes to functional and structural asymmetry and nicely demonstrated in the overlap in reduction of fMRI functional activation and MRI structural gray matter density.

DYNAMIC MODULATION OF THE TIME COURSE OF HEMISPHERIC INTERACTION fMRI is an excellent method when it comes to spatial localization of function, in the millimeter range. It is however less efficient in the temporal domain, since the BOLD response is rather a sluggish response, being recorded in the seconds range, while neuronal 472

events happen in the microseconds range. This can be overcome. Using an EEG measures (event-related potentials, ERPs) this problem can be resolved. In a recent EEG/ERP study, Sinai and Pratt106 recorded interhemispheric interaction on a microsecond-bymicrosecond basis when subjects were exposed to auditory stimuli in a lexical decision task. By using a special data analysis procedure (LORETA), the authors mapped the regional localization across the cortex of current densities in the ERPs in response to the stimuli, and compared the time course of the ERPs across the hemispheres. The results showed that hemispheric dominance is time dependent and that it alternates between the hemispheres across time during the execution of a cognitive task. Interestingly, Sinai and Pratt97 also found that the time course for the left and right hemispheres differed when the subjects were





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FIGURE 8 | fMRI brain imaging data to presentations of isolated phoneme consonant sounds, isolated from a CV syllable. Note the prominent left-sided asymmetry with significant activation seen only on the left side in the peri-Sylvian region in the posterior temporal lobe. (Reprinted with permission from Ref 9. Copyright 2005 Elsevier Publishing.)

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processing a language task. Thus, the time course of hemispheric dominance is a modulating factor, with dynamic effects on the right and left hemispheres, and also between left and right homologous regions, and with different time courses for different stimulus classes (see Ref 97 for further details).

A REDUCTIONIST VIEW: WHAT IS THE UNIT OF HEMISPHERIC ASYMMETRY To further explore the left hemisphere specialization for phonological decoding, Rimol et al.9 asked the question if asymmetry for phonological processing in the dichotic listening situation would also be present at the lowest level of language processing which would be the phoneme level (phonemes are the smallest meaningful auditory units in the language). Rimol et al.9 extracted the consonant segment of the CV-syllable stimuli typically used in dichotic listening studies (a CV syllable is the next to the lowest level of phonological organization, containing two phonemes, a consonant and a vowel). With this manipulation, a subsyllabic stimulus basically containing only the isolated phoneme-structure of the speech signal was extracted. The subsyllabic phoneme stimuli were presented to adult subjects while they were lying in the MR scanner, measuring changes in blood flow regionally while the subjects were processing the stimuli. The paradigm and stimulus setup was otherwise similar to the setup in the traditional dichotic listening task.107 The stimuli were Vo lu me 2, September/Octo ber 2011

thus reduced from the six CV syllables that were formed from the six stop consonants and the vowel /a/, to the three two-consonant segments /p/, /t/, /k/, and used in Hugdahl et al.’s94 study. The full CV syllables /pa/, /ta/, /ka/ were used as control stimuli for the consonant-segment stimuli. The results are shown in Figure 8, which illustrates an even more marked left hemisphere lateralization for the subsyllabic phoneme structure of the CV-syllable stimulus than the lateralization observed for the full CV syllables. The presence of right hemisphere activation to the complete syllable compared to the isolated consonant-segment stimulus as shown in Figure 8 may be a similar effect as the one seen in the Hugdahl et al.’s94 study to the music instrument stimuli. It is possible that the right hemisphere activation in both studies was caused by the melodic (and prosodic) nature of the stimulus, i.e., in the case of the CV syllables it may be the prosodic nature of the vowel segment that caused right hemisphere activation. The most important finding was, however, that the structural asymmetry seen in the PT and adjacent areas in the left hemisphere has a functional correspondence that is tuned to the most elementary feature of a speech stimulus, namely the isolated phoneme structure of the signal. The results of the Rimol et al.’s9 study may point to a unique aspect of left hemisphere language specialization, namely its reductionist nature, i.e., extending down to the most fundamental properties of a speech stimulus. This would also make sense


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from an evolutionary perspective; evolution is a strong modifier of both brain structure and function. Thus, it is unlikely that the most conspicuous anatomical feature of the brain, the longitudinal fissure that literally splits the brain into two hemispheres, would have evolved for a highly complex cognitive feature that in it self contains several more basic elements. A more parsimonious argument is that hemispheric asymmetry evolved for the basic element(s) in the first place, with neuronal tuning to the specific features of a phoneme-like structured stimulus as the core element of lateralization involving the posterior parts of the left temporal lobe, including the PT.

SUMMARY AND SUGGESTIONS In this paper I have advanced a view of hemispheric asymmetry as one of the fundamental principles of

neuronal organization in the nervous system, and as such subserving fundamental cognitive functions linked to the development of speech and the ability for efficient orientation in the environment. I moreover advance the view that hemispheric asymmetry was advantageous to the evolving human mind for allowing efficient symbolic communication through speech and the orientation in space. The evolution of the two hemispheres of the brain is therefore fundamentally connected to the evolution of man and the later development of higher cognitive functions. The introduction of functional neuroimaging methods, like fMRI, and new ways of quantifying anatomical information (VBM, DTI) have further advanced our understanding of the functioning of the cerebral hemispheres, also providing new evidence for how anatomical differences between the hemispheres may be underlying functional asymmetry.

ACKNOWLEDGEMENTS The present research was financially supported by grants to Kenneth Hugdahl from the Research Council of Norway (RCN) and the Health Authority for western Norway (Helse-Vest). Portions of this article were adapted with permission from Hugdahl and Westerhausen108 (Copyright 2009 Hogrefe Publishing).

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FURTHER READING Friston describes and discusses experimental designs and analysis of functional brain imaging data with emphasis on asymmetry and lateralization in brain architecture, taking examples from PET and fMRI studies. It is suggested that an important issue in neuroimaging studies of laterality is the relationship between conceptual models of brain organization and neurophysiology evidence, and that this has consequences in terms of statistical models and data analysis. Hirnstein, ¨ urk ¨ un ¨ in their article argue that cerebral lateralization is a fundamental principle of brain organization Hausmann, and Gunt across species, and possible pathways for its evolutionary origin, arguing that this should be advantageous for parallel processing. Hugdahl and Westerhausen in their article argue for the primacy of language and the evolution of language as a determining factor for the division of labor between the hemispheres as a means of avoiding message duplicates and slowing of information processing. The new book by Hugdahl and Westerhausen is the third in the MIT Press series on brain asymmetry (previous books are R.J. Davidson & K. Hugdahl (Eds) Brain Asymmetry, 1995, and K. Hugdahl & R.J. Davidson, The Asymmetrical Brain, 2003). In the third volume, the ambition has been to provide a comprehensive update on research on hemispheric asymmetry and laterality during the last 10 years, with focus on recent developments in neuroimaging, genetics, and new applications in cognitive psychology, neuropsychology, and cognitive neuroscience. Toga and Thompson in their article give an excellent overview of structural asymmetries in the brain through the use of MR morphometry techniques. The authors review the literature on brain asymmetry, focusing on structural (anatomical) differences, and show how an understanding of underlying structural asymmetries may cast new light on our understanding of functional asymmetry and for cognitive factors that modulate asymmetry patterns.



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Friston K. Characterizing brain asymmetries with brain mapping. In: Hugdahl K, Davidson RJ, eds. The Asymmetrical Brain, Cambridge, MA: MIT Press; 2003. ¨ urk ¨ un ¨ O. The evolutionary origins of functional cerebral asymmetries in humans: does Hirnstein M, Hausmann M, Gunt lateralization enhance parallel processing? Behav Brain Res 2008, 187:297–303. Hugdahl K. Lateralization of cognitive processes in the brain. Acta Psychol 2000, 105:211–235. Hugdahl K, Thomsen T, Ersland L. Sex differences in visuo-spatial processing: an fMRI-study of mental rotation. Neuropsychologia 2006, 44:1575–1583. Hugdahl K, Westerhausen R, eds. The Two Halves of the Brain—Information Processing in the Cerebral Hemispheres, Cambridge, MA: MIT Press; 2010. Toga AW, Thompson PM. Mapping brain asymmetry. Nat Rev Neurosci 2003, 4:37–48.

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Putting Hemispheric Asymmetry to Use in Understanding Brain Diseases.

Dichotic listening studies of hemispheric asymmetry in brain damaged patients.

Hemispheric asymmetry of electroencephalography-based functional brain networks.

Pharmacologic implications of hemispheric asymmetry.

Self-regulation of hemispheric asymmetry.

Letter: Hemispheric asymmetry and musical performance.

Hemispheric Asymmetry of Human Brain Anatomical Network Revealed by Diffusion Tensor Tractography.

Hemispheric asymmetry measured by texture analysis and diffusion tensor imaging in two multiple sclerosis subtypes.

Preschoolers' mental rotation of letters: Sex differences in hemispheric asymmetry.

Hemispheric Asymmetry of Development Due to Drug Exposure.

Hemispheric asymmetry, cardiac response, and performance in elite archers.

Relative Spatial Frequency Processing Drives Hemispheric Asymmetry in Conscious Awareness.

Hemispheric asymmetry in reaction time to color stimuli.

Reversed hemispheric asymmetry of imipramine binding in suicide victims.

Matching asymmetry of tremor with asymmetry of postmortem cerebellar hemispheric changes in essential tremor.

Hemispheric asymmetry non-linear analysis of EEG during emotional responses from idiopathic Parkinson's disease patients.

The Abnormality of Topological Asymmetry between Hemispheric Brain White Matter Networks in Alzheimer's Disease and Mild Cognitive Impairment.

Assessment of inter-hemispheric imbalance using imaging and noninvasive brain stimulation in patients with chronic stroke.

Contributions from different model organisms to brain research: Introduction.

Hemispheric Asymmetry of Endogenous Neural Oscillations in Young Children: Implications for Hearing Speech In Noise.

Hemispheric asymmetry of emotion words in a non-native mind: a divided visual field study.

The role of regional heterogeneity in age-related differences in functional hemispheric asymmetry: an fMRI study.

Functional cortical connectivity analysis of mental fatigue unmasks hemispheric asymmetry and changes in small-world networks.

Hemispheric functional asymmetry in visual discrimination between univariate stimuli: an analysis of sensitivity and response criterion.