Contribution of Callosal Connections to the Interhemispheric Integration of Visuomotor and Cognitive Processes

REVIEW

Contribution of Callosal Connections to the InterhemisphericIntegration of Visuomotor and Cognitive Processes

Tilman Schulte & Eva M. Müller-Oehring

Received: 6 February 2010 /Accepted: 6 April 2010 /Published online: 17 April 2010# Springer Science+Business Media, LLC 2010

Abstract In recent years, cognitive neuroscience has beenconcerned with the role of the corpus callosum andinterhemispheric communication for lower-level processesand higher-order cognitive functions. There is empiricalevidence that not only callosal disconnection but also subtledegradation of the corpus callosum can influence thetransfer of information and integration between the hemi-spheres. The reviewed studies on patients with callosaldegradation with and without disconnection indicate adissociation of callosal functions: while anterior callosalregions were associated with interhemispheric inhibition insituations of semantic (Stroop) and visuospatial (hierarchicalletters) competition, posterior callosal areas were associatedwith interhemispheric facilitation from redundant informationat visuomotor and cognitive levels. Together, the reviewedresearch on selective cognitive functions provides evidencethat the corpus callosum contributes to the integration ofperception and action within a subcortico-cortical networkpromoting a unified experience of the way we perceive thevisual world and prepare our actions.

Keywords Corpus callosum . Crossed-uncrossed difference(CUD) . Redundant targets effect (RTE) . Functionallateralization . Stroop . Hierarchical perception . Attention .

Neuroimaging

The pioneering work of Norman Geschwind (1965)introduced the idea that deficits in language, learning,emotion and action are manifestations of a ‘disconnectionsyndrome’ that result not only from cortical lesions butfrom white matter lesions disrupting the connectivitybetween sensory and association cortices. Geschwind’smodel included both connections between brain regionsand the functional specialization of association cortices(Catani and ffytche 2005). The concept of a distributedneural circuitry has inspired investigations into how brainconnectivity enables hemispheric specialization for mentalprocesses, which range from basic perception (Nassi andCallaway 2009) to higher cognitive functions and con-sciousness (Galaburda and Geschwind 1980; Zaidel andIacoboni 2003). A common theme of these investigations ishow perceptions, thoughts and actions emerge from theintegration of sensory, cognitive and motor inputs receivedor processed in separate cerebral hemispheres.

Pathways Subserving Intra-and InterhemisphericCommunication

Cortico-cortical communication within and between hemi-spheres relies on a widespread white matter network thatalso connects to subcortical gray matter. The white mattertracts can be divided in association pathways that areintrahemispheric fibers connecting cortices of the frontal,parietal, temporal and occipital lobes and commissuralpathways that are interhemispheric fibers connecting thecortical areas of both hemispheres (Aralasmak et al. 2006).Geschwind’s disconnection hypothesis assumed that notcortical damage alone but cortical disconnection by whitematter fiber pathway disruption makes substantial contri-

T. Schulte (*) : E. M. Müller-OehringSRI International, Neuroscience Program,333 Ravenswood Avenue,Menlo Park, CA 94025-3493, USAe-mail: [email protected]

E. M. Müller-OehringDepartment of Psychiatry & Behavioral Sciences,Stanford University School of Medicine,Stanford, CA 94305, USA

Neuropsychol Rev (2010) 20:174–190DOI 10.1007/s11065-010-9130-1

butions to functional deficits in neurological and psychiatricdisorders.

Intrahemispheric Communication Several cortico-corticalassociation and cortico-subcortical projection pathwaysensure communication within each hemisphere. Superiorlongitudinal fasciculus (SLF) fibers, for example, connecttemporo-parieto-occipital regions with the frontal lobe.While left-hemispheric SLF fibers have been related tospeech (Duffau et al. 2002) and language comprehension(Tanabe et al. 1987), right-hemispheric fibers have beenrelated to the spatial-attention network (Doricchi andTomaiuolo 2003). The inferior longitudinal fasciculi con-nect temporal to occipital lobes in each hemisphere andhave been associated with higher-order visual functionssuch as object recognition (left-lateralized; Salvan et al.2004), face recognition, and visually evoked emotions(bilateral or right-lateralized; Bauer 1982; Habib 1986).The inferior fronto-occipital fasciculi connect visual asso-ciation areas with the frontal eye fields, and there is someevidence that they mediate simultaneous perception intra-hemipherically needed for selecting visual information incrowded scenes (right-lateralized or bilateral; Battelli et al.2003; Rizzo and Vecera 2002). The cingulum is a largefiber bundle of the limbic system connecting cingulate andhippocampal gyri with amygdala, nucleus accumbens,thalamus and frontal cortices, areas involved in emotion,reward and executive control. Thus, each hemisphere hasextensive cortico-cortical and cortico-subcortical connec-tions (Mori et al. 2002). The myriad information trans-ferred via these fiber tracts and processed in eachhemisphere is also available for integration between thetwo hemispheres via commissural pathways to form aunified perception.

Interhemispheric Communication The major commissuralpathway is the corpus callosum (CC), a thick band of white

matter fibers consisting of more than 200 million axonsconnecting the right and left cerebral hemispheres of thebrain and playing an important role in interhemispherictransfer of information (Aboitiz et al. 1992; Banich 1995;Banich and Shenker 1994; Innocenti 1986; Schmahmannand Pandya 2006). Although callosal fibers mostly projectto homotopic regions of the hemispheres (e.g., parietal lobeto parietal lobe, etc.) along an anterior-posterior gradient(McCulloch and Garol 1941; Putnam et al. 2008), somecallosal fibers also project to heterotopic regions (e.g.,parietal to frontal lobe, etc.) (Clarke and Zaidel 1994; Cook1984; Rakic and Yakovlev 1968). The CC has nomacroscopic anatomical landmarks that delimit anatomicaland functionally distinct regions (Hofer and Frahm 2006).It has been geometrically divided into three regions(Duara et al. 1991; Sullivan et al. 2002) (1) an anteriorpart (genu+rostrum) that connects frontal and premotorregions of the two hemispheres, (2) a middle part (body)that interconnects motor, somatosensory and parietal areas,and (3) a posterior part of the corpus callosum (splenium)that interconnects temporal and occipital cortices (Fig. 1)(Park et al. 2008; Putnam et al. 2009; Wahl et al. 2007) butthere have been numerous geometric models for differentiatingsections of the CC (e.g., Ryberg et al. 2007; Witelson 1989;see also Chanraud et al., in this issue). Although ourunderstanding of the organization of CC white matterpathways has considerably increased (Poupon et al. 2001;Putnam et al. 2009) in the advent of recent development ofdiffusion tensor imaging (DTI) techniques (Baird and Warach1998; Le Bihan et al. 2001; Le Bihan 2003; Moseley et al.1990; Pfefferbaum et al. 2003; Sullivan and Pfefferbaum2003; Wahl et al. 2007; Westerhausen et al. 2009) relativelylittle is still known about the relation between callosal regionsand interhemispheric integration of sensory and cognitiveinformation (Bloom and Hynd 2005).

In humans, primary visual, auditory and motor cortexfunctions are highly lateralized with the left cerebral

Sagittal Axial Coronal

Fig. 1 Sagittal, axial andcoronal section of the humanbrain (The SRI24 multichannelatlas of normal adult humanbrain structure; Rohlfing et al.2010) illustrating the anterior(genu), middle (body) andposterior (splenium) sectors ofcorpus callosum (CC). Otherillustrated interhemisphericconnections are the anteriorcommissure (AC) and thesuperior colliculi (SC)

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hemisphere processing right-sided sensory input and motoroutput and the right cerebral hemisphere processing left-sided sensory input and motor output. Input from bothhemispheres needs to be integrated and selected for furtherhigher-order cognitive processing and for a unified motorresponse (Stephan et al. 2003). From an evolutionarystandpoint the CC is assumed to play an integral role inthe development of higher cognitive processes and hemi-spheric specialization (Doron and Gazzaniga 2008). Duringhuman evolution, brain and CC size increased considerably.Some studies suggest that the communication speedbetween the two hemispheres is faster with increased brainsize (Caminiti et al. 2009; Innocenti 1995) and that largercallosal area indicate faster interhemispheric communica-tion (Jancke and Steinmetz 1994; Paul et al. 2007), whileothers suggest a progressive slowing of interhemisphericcommunication in larger brains (Ringo et al. 1994).Interestingly, recent animal studies have suggested thatmore lateralized brains are better to act directly on manysources of information at the same time (Magat and Brown2009). For example, chimpanzees that use one hand tofish termites out of their mounds are more efficientthan chimpanzees that are ambidextrous (Marchant andMcGrew 1996).

Although the CC is the largest interhemispheric com-missure, other commissural pathways include the anterior,hippocampal, posterior, habenuar, and tectal commissuresand also the two sides of the brainstem reticular formationhave extensive connections (Aralasmak et al. 2006). Thesuperior colliculus and the tectal commissure are thought toplay a role in visual transfer and to maintain interhemispherictransfer of basic visual information in patients with callosalagenesis, callosotomy and commissurotomy (Tardif andClarke 2002). Nevertheless, studies in acallosal and split-brain patients state quite clearly that absence or loss of CCintegrity contributes to impairment in sensory and cognitiveintegration (Fabri et al. 2001; Yamauchi et al. 1997). In fact,many years of research have demonstrated a relationshipbetween callosal connectivity and prolonged interhemispherictransfer time in split-brain patients and in acallosal patients(Corballis 1998; Iacoboni et al. 2000; Marzi et al. 1991;Mooshagian et al. 2009; Paul et al. 2007; Reuter-Lorenzet al. 1995; Roser and Corballis 2002). Less radicaldisruption of callosal fiber integrity such as seen in patientswith multiple sclerosis (Warlop et al. 2008), schizophrenia(Schrift et al. 1986; Woodruff et al. 1997), alcoholism(Hutner and Oscar-Berman 1996; Schulte et al. 2004,2005, 2008), autism (Keary et al. 2009), and even innormal aging (Jeeves and Moes 1996; Schulte et al. 2005)has been also associated with prolonged interhemispherictransfer time (IHTT).

Callosal Function in Interhemispheric Communication

Different callosal functions have been proposed for inter-hemispheric communication. For example, the hemisphericinsulation view states that the CC acts as a shield to reduceinterference and to prevent potentially harmful intrusionsfrom the opposite hemisphere (Kinsbourne and Hicks 1978;Liederman and Meehan 1986), whereas the callosalinhibition view assumes that stimulus-driven activity inone hemisphere suppresses activity in the other, thereby, forinstance, causing a shift in attention to the contralateral sideof the more activated hemisphere (Chiarello and Maxfield1996). Callosal reciprocal inhibition may further equilibrateactivation and prevent attention from being skewed to thecontralateral side when one hemisphere is disproportion-ately active (Kinsbourne 2003). Interhemispheric coopera-tion between the hemispheres has been assumed to be moreadvantageous than within hemispheric processing in situa-tions of high processing demand (Banich and Belger 1990).Interhemispheric sharing of information and the need forinhibiton or isolation from each other are not mutuallyexclusive and may depend on the kind of informationprocessed. It is, for example, well established that the twohemispheres have different functions, with a left-hemisphericsuperiority in processing speech and language and a right-hemispheric superiority for certain visuospatial functions.Thus, when one hemisphere is superior to the other inprocessing specific information, intrahemispheric processingmay be more advantageous, and callosal isolation orinhibition would increase processing efficiency and perfor-mance. By contrast, when both hemispheres are qualified toprocess the same information, sharing of hemisphericresources may be more advantageous and require callosalinterhemispheric cooperation (Bloom and Hynd 2005).

Interhemispheric Communication for Visuomotorand Cognitive Functions

First, we will provide an overview of the role of the CC inlower-level processes and interhemispheric visuomotorintegration as documented in recent behavioral and neuro-imaging studies on the crossed-uncrossed difference, anestimation of interhemispheric transfer time (Poffenberger1912), and on redundancy gain, a measure of visuomotorintegration (Miller 1991; Mordkoff and Yantis 1991, 1993).Secondly, we will explore the contribution of the CC tohigher-order cognitive functions, such as attention andexecutive control, and to integrating the left hemisphere,specialized for processing local details and language, andright hemisphere, specialized for processing holistic, global

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forms and spatial attention functions (Aziz-Zadeh et al.2006; Gazzaniga 2000; Gazzaniga 2005; Hugdahl andDavidson 2003).

The Role of the CC for the Integration of Lower-LevelFunctions

Interhemispheric Transfer Time and the Corpus CallosumApproaches describing and analyzing interhemisphericintegration of information in humans include simplereaction time (RT) tasks in which targets are presented inthe same (uncrossed) or opposite (crossed) visual field inrelation to the responding hand (Poffenberger 1912; Zaideland Iacoboni 2003). The difference between crossedand uncrossed reaction times relative to the respondinghand (Crossed-Uncrossed Difference, CUD; crossed: lefthemifield/right hand and right hemifield/left hand;uncrossed: left hemifield/left hand, right hemifield/righthand) provides an index of interhemispheric transfer time(IHTT), because the uncrossed response can be processedwithin the same hemisphere, whereas crossed responsesrequire transfer of visuomotor information between hemi-spheres via the CC (Corballis 1998, 2002; Iacoboni andZaidel 1995, 2004; Mooshagian et al. 2008; Pollmann andZaidel 1998; Tettamanti et al. 2002).

In normal subjects the CUD is approximately 4–6 ms(Marzi et al. 1991), and shorter in younger than older adults(Schulte et al. 2004; Reuter-Lorenz and Stanczak 2000).Hanajima et al. (2001) found that muscle responses totranscranial stimulation over the left-hand motor cortex canbe facilitated when transcranial stimulation has beenapplied 4–5 ms earlier over the right-hand motor cortex,about the same time as the CUD value estimated frombehavioral studies in normal subjects. In acallosal andcommissurotomized patients the CUD is prolonged (∼30–70 ms) because of longer reaction times to lateralizedstimuli in the crossed compared to the uncrossed conditionowing to the indirect route required for interhemispherictransfer (e.g., Berlucchi et al. 1971; Berlucchi et al. 1995;Clarke and Zaidel 1989; Forster and Corballis 1998, 2000).

There is an ongoing debate whether the CUD is basedsolely on the anatomy of callosal fibers or whether theCUD may also be mediated by attentional components(Mooshagian et al. 2008). Support for an anatomicalinterpretation of the CUD comes from DTI studies. DTIyields estimates of fractional anisotropy (FA) that indexeswhite matter structural integrity and measures the orienta-tional displacement and distribution of water molecules invivo across tissue components (Pierpaoli and Basser 1996).FA is typically higher in fibers with a homogeneous orlinear structure than in tissue with an inhomogenousstructure, such as areas with pathology (Lansberg et al.

2001; Neumann-Haefelin et al. 2000) or crossing fibers(Pfefferbaum and Sullivan 2003; Virta et al. 1999). DTIstudies have revealed correlations between subtle variationsin regional white matter callosal microstructure andbehavioral measures of IHTT and cognitive ability (Muetzelet al. 2008; Schulte et al. 2005; Sullivan et al. 2010). Inadolescence (9–23 years), for example, age-relatedincreases in callosal FA were associated with betterbimanual coordination using an alternating finger-tappingtask (Muetzel et al. 2008), and in adults (20–78 years), age-related white matter degradation correlated with poorermotor and cognitive performance (Sullivan et al. 2010). Innormal aging, Schulte et al. (2005) found that low FA incallosal genu and splenium correlated with longer IHTTmeasured with the CUD (Poffenberger paradigm, 1912).By contrast, Westerhausen et al. (2006) did not find acorrelation between callosal diffusion parameters and theCUD (2.5 ms) but did find negative correlations betweenmean diffusion and IHTT, derived from the P100 event-related potential. Methodological variables such as stimulusparameters (eccentricity and luminance, fixation control,forehead-chin rest) (Schiefer et al. 2001), calculation ofthe CUD using median or mean reaction times (RT)(Braun et al. 1995), and a reduced variance by choosing ahomogenous sample of young male healthy collegestudents (Westerhausen et al. 2006) may have contributedto the relative insensitivity of behavioral CUD measures(Bashore 1981).

There is also evidence that attention influences CUDmeasures. In a functional magnetic resonance imaging(fMRI) study, Weber et al. (2005) tested healthy right-handed volunteers with a modified Poffenberger paradigmin which the attentional focus was implicitly directedtoward the contra-or ipsilateral hemifield relative to theresponding hand. They found that crossed relative touncrossed trials (CUD) activated anterior callosal area, butwhen attentionally manipulated, activated superior colliculiand right superior parietal cortex, a region typicallyassociated with attentional shifts. This is consistent withfindings of Iacoboni and Zaidel (2004) suggesting thatshifts in spatial attention (Corbetta et al. 1995) can criticallyinfluence sensory-motor integration (Creem-Regehr 2009).Activations of premotor and parietal cortex regionsobserved with fMRI also map to fibers linking throughthe mid-body and anterior regions of the CC (Iacoboni andZaidel 2004; Schulte et al. 2005). Recently, Mooshagianand colleagues examined the influence of spatial attentionalshifts on CUD in patients with agenesis of the CC andcomplete commissurotomy (2009) and in healthy subjects(2008) by alternating between natural (arms uncrossed) andunnatural arm positions (arms crossed). The CUD wassmaller with arms crossed (unnatural arms position) thanuncrossed (natural arms position) in patients as well as


normal controls indicating that the relative arm positionis sufficient to modulate the CUD even in the absence ofthe CC.

To summarize, the CUD indexes the time required forinformation to cross the CC (Berlucchi et al. 1995; Fendrichet al. 2004), but there is also evidence that the CUD canbe modulated by spatial attention (Braun et al. 1995;Mooshagian et al. 2008). Other possible factors thatinfluence the CUD are age (Jeeves and Moes 1996; Schulteet al. 2004; Reuter-Lorenz and Stanczak 2000) and sexdifferences in callosal structure and size (Luders et al. 2003).In a recent event related potential (ERP) experiment, Moeset al. (2007) revealed shorter and more symmetrical IHTTfor women than men. It appears that IHTT betweenhemispheres is faster from right-to-left than from left-to-right (Barnett and Corballis 2005; Iwabuchi and Kirk 2009).The reduced asymmetry in women is mainly due to shorterleft-to-right IHTT in women than men. Different assump-tions have been made to explain this asymmetry in IHTTsuch as a smaller average size in the right occipital loberesulting in fewer callosal fibers projecting from left-to-rightposterior areas (Saron and Davidson 1989), faster axonalconduction in the right hemisphere relative to the left(Barnett and Corballis 2005), or the degree of hemisphericspecialization as suggested by a reversal of asymmetrictransfer times for verbal and non-verbal stimuli (Nowickaet al. 1996; Rugg and Beaumont 1978). Alternatively,differences in the distribution of gray and white matter inthe two cerebral hemispheres have been proposed to reflectneuronal organization promoting inter-or intrahemisphericprocessing with more gray matter relative to white matter inthe left hemisphere than in the right, particularly in thefrontal regions, emphasizing parallel intrahemispheric pro-cessing rather than interhemispheric transfer (Gur et al.1980). Current volumetric magnetic resonance imaging(Pujol et al. 2002) and DTI (Hagmann et al. 2003; Krauset al. 2007) protocols have reported left–right asymmetries ofthe superior longitudinal tract, the upper cerebellar peduncleand in frontal and temporal white matter supporting theassumption that anatomical differences between both hemi-spheres and the proportion of gray and white matter mayunderlie functional asymmetry.

Parallel Processing, Redundancy Gain and the CorpusCallosum To explore our visual environment, we integratevisual information from each visual hemifield as it reachesthe contralateral cerebral hemisphere. Because of theanatomical arrangement of the human visual system thatprojects visual inputs from each visual hemifield to thecontralateral visual cortex, the independent contributionsfrom each hemisphere and the role of the corpus callosumfor the integration of parallel visuomotor processes can bereadily assessed by comparing paired with single targets

presented to one or both visual hemifields. Typically,responses are faster to stimulus pairs than single stimuli, aphenomenon called the redundant targets effect (RTE), orsummation effect (Miller 1986; Mordkoff and Yantis 1991;Roser and Corballis 2003). The RTE is usually tested withbrief light flashes presented for less than 150ms to prevent eyemovements that would shift the visual field (Reuter-Lorenzet al. 1995; Miniussi et al. 1998; Iacoboni et al. 2000).

Researchers have proposed two explanations for redun-dancy gains from paired stimulation, the ‘horse race’ model(Raab 1962) and the ‘co-activation’ model (Miller 1982). Iftwo stimuli, one within each hemisphere, are processedindependently or in parallel, the faster processed stimulus‘wins the race’ (Miller and Ulrich 2003; Raab 1962).Statistically, the probability of eliciting a fast response istwice as high when two stimuli are presented simultaneouslythan when only one is presented. The probability or ‘race’model assumes that each stimulus is transmitted alongseparate channels and the response is triggered as soon as adecision is made by either one of the two channels (Mordkoffand Yantis 1991). An alternative to the ‘race’ model isrequired to explain the situation when gain from doublestimulus presentations exceeds probability (Raab 1962),i.e., an enhanced redundancy gain. Here, co-activation fromotherwise independent processing channels may occur toincrease signal strength of redundant targets and produce aspeeded response (Miller 1982).

Millers’ use of the term co-activation was theoretical andnot founded on measured brain activity. Recent studieshave associated enhanced redundancy gain (co-activationmodel) with neural correlates and implied a possible role ofthe CC (Bucur et al. 2005; Miniussi et al. 1998; Savazziand Marzi 2002; Schulte et al. 2006a; Turatto et al. 2004),in contrast to the horse race model that assumes twoindependent processing channels and does not require thecorpus callosum. For example, studies on split brainpatients and on normal subjects testing redundancy gainfor paired targets within the same visual hemifield, i.e.,intrahemispheric summation, and in both hemifields, i.e.,interhemispheric summation, report larger redundancy gainsfor paired bilateral than unilateral stimulation (Iacoboni et al.2000; Marks and Hellige 2003; Ouimet et al. 2009;Pollmann and Zaidel 1998; Reuter-Lorenz et al. 1995;Schulte et al. 2006a) indicating that interhemisphericcommunication may mediate neural co-activation. However,split-brain and acallosal patients typically show abnormallyenhanced bilateral RTEs compared to healthy adults, whichimplies that other than callosal commissures can mediateinterhemispheric processing advantages (Aglioti et al. 1996;Corballis 1998; Corballis et al. 2003; Iacoboni et al. 2000;Reuter-Lorenz et al. 1995; Roser and Corballis 2002, 2003).It has been argued that healthy individual may not benefit asmuch from a bilateral presentation as do the split-brain


individuals because an intact corpus callosum assures fasttransfer of information between hemispheres even when onlyone hemisphere is stimulated directly by visual input, i.e.,when a single lateralized stimulus is presented.

But how can enhanced RTEs in the split-brain dependupon convergence of information from separated hemi-spheres when at the same time prolonged CUDs in split-brain patients reflect slow subcortical transmission? Toexplicate this paradox in the split-brain, Reuter-Lorenz etal. (1995) proposed in their “and-or model” that the RTE isbased on response competition between the cerebral hemi-spheres that depends on callosal connectivity. According tothis model, co-activation occurs at a response selectionstage (see also Miller 2004; Roser and Corballis 2003), andacts as an ‘and’ gate that requires input from bothhemispheres, while prolonged CUDs in split-brain patientsare due to the use of relatively inefficient ipsilateralpathways in making crossed responses. Corballis et al.(2002) assumed that summation is due to cortical projectionto a subcortical arousal system that is normally inhibitedby the corpus callosum, while in the split-brain patient,interhemispheric inhibition is released, resulting in aparadoxically enhanced redundant targets effect.

Even though the CC is the largest commissure at thecortical level, there are other pathways connecting thehemispheres: the anterior and posterior commissures, andsubcortical projections through the hippocampal, habenular,and intercollicular brain systems (Bayard et al. 2004).Activation of the superior colliculi, part of the retino-tectalpathway within the visual brain system, has been associatedwith the initiation of fast responses (e.g., eye movements:Klier et al. 2003; arm-reaching movements: Dean et al.1989; and even shifts in attention that do not involve anyovert movements: Ignashchenkova et al. 2004). Iacoboni etal. (2000) proposed that the superior colliculi and theposterior callosal area connecting visual extrastriate areasare the key structures for interhemispheric neural co-activation explaining visuomotor integration betweenhemispheres: Activity in the extrastriate cortex followingvisual input feeds into the superior colliculi, which thenfeeds back to extrastriate cortices. In split-brain patientswith long interhemispheric transfer times (IHTT) asmeasured with the CUD, feedback to the superior colliculiwould be asynchronous and sum up over time to be largerthan in normal subjects with short IHTT and synchronoussuperior colliculus input. The larger superior colliculusactivation would feed a stronger signal back to theextrastriate cortices, which in turn send stronger activationto the premotor cortex, speeding the response. Consistentwith his model, Iacoboni et al. (2000) found enhancedRTEs in split-brain patients with long CUDs (> 15 ms) butnot in patients with short CUDs (< 15 ms). Furtherevidence for an involvement of subcortical structures, such

as the superior colliculus, or cortico-subcortical interactions(Roser and Corballis 2003) comes from split-brain studies(Corballis 1998; Savazzi and Marzi 2004) demonstratingreduced RTEs with equiluminant stimuli that are invisibleto the superior colliculi and thus restrict processing tocortical pathways of the retino-geniculate parvocellularsystem (Livingstone and Hubel 1987). However, despiteconverging evidence for a perceptual explanation for theRTE (Corballis et al. 2003; Iacoboni et al. 2000; Miniussiet al. 1998; Murray et al. 2001; Schulte et al. 2006a),others argue that there could also be a premotor explana-tion (Diederich and Colonius 1987; Giray and Ulrich1993; Iacoboni and Zaidel 2003; Ouimet et al. 2009).

In healthy subjects, considerable inter-subject variabilityhas been observed: approximately half showing enhancedRTEs that violate the ‘race’ model while half do not(Corballis 2002; Schulte et al. 2006a). This normalvariability in RTE suggests involvement of different neuralloci (extrastriate, premotor or frontal cortical areas) depend-ing on strategy selection, task demands, and stimuluscharacteristics. In an fMRI study comparing normalindividuals with small and enhanced RTEs, we foundevidence for both perceptual and premotor/decisional locifor the RTE. Whereas all individuals showed bilateralactivation of extrastriate cortices to paired in contrast tosummed single stimulus conditions, individuals with smallRTEs activated frontal and premotor areas more than thosewith large RTEs (Schulte et al. 2006a) (Fig. 2).

Our analysis was between individuals, whereas that ofMooshagian et al. (2008) compared activation between fast‘co-activation’ trials and slower ‘not co-activation’ trialswithin the same healthy subjects. They found righttemporo-parietal junction activation for ‘co-activation’trials, specifically in the angular gyrus. This finding is ofparticular interest because the temporo-parietal junction hasbeen implicated in spatial attention and, when damaged, inthe occurrence of visuo-spatial neglect (Lux et al. 2006;Mort et al. 2003; Müller-Oehring et al. 2007, 2009a;Shirani et al. 2009). A phenomenon closely associated withvisuo-spatial neglect is ‘extinction to paired simultaneousstimulation,’ when patients see single visual stimuli, but failto report contralesional stimuli when an ipsilesionalstimulus is presented at the same time. In this case, thecontralesional stimulus is extinguished from awareness(Meister et al. 2006; Schendel and Robertson 2002).

In patients with unilateral left extinction after righttemporo-parietal damage, enhanced redundancy gains havebeen observed even when one stimulus in a pair waspresented to the left hemifield and therefore was notperceived (Marzi et al. 1996; Müller-Oehring et al. 2009a,b, 2010). We recently found that visual extinction of left-sided stimuli, but not RTE, was correlated with prolongedCUDs in neglect patients with right temporo-parietal


lesions (Müller-Oehring et al. 2009a). Thus, despiteextinction of left-sided stimuli in paired trials, neglectpatients showed unconscious parallel processing of con-tralesional stimuli (RTE). This was the case even whencontralesional visual field input was lacking, as evidencedby additional visual field defects in these patients, ordelayed, as evidenced by prolonged CUDs (Müller-Oehringet al. 2009a). Hence, under competitive bilateral stimulusconditions, the delayed contralesional visual field inputmay not be detected by the intact left hemisphere, whichpresumably mediates the task given the impairment of theright hemisphere, leading to extinction of this stimulus fromthe patient’s awareness. This is supported by surprisingresults from Marzi et al. (1997), who recorded event-relatedpotentials (ERPs) in unilateral brain damaged patients, andfound that the ispilesional (commissural) response waslacking or reduced in patients with a right hemispherelesion but not in patients with a left hemisphere lesion.They speculated that this laterality difference might berelated to a left–right asymmetry in callosal projectionswith callosally projecting neurons being more numerous inthe right than the left hemisphere (Marzi et al. 1991).Consequently, they argued, it would be reasonable toassume that unilateral right-hemispheric lesions will cause

a greater loss of callosal fibers than similar left-hemisphericlesions. That RTEs after right temporo-parietal damagewere not abolished due to reduced or delayed visual inputfrom the contralesional visual hemifield (Marzi et al. 1997;Müller-Oehring et al. 2009a) provides behavioral evidencefor a post-perceptual stage of neural co-activation. It furthersupports the assumption that subcortical interhemisphericpathways play a role in redundancy gain and that corticalinterhemispheric pathways mediate visual awareness(Marzi et al. 1997; Silvanto et al. 2009).

In addition, current research indicates that these neuralco-activation systems of bilateral sensorimotor integration(as measured by redundancy gain) further depend oncognitive processes engaged by task characteristics (Reinholzand Pollmann 2007), and individual differences in strategyselection (Schulte et al. 2006a). For example, usingfunctional MRI in healthy subjects, Reinholz and Pollmann(2007) studied redundancy gain for higher-level visualidentification and categorization processes using combina-tions of pictures of faces and houses presented simulta-neously to both visual hemifields. They observed fusiformface area (FFA) activation for redundant pictures of faces andparahippocampal place areas (PPAs) activation for redundantpictures of buildings suggesting involvement of task-specific

A. RTE paradigm for bilateral visual field stimulation

bilateral paired single right single left

B. RTE: Paired bilateral > single left + single right

sagittal x = 20 coronal y = -74 axial z = -3

C. Small RTE > enhanced RTE

sagittal x = 32 coronal y = -13 axial z = 60

Fig. 2 Redundant TargetsEffect (RTE): a Paradigmillustrating the contrast of inter-est: bilateral vs. unilateralstimulation. b Activation ofbilateral extrastriate areas in thepaired>single contrast (SPM2;T=4.30). c Violation of the‘race’ model predictions:activation of premotor, motorand frontal brain regions inindividuals with small RTEs(no violation) compared to thosewith enhanced RTEs (violation)(SPM2; T=4.03). Modified fromSchulte et al. (2006a)


higher-order visual object-selective areas in visuomotorintegration of redundant information.

Despite the ongoing debate over the cortical locus ofco-activation, results from split-brain research clearlydemonstrate that interhemispheric integration of simplepercepts can occur without the presence of the CC throughsubcortical transmission of information that is projected tocortical sites in both hemispheres. In the split-brain,enhanced RTEs have been interpreted as an absence ofcallosal inhibition (Corballis et al. 2002; Zaidel andIacoboni 2003). Yet, in healthy individuals, a recent studyshowed greater RTEs for equiluminant than high-contraststimuli implying cortical rather than subcortical integrationmechanisms (Schulte et al. 2004), in contrast to split-brainpatients, who typically show reduced RTEs with equilu-minant stimuli (Corballis 1998; Roser and Corballis 2002).Furthermore, callosal degradation without disconnection,e.g., in chronic alcoholics (Lim and Helpern 2002; Kubickiet al. 2003; Pfefferbaum and Sullivan 2003) has been foundto correlate with reduced RTE with equiluminant stimuli(Schulte et al. 2005). These results imply a cooperative roleof the CC and that such cooperation is reduced by subtledegradation of callosal integrity. In addition, data in healthysubjects with an intact CC showed bilateral extrastriateactivation for RTEs (Schulte et al. 2006a) (Fig. 2) andtemporo-parietal activations for enhanced RTEs (Mooshagianet al. 2008) and support an interhemispheric cooperationmodel for neural summation. Subtle degradation ofcallosal structure also occurs in healthy aging (Bartzokiset al. 2004; Bucur et al. 2005; Madden et al. 2009;Sullivan et al. 2001) and can result in disturbed bilateralintegration of visual (Müller-Oehring et al. 2007; Schulteet al. 2004, 2005), cognitive (Kennedy and Raz 2009;Zahr et al. 2009), and motor functions (Bartzokis et al.2008; Sullivan et al. 2006, 2010).

In summary, the role of the corpus callosum for theintegration of lower-level visuomotor functions is contro-versial. While split-brain research indicates that the CC actsin an inhibitory fashion within a subcortico-corticalnetwork (Corballis et al. 2002; Roser and Corballis 2003),recent research on callosal degradation without disconnec-tion suggests that the corpus callosum acts cooperatively.The review of the few studies on interhemisphericcommunication emanating from the right temporo-parietaljunction further suggests a special role of the corpuscallosum in conscious perception (Marzi et al. 1991,1997; Müller-Oehring et al. 2009a). Activation of the righttemporo-parietal junction appears to mediate co-activationfor visuomotor integration in conjunction with homologoustemporo-parietal regions in the contralateral hemisphere(Mooshagian et al. 2008) probably associated with bilateralattentional mechanisms normally equilibrated by reciprocal

callosal inhibition (Kinsbourne 1993) supporting consciousperception (Reuter-Lorenz et al. 1995).

The Role of the CC for the Integration of HigherCognitive Functions

Hemispheric specialization for higher-order cognition suchas the left-hemispheric dominance for language and right-hemispheric dominance for visuospatial attention (Damasioand Damasio 1993; Gazzaniga 2005) has been assumed tobe a consequence of interhemispheric connectivity, i.e., thelikelihood of intrahemispheric processing and hemisphericspecialization of brain functions increases with increasedtime constraints of callosal conduction delay (Hopkins andRilling 2000). Although the functions of the CC are moreassociated with transferring sensory information and visuo-motor integration (Banich 1998) recent studies highlightthe pivotal role of CC for higher-order cognitive functionssuch as identification of complex stimuli (Banich et al.2000; Schulte et al. 2006b; Skiba et al. 2000). Studyingneuropsychiatric diseases, such as alcoholism, that aremarked by subtle white matter neuropathology, particularlyof the CC (Harper and Kril 1988, 1990; Harper andMatsumoto 2005; Pfefferbaum and Sullivan 2002, 2005;Pfefferbaum et al. 2006; Tarnowska-Dziduszko et al. 1995),provides a window of opportunity to investigate the contri-bution of CC degeneration to the functional integration ofinformation across the hemispheres to perform complex tasks(Hiatt and Newman 2007).

It has been assumed that both hemispheres interactwith each other in a dynamic push-pull fashion to equalizethe direction of visuospatial attention (Kinsbourne 1977,Kinsbourne and Bruce 1987; Reuter-Lorenz et al. 1990;Corbetta et al. 2005). In this activation-orienting model it ispostulated that visuospatial attention is biased in thedirection contralateral to the more activated hemisphere(Schulte et al. 2001). Based on the assumption that dynamicinteractions between the hemispheres via the CC affectattentional processing (Banich 1998), we recently testedwhether the integrity of the CC in alcoholics predicts thefunctioning of neural systems known to underlie higher-order component processes of selective attention andconflict processing. To identify the role of hemisphericlateralization and interhemispheric transfer within thefronto-parietal attention system, we developed a lateralizedStroop paradigm (Schulte et al. 2006b). For nearly 75 years,the Stroop color-word effect has provided a rich paradigmfor parsing and manipulating processes of attention andconflict in the context of stimuli naturally compellingbecause of their semantic content (Stroop 1935; MacLeod1991). Processing words at their semantic level is involun-


tary and automatic and naturally overrides perceptual tags,such as the color of the ink of a written word that has nointrinsic value (Carter et al. 2000; MacDonald et al. 2000;Schulte et al. 2009). The Stroop effect can be conceptuallyconsidered as a left hemisphere lateralized task with greaterinterference arising from the semantic content of the word(MacLeod 1991). Because of its preferentially processingof verbal information (e.g., language, speech, and writing),the left hemisphere should be more affected than the rightby semantic competition (Luo et al. 1999). This lateralityeffect was demonstrated in a study (Weekes and Zaidel1996), which used separate color words and color patchesand found greater Stroop interference when color wordswere presented to the left than right hemisphere indepen-dent of the location of the color patch (i.e., within the samehemifield or in the opposite hemifield).

In our lateralized Stroop match-to-sample task, weanalyzed hemispheric preference for Stroop word-colorinformation by comparing reaction times to right visualfield trials (preferred left cerebral hemisphere for wordprocessing) with reaction times to left visual field trials(non-preferred right hemisphere). We found that controlsubjects and patients with chronic alcoholism differed inperformance as a function of lateralized stimulus presenta-tions and attentional processes when color cues matched ordid not match the word’s color (Schulte et al. 2006b): Formatching colors, both groups showed a right visual fieldadvantage; for nonmatching colors, however, controlsshowed a left visual field advantage, whereas alcoholicsshowed no visual field advantage. We speculated thatcontrols were more successful than alcoholics in disengag-ing their attention from the invalidly cued color to correctlyprocess the color of the Stroop stimulus in nonmatch colortrials. Subsequent disengagement and shift of attentionaway from the invalidly cued color to the correct target colorof the Stroop stimulus is associated with right-hemispherefunctions (Blumstein and Cooper 1974; Christman 2001;Hartje et al. 1985; Posner 1980) and may be responsible forthe left visual field advantage in nonmatch trials observed inhealthy controls. This left visual field advantage in nonmatchtrials was correlated with a larger callosal splenium area incontrols but not alcoholics indicating that informationpresented to the non-preferred hemisphere is transmittedvia the splenium to the hemisphere that is specialized forefficient processing. This processing route for visual hemi-field information was disrupted in alcoholics, possibly as aresult of callosal thinning.

Furthermore, our visual world can be decomposed intocomponent features and then integrated into more complexstimuli, objects and scenes—a concept originated from inves-tigations of the visual cortex (Felleman et al. 1997; Pandya andSanides 1973). Thus, whole-part perception is based on the

extraction of higher-order or global features (such as thesilhouette of a face, or street scene) and details on the locallevel (e.g., facial details like eyes and nose, or details in a streetscene like cars and traffic lights). A widely used paradigm tostudy whole-part perception is a target detection task that useshierarchical letters, where a large (global) letter is made ofsmaller (local) letters, modeling the hierarchical structure ofvisual world scenes (Fink et al. 1997; Navon 1977).

Current models of local-global perception assume thatlocal and global processes proceed in parallel, with a lefthemisphere advantage in processing local features and aright hemisphere advantage in processing the global“gestalt”, as indicated by brain lesion studies (Delis et al.1986, 1988; Lamb et al. 1989; Robertson et al. 1988, 1991;Yamaguchi et al. 2000) and neuroimaging studies in healthysubjects (Evans et al. 2000; Fink et al. 1996, 1999; Han etal. 2002; Heinze et al. 1998; Weber et al. 2000; Yamaguchiet al. 2000). Thus, the study of local-global perception maycontribute to our understanding of the role of the CC forhigher-order visual integration.

Although RT studies using lateralized hemifield presen-tations have not always shown local-global hemisphericdifferences (Blanca et al. 1994; Evert and Kmen 2003;Hübner 1997; Yovel et al. 2001), electrophysiologicalstudies using central stimulus presentations do support thishemispheric processing bias for left-local and right-globalinformation (Heinze and Münte 1993; Heinze et al. 1998;Malinowski et al. 2002; Yamaguchi et al. 2000). Together,these studies suggest that, in principle, each hemisphere canprocess local and global information; however, hemisphericprocessing advantages emerge when local and globalinformation is processed simultaneously in both hemi-spheres. The competition hypothesis (Han et al. 2002;Volberg and Hübner 2004) proposes that with centralstimulation both hemispheres have simultaneous access tothe same visual information and the specialized hemisphereassigns more resources to a given local or global targetlevel bringing hemispheric differences for local and globalfeature processing to light (Fig. 3). With lateralizedpresentations, the hemisphere contralateral to the stimulatedhemifield receives the visual information prior to theipsilateral hemisphere that receives information after inter-hemispheric transfer through the CC. The resulting timedifference in processing between hemispheres may elimi-nate interhemispheric competition, and also hemisphericdifferences associated with local and global feature pro-cessing. Results from an ERP study (Han et al. 2002) thatfound hemispheric differences only for centrally presentedhierarchical stimuli and not for lateralized stimulus pre-sentations, are consistent with the competition hypothesis.

Local-global paradigms have yielded two measures: (a)the difference in response times to local and global targets,


or precedence effect, which indexes parallel local andglobal processes assuming independent processing channelsfor local and global features, and (b) the difference inresponse times to incongruent (e.g., a global F made up oflocal Ts) and congruent stimuli (e.g., a global T made up oflocal Ts), or interference effect, which indexes local-globalinhibition in situations of competition. Several studiesindicate a global-over-local precedence effect, i.e., fasterresponses to global than local features, and global interfer-ence, i.e., slower responses when the global feature wasincongruent than when it was congruent with the localfeature (Navon 1977). However, local precedence and localinterference have also been reported (Müller-Oehring et al.2007). Which level—local or global—is processed fasterdepends on stimulus size (Kinchla and Wolfe 1979), thesize ratio between global and local forms (Kimchi andPalmer 1982), the stimulus’ location in the visual field(central or peripheral) (Kimchi 1992; Lamb and Robertson1987, 1988), and attentional selection (Broadbent 1977;Han et al. 2001; Pomerantz 1983; Robertson et al. 1993;Weissman et al. 2005; Yamaguchi et al. 2000).

Up to date, only a few studies have investigated the roleof the CC in local-global precedence and interference. In1993, Robertson et al. found that split-brain patients did notshow global interference despite normal global precedence.However, Weekes et al. (1997) repeated the experiment intwo of the same split-brain patients and found bothpreserved global precedence and global interference. Thus,in contrast to Robertson et al. (1993), their findings implythat the CC is not necessary for eliciting global interference.Rather, because each hemisphere can process local andglobal information, interference effects occur within one

hemisphere in the absence of the CC. The different resultsfrom these two studies may be due to slight differences instimulus characteristics and presentation: Robertson et al.(1993) used stimulus eccentricities of 2.7° while Weekes etal. (1997) used stimulus eccentricities of 1° for each visualhemifield. Given that there is a 1–2° stripe overlap at theretinal vertical meridian between the two visual hemifields,the smaller stimulus eccentricity and enhanced stimulus-background contrast used by Weekes et al. (1997) may havein fact sent information to the left and right visual corticesand contributed to intrahemispheric local-global competi-tion. Thus neither study provides clear evidence for callosalinvolvement in local-global interference.

Our own recent studies in normal aging (Müller-Oehringet al. 2007), alcoholism (Müller-Oehring et al. 2009b), andHIV infection (Müller-Oehring et al. 2010), all conditionswith callosal thinning or impaired integrity, provide newevidence for CC involvement in local-global processing. Inhealthy aging, for example, we found that larger localprecedence effects and greater local interference correlatedwith smaller callosal genu area (Müller-Oehring et al.2007). In addition to precedence and interference, we alsotested the relation between the CC and local-globalfacilitation. Local-global facilitation effects have beenfound previously for attentional cueing (Lamb and Yund2000; Robertson et al. 1993), and repetitive priming (Hanet al. 2003; Schatz and Erlandson 2003). We found, that inhealthy subjects posterior callosal splenium area wasassociated with local-global facilitation from repetitionpriming independent of age (Müller-Oehring et al. 2007).Converging evidence for a differentiated role of the CC inlocal-global integration comes from two recent DTI studieson chronic alcoholism (Müller-Oehring et al. 2009b) andHIV-infection (Müller-Oehring et al. 2010) indicating thatlocal-global interference is mediated by anterior callosalgenu integrity and local-global facilitation by posteriorcallosal splenium integrity.

Together, these findings suggest that the CC mediateslateralized higher-order cognition such as whole-partperceptual integration. Specifically, anterior callosal integ-rity appears to mediate local-global interference (callosalinhibition), whereas posterior callosal integrity seems tomediate local-global facilitation (callosal cooperation).Thus, component processes of visuospatial perception andattention are attributable, at least in part, to the integrity ofcallosal pathways, relevant for the integration of lateralizedbrain functions.

Conclusion

Geschwind (1965) formulated the idea that many neuro-logical disorders can be understood as ‘disconnections

Fig. 3 Model of whole-partperception: Parallel intrahemi-spheric and transcallosal inter-hemispheric processing of localand global features. With centralstimulation, the specializedhemisphere assigns moreresources to a given local orglobal target level promotinghemispheric differences withglobal features (e.g., big letter F)preferentially processed in theright cerebral hemisphere andlocal features (e.g., smallletters T) in the left hemisphere(competition hypothesis)


syndromes’ in which white matter damage degradesnetwork functions leading to specific cognitive disabilitiessuch as visuospatial neglect (Doricchi et al. 2008).Numerous studies have since contributed to our currentunderstanding of interhemispheric sharing of informationfrom early visual input to complex decision-making. Manyof these studies have focused on split-brain patients whosecerebral commissures had been surgically disconnected toimprove intractable epilepsy (for reviews see Gazzaniga2000, 2005; Lassonde and Ouimet 2010). The recentadvance of neuroimaging techniques such as DTI andfMRI have provided the opportunity to study CC functionin situations of callosal degradation without disconnection.These studies have documented a central role of the CC forinterhemispheric visuomotor integration and for higher-order cognitive functions, and have shown that even subtledegradation of the CC in neurologically impaired patientscan be related to deficits in the transfer of informationbetween the hemispheres. For visuomotor integration, split-brain research suggests that the CC exerts an inhibitoryfunction on the hemispheres and that absence of callosalinhibition results in enhanced bilateral processing advan-tages. Recent DTI and fMRI studies that tested bihemi-spheric visuomotor integration in the connected brain,however, provide evidence for callosal cooperation. Whetherthe specific role of the CC for visuomotor integration isinhibitory or cooperative remains unclear. At this point, itappears plausible to assume that callosal inhibition andcooperation are not mutually exclusive but depend oncomplex interactions within a subcortico-cortical networkthat probably equilibrate hemispheric activation according totask demands.

A further aim of this review was to focus on the role ofthe CC for higher-order lateralized cognitive functions.Together, the reviewed research provides clear indicationthat the CC contributes to the integration of perception andaction, promoting a unified experience of the way weperceive the visual world and prepare our actions. Ofparticular interest is emerging evidence from neuroimagingthat the CC employs a differentiated role with callosal areastransmitting different types of information depending on thecortical destination of connecting fibers. Studies on patientswith callosal degradation indicated that anterior callosalfibers linking frontal and premotor areas of the twohemispheres were associated with inhibitory functions insituations of semantic competition (Stroop) and local-globalinterference, whereas posterior callosal areas connectingtemporo-parietal and occipital cortical regions were relatedwith facilitation from redundant targets and local-globalfeatures. Thus, to achieve an interhemispheric balancebetween component brain functions, the CC appears toexert both functional inhibition and excitation (Bloom andHynd 2005).

Future directions should include new imaging techniquessuch as fiber tractography in combination with functionalneuroimaging and electrophysiological methods to explorethe specific role of regional callosal connectivity for brainfunctions in the healthy brain and callosal degradation.

Acknowledgments We thank Margaret J. Rosenbloom for com-ments on the manuscript. Preparation of this article was supported byNational Institutes of Health research grants: AA018022, AA010723,AA005965, AA012388, AA017168, AA017432

Disclosures The authors declare that no conflicts of interest areassociated with the preparation of this article.

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Contribution of Callosal Connections to the Interhemispheric Integration of Visuomotor and Cognitive Processes

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