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Efferent Association PathwaysOriginating in the Caudal Prefrontal

Cortex in the Macaque Monkey

M. PETRIDES1,2* AND D.N. PANDYA3–5

1Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada2Department of Psychology, McGill University, Montreal, Quebec H3A 1B1, Canada

3Departments of Anatomy and Neurology, Boston University School of Medicine,Boston, Massachusetts 02118

4Department of Neurology, Beth Israel Deaconess Medical Center,Boston, Massachusetts 02215

5ENR Memorial VA Hospital, Bedford, Massachusetts 01730

ABSTRACTThe efferent association fibers from the caudal part of the prefrontal cortex to posterior

cortical areas course via several pathways: the three components of the superior longitudinalfasciculus (SLF I, SLF II, and SLF III), the arcuate fasciculus (AF), the fronto-occipitalfasciculus (FOF), the cingulate fasciculus (CING F), and the extreme capsule (Extm C).Fibers from area 8Av course via FOF and SLF II, merging in the white matter of the inferiorparietal lobule (IPL) and terminating in the caudal intraparietal sulcus (IPS). A group ofthese fibers turns ventrally to terminate in the caudal superior temporal sulcus (STS). Fibersfrom the rostral part of area 8Ad course via FOF and SLF II to the IPS and IPL and via theAF to the caudal superior temporal gyrus and STS. Some fibers from the rostral part of area8Ad are conveyed to the medial parieto-occipital region via FOF, to the STS via Extm C, andto the caudal cingulate gyrus via CING F. Fibers from area 8B travel via SLF I to thesupplementary motor area and area 31 in the caudal dorsal cingulate region and via theCING F to cingulate areas 24 and 23 and the cingulate motor areas. Fibers from area 9/46dcourse via SLF I to the superior parietal lobule and medial parieto-occipital region, via SLFII to the IPL. Fibers from area 9/46v travel via SLF III to the rostral IPL and the frontopa-rietal opercular region and via the CING F to the cingulate gyrus. J. Comp. Neurol. 498:227–251, 2006. © 2006 Wiley-Liss, Inc.

Indexing terms: monkey; frontal cortex; prefrontal cortex; association pathways;

autoradiography; connections

The caudal part of the lateral prefrontal cortex, consist-ing of the cortex lying immediately in front of the arcuatesulcus (i.e., the prearcuate cortex), receives its main inputfrom the posterior parietal, posterior temporal, and extra-striate cortical regions (e.g., Kuypers et al., 1965; Jonesand Powell, 1970; Chavis and Pandya, 1976; Barbas andMesulam, 1981; Petrides and Pandya, 1984, 1988; Barbas,1988; Cavada and Goldman-Rakic, 1989; Ungerleider etal., 1989; Andersen et al., 1990; Hackett et al., 1999;Romanski et al., 1999a,b). The fibers originating from theparietal cortex course as part of the superior longitudinalfasciculus (SLF), which has been demonstrated to consistof three distinct fiber bundles: SLF I leading to the cau-dodorsal lateral and medial frontal cortex, SLF II to thedorsal premotor, prearcuate, and caudal mid-dorsolateralfrontal cortex, and SLF III to the ventral premotor and

ventrocaudal lateral prefrontal cortex (Petrides and Pan-dya, 1984). Fibers originating from the caudal superiortemporal gyrus and adjacent superior temporal sulcusterminate predominantly in dorsal area 8 and area 9/46d,

Grant sponsor: Canadian Institutes of Health Research (CIHR); Grantnumber: MOP-14620; Grant sponsor: Natural Sciences and EngineeringResearch Council of Canada (NSERC); Grant sponsor: ENR Memorial VAHospital, Bedford, Massachusetts.

*Correspondence to: Michael Petrides, Montreal Neurological Institute,3801 University St., Montreal, Quebec H3A 2B4, Canada.E-mail: [email protected]

Received 7 October 2005; Revised 1 February 2006; Accepted 3 April2006.

DOI 10.1002/cne.21048Published online in Wiley InterScience (www.interscience.wiley.com).

THE JOURNAL OF COMPARATIVE NEUROLOGY 498:227–251 (2006)

© 2006 WILEY-LISS, INC.

while input from the middle superior temporal regiontargets primarily more anterior prefrontal areas (Petridesand Pandya, 1988; Hackett et al., 1999; Romanski et al.,1999a,b). The fibers from the caudal superior temporalregion run via the arcuate fasciculus, while those from themiddle superior temporal region course predominantlythrough the extreme capsule (Petrides and Pandya, 1988).In addition, connections from the extrastriate region tothe caudolateral prefrontal cortex have consistently beenreported (e.g., Kuypers et al., 1965; Pandya and Kuypers,1969; Jones and Powell, 1970; Ungerleider et al., 1989).

Although it is known that the caudal lateral prefrontalcortical areas project back to post-Rolandic associationcortex (e.g., Jones and Powell, 1970; Pandya and Vignolo,1971), there is no information regarding the precise courseand the pathways utilized by the efferent association fi-bers originating from the caudolateral prefrontal cortex.The present study examined the pathways originatingfrom this region by means of the autoradiographic tech-nique, which allows the precise delineation of the entirecourse of pathways and their terminations. A major ques-tion of interest is whether the efferent fibers from thecaudal prefrontal region course via the same general path-ways that relay afferent information to this region?

The caudal lateral prefrontal region in interaction withposterior parietal, posterior temporal, and extrastriateregions comprises the main cerebral circuits underlying

visual and auditory spatial attentional processing, as wellas body-centered multimodal interactions. Furthermore,it is generally accepted that the prefrontal cortex exercisesa top-down control over posterior cortical regions (e.g.,Petrides 1996, 2005; Barcelo et al., 2000; Moore and Arm-strong, 2003). Thus, a clear understanding of the regula-tion by the frontal cortex of posterior cortical attentionalprocessing must be based on a solid understanding of thepathways via which this control is exerted. This is ofimportance because many disease processes involve dam-age to the white matter and the behavioral/cognitive ef-fects observed may reflect damage to both the inputs andoutputs of particular areas.

MATERIALS AND METHODS

Surgery

Injections of radioactively labeled amino acids wereplaced in different parts of the prefrontal cortex in sevenrhesus monkeys (Macaca mulatta). The animals were im-mobilized with ketamine hydrochloride (10 mg/kg) andthen deeply anesthetized with sodium pentobarbital (30mg/kg) (Sigma, St. Louis, MO) administered intrave-nously. A craniotomy was then performed, under asepticsurgical technique, over the target area in the frontal lobe.In each case, an attempt was made to place two juxta-posed isotope injections into an architectonic area accord-ing to the parcellation of Petrides and Pandya (1994) (Fig.1). The intracortical injections consisted of radioactivelylabeled amino acids (3H-leucine and/or proline; volumerange, 0.4–1.0 �L; specific activity range, 40–80 �Cu,aqueous solution; New England Nuclear Brand Radio-chemicals from PerkinElmer, Norwalk, CT). After sur-vival periods ranging from 7–10 days the animals weredeeply anesthetized with sodium pentobarbital and per-fused transcardially with physiologic saline, followed by a10% formalin solution.

The brains were divided into two blocks by a coronal cutand photographed from all angles. They were subse-quently embedded in paraffin and sectioned at 16 �mthickness. The brains were then processed for autoradiog-raphy according to the technique described by Cowan etal. (1972). The exposure times varied between 3 and 6months. During this period, trial sections were developedat monthly intervals for identification of optimal radiola-beling. The sections were also counterstained with thi-onine to permit identification of the architectonic areas. Aseries of coronal sections of the hemisphere were exam-ined microscopically with darkfield illumination. The la-beled fibers in the white matter and the terminal labelingin the cerebral cortex and subcortical structures wererecorded with the aid of an X-Y plotter (Hewlett Packard,Corvallis, OR) that was electronically coupled to the stageof the microscope (Leitz Aristoplan, Wetzlar, Germany).This information was then used to reconstruct the injec-tion and termination sites, as well as the course of thelabeled fibers. The cytoarchitectonic boundaries of the pro-jection areas within the cerebral cortex, as well as thesites of origin of the pathways within the prefrontal cor-tex, were established in the experimental material underlight field illumination.

The distribution of the terminations of the labeled fiberswas transferred onto two-dimensional reconstructions(i.e., flattened views) of the lateral, medial, and ventral

Abbreviations

Area 6DC dorsocaudal area 6Area 6DR dorsorostral area 6AF arcuate fasciculusAS arcuate sulcusASi arcuate sulcus (inferior limb)ASu arcuate sulcus (upper limb)CING S cingulate sulcusCING F cingulate fasciculusCC corpus callosumCF calcarine fissureCS central sulcusEC external capsuleExtm C extreme capsuleFOF fronto-occipital fasciculusIC internal capsuleILF inferior longitudinal fasciculusLF lateral fissureLS lunate sulcusIPL inferior parietal lobuleIPS intraparietal sulcusIOS inferior occipital sulcusLOS lateral orbital sulcusMB Muratoff bundleMdLF middle longitudinal fasciculusMOS medial orbital sulcusOTS occipitotemporal sulcusPOMS medial parieto-occipital sulcusPreSMA presupplementary motor areaPresub presubiculumPro M proisocortical motor areaPS sulcus principalisRS rhinal sulcusRsp retrosplenial cortexSB subcortical bundleSLF I superior longitudinal fasciculus (bundle I)SLF II superior longitudinal fasciculus (bundle II)SLF III superior longitudinal fasciculus (bundle III)SMA supplementary motor area (secondary motor area MII)St B striatal bundleSTS superior temporal sulcusUF uncinate fasciculus

The Journal of Comparative Neurology. DOI 10.1002/cne

228 M. PETRIDES AND D.N. PANDYA

surfaces of the examined cerebral hemispheres. These 2Dreconstructions of the hemispheres were achieved using aprecision technical drawing software program (Au-toSketch, Release 7, Autodesk, San Rafael, CA). In orderto minimize the distortion in the normal view of the cere-

bral hemisphere that inevitably follows such flattenedmaps, we unfolded the cortex lying within the major sulciseparately. These unfolded sulci are presented next to thelateral and medial views of the hemispheres so that thereader can appreciate the details of the terminationswithin the sulci. On the coronal sections of the hemispherethat was to be reconstructed, we traced the distance fromthe midline (i.e., the border of the lateral with the medialsurface of the hemisphere) to the first sulcus encounteredlaterally. We then measured the distance from that sulcusto the next sulcus and so on until the lateral-to-ventraledge of the hemisphere was reached. These measurementswere used for the lateral surface reconstruction. For thereconstruction of the medial surface of the frontal lobe, wemeasured the distance from the dorsalmost part of themidline to the first sulcus encountered ventrally and thento the next sulcus until the ventralmost part of the medialsurface was reached. The orbital surface of the frontal lobewas reconstructed by measuring the distance, on eachcoronal section, from the midline to the first sulcus en-countered laterally (i.e., the medial orbital sulcus) andthen from there to the lateral orbital sulcus and then tothe ventral-to-lateral edge of the hemisphere. The medial/ventral surface of the temporal lobe was included with thereconstruction of the medial surface of the hemisphereand the origin of the measurements was the hippocampalsulcus. The measurements obtained for the lateral, me-dial, and orbital surfaces, as well as the cortex within thesulci, were thus a series of line segments (the y coordi-nates) arranged in the anteroposterior direction (x coordi-nates). In separate spreadsheets, the points (x, y coordi-nates) were plotted and joined together in order toreconstruct the 2D flattened outlines of surfaces of thehemisphere and the sulci.

The labeled long association fibers that were traced oncoronal sections of selected cases were transferred ontothe corresponding coronal sections of a monkey brain(male, Macaca mulatta) that was scanned with magneticresonance imaging (MRI). A high-resolution T1-weighted3D MRI anatomical image of this monkey brain was ac-quired from a 1.5 T Siemens (Erlangen, Germany) SonataVision scanner (TR � 22 ms, TE � 9.2 ms, flip angle � 30°,1.0 � 1.0 � 1.0 mm, coronal slices, 1.0 mm in thickness).3D surface reconstructions of this brain were obtainedusing an automated, model-based, surface deformationalgorithm (MacDonald et al., 1994). The position of thelabeled fibers were marked on the MRI monkey brainusing DISPLAY, an interactive 3D imaging software pack-age (MacDonald, 1996) that allows the MRI file to beviewed and marked simultaneously in the coronal, hori-zontal, and sagittal planes, as well as in one other arbi-trary plane of the investigator’s choice. All views are au-tomatically updated as the cursor is moved to any point ina given section and the investigator can mark any point inthe MRI volume. The markings of the charted fibers on aseries of contiguous 2D sections could then be transferredonto comparable coronal sections of the standard MRIbrain using local details in the anatomy of the sections.Once the marked fibers from the charted case were trans-ferred into the MRI brain, they could be reconstructed andviewed on the 3D rendering of the standard MRI brain,permitting a clear visualization of the course of the entirepathway from various angles. This 3D reconstructionhelped provide a clearer appreciation of the course of thevarious pathways within the white matter of the cerebral

Fig. 1. Cytoarchitectonic map of the lateral (A), orbital (B), andmedial (C) surfaces of the frontal lobe of the monkey according toPetrides and Pandya (1994).


229CAUDAL PREFRONTAL CORTICAL CONNECTIONS

hemisphere and is illustrated in summary diagrams (Figs.10–12). The 3D hemispheric view provides an impressionof the trajectories of the identified association pathways,whereas the coronal sections indicate the location of thesepathways at different levels.

The care and use of the animals were in accordance withthe guidelines of the National Institutes of Health.

Terminology, architectonic parcellation, andborders

The architectonic delineation of the prefrontal cortexwas determined according to the criteria of Petrides andPandya (1994) (Fig. 1), the posterior parietal cortex ac-cording Pandya and Seltzer (1982), the superior temporalgyrus according to Pandya and Sanides (1973), the infero-temporal cortex and the cortex of the superior temporalsulcus according to Seltzer and Pandya (1978), and theposterior parahippocampal gyrus according to Rosene andPandya (1983). The parcellation of the cingulate cortex,and that of the retrosplenial cortex, which lies on thedorsal aspect of the corpus callosum, follows Vogt et al.(1987). The location of these and other cortical architec-tonic areas are shown in Figure 2. The Paxinos et al.(2000) atlas of the macaque monkey brain also displaysthe limits of the architectonic areas that were used in thepresent analysis.

The association fibers that occupy the white matter ofthe cingulate gyrus are referred to as the cingulate fascic-ulus. Note that the term “cingulum” or “cingulum bundle”has sometimes been used to refer to all of the white matterunderneath the cingulate gyrus. This term, however, isconfusing since the cingulate white matter contains corti-cal association fibers, as well as subcortical and commis-sural fibers. In order to be more specific, Mufson andPandya (1984) restricted the term “cingulum bundle” tothe subcortical fibers that originate from and are directedto the cingulate cortex (e.g., the thalamocingulate andcingulothalamic fibers), while referring to the cortical as-sociation fibers as the “cingulate fasciculus.” The subcor-tical fibers in general course in the central and ventralpart of the cingulate white matter, while the long associ-ation fibers (cingulate fasciculus) occupy a more dorsaland medial position around the subcortical fibers.

RESULTS

Case 1

In this case, the isotope injections were placed in therostral part of area 8Ad, but the isotope spread partiallyinto its caudal part (Fig. 3A). Rostral to the injection site,there were a number of labeled fibers in the white matterof the frontal lobe that terminated predominantly in thedorsolateral frontal cortex in areas 6DR, 8B, 9, dorsal 46,as well as the dorsal and medial parts of area 10. In theventral part of the frontal lobe, terminations were noted inareas 8Av, 45, and 47/12. Labeled long association fiberscould be traced into four fiber bundles, namely, the fronto-occipital fasciculus (FOF), the middle segment of the su-perior longitudinal fasciculus (SLF II), the cingulate fas-ciculus (CING F), as well as the extreme capsule (Extm C)(Fig. 3C, section 3). The fronto-occipital fibers coursedabove the subcallosal fascicle (Muratoff bundle, MB) (Fig.3C, sections 3, 4). Note that the Muratoff bundle is acrescent-shaped bundle located above the head and body

of the caudate nucleus. Muratoff described it as a subcal-losal fascicle in his experimental studies on dogs. Subse-quent investigators designated this bundle as the Murat-off bundle (see Dejerine, 1895) and more recent work hasshown that it carries corticostriatal fibers (see Schmah-mann and Pandya, 2006). Further caudally, the fibersforming the FOF moved medially to terminate in areasPGm and PO in the medial parieto-occipital region. Someof these fibers terminated in area IPd along with those ofSLF II (see below) in the intraparietal sulcus. The fibersrunning in the white matter of the cingulate gyrus coursedcaudally as far as the splenium of the corpus callosum andterminated in a columnar manner in areas 23 and 31 (Fig.3C, sections 2–6). Some of the fibers that entered theextreme capsule continued caudally in the white matter ofthe superior temporal gyrus, i.e., the middle longitudinalfasciculus (MdLF). The MdLF is an association fiber bun-dle that occupies the white matter of superior temporalgyrus and was first described by Seltzer and Pandya(1984). These fibers that first coursed in the extreme cap-sule and then in the MdLF terminated in areas PaAlt,TPO, and PGa in the middle sector of the superior tempo-ral region (Fig. 3C, sections 2–5). These latter fibers min-gled with the fibers of the arcuate fasciculus describedbelow (Fig. 3C, section 5). The SLF II fibers coursed in thewhite matter above the upper part of the lateral fissure inthe caudal part of the inferior parietal lobule. Some ofthese fibers terminated in a columnar manner in areasIPd and POa of the intraparietal sulcus, as well as inareas PG and Opt of the inferior parietal lobule (Fig. 3C,sections 5, 6). A significant number of the labeled fibersrunning in SLF II arched around the caudal portion of thelateral fissure to occupy the white matter of the caudalsuperior temporal gyrus (Fig. 3C, sections 5, 6). This con-tingent of fibers corresponds to the arcuate fasciculus (AF)and terminated in areas Tpt and paAc in the caudal por-tion of the superior temporal gyrus and in area TPO of thesuperior temporal sulcus. The trajectory of the associationpathways are schematically depicted in the inset diagramof Figure 3C.

Since the aim of this article is to examine the longassociation fiber systems, the subcortical fiber pathwaysand their terminations are only briefly alluded to in thisand subsequent cases. At the level of the injection site, acord of labeled fibers was observed in the white matter.One contingent of labeled fibers from this cord was di-rected medially and entered the genu of the corpus callo-sum, whereas a laterally directed contingent of fibers en-tered the internal capsule to terminate in the dorsomedialnucleus of the thalamus (Fig. 3C, sections 1–4). Manyfibers ran further ventrally via the cerebral peduncle tothe basis pontis. Another group of fibers proceeded medi-ally and entered a compact bundle running above the headof the caudate nucleus: the subcallosal fasciculus (MB)(Fig. 3C, sections 1–4). These fibers terminated in thehead and the body of the caudate nucleus. Another groupof labeled striatal fibers entered the external capsule (EC)and terminated in the claustrum and the putamen.

Case 2

In this case the isotope injections were placed in thecaudal part of area 8Ad with some spreading into area8Av (Fig. 4A). Rostral to the injection site, distinctclusters of terminal label were noted in areas 6DR, 8B,9/46d, 45, and caudal 47/12. Labeled long association



fibers were observed in the FOF and the SLF II (Fig. 4C,sections 3– 6). The FOF fibers occupied a position abovethe head and body of the caudate nucleus, dorsal to theMB. The SLF fibers occupied a position more lateral tothe FOF and continued caudally in the white matterabove the lateral fissure. Both these fiber bundlescoursed parallel to each other for a considerable dis-tance (Fig. 4C, sections 4 – 6), but in the white matter ofthe caudal part of the inferior parietal lobule, they

merged and terminated in areas IPd and POa in thelower bank of the intraparietal sulcus and in areas PGand Opt of the inferior parietal lobule (Fig. 4C, sections7–9). Unlike Case 1, in which the injection was placed inthe rostral part of area 8Ad, no labeled fibers wereobserved in the arcuate fasciculus in this case. On theother hand, some of the fibers running in SLF II coursedventrally in the inferior longitudinal fascicle (ILF) andterminated in areas FST, PGa, and MST in the superior

Fig. 2. Diagram of the medial, lateral, and ventral views of themonkey left cerebral hemisphere to show the location of the architec-tonic areas used in the present article to describe the results. Dottedlines indicate the lips of the opened sulci to show architectonic areas

within them. The posterior part of the corpus callosum was removedto show the retrosplenial areas 29 and 30. CC, corpus callosum;Presub, presubiculum; Rsp, retrosplenial cortex.



Fig. 3. Diagrammatic representation of the unfolded lateral(A) and medial (B) surfaces of the cerebral hemisphere in Case 1 withisotope injection in rostral area 8Ad (shown in solid black) and theresulting distribution of terminal label (shown as dots). C: Coronalsections (1–6), taken at the levels indicated in A, show the location ofthe injection site and the labeled pathways in the white matter. The

inset in C summarizes schematically the origin, trajectories, andterminations of the long association pathways observed in this case.In A, the principal sulcus, the upper and inferior limbs of the arcuatesulcus, the intraparietal sulcus, the superior temporal sulcus, and thelateral fissure have been opened up to show the terminal label in theirbanks. For abbreviations, see list.


temporal sulcus (Fig. 4C, section 7). These latter termi-nations could be due to some spreading of the isotope inthe ventral part of area 8 (i.e., area 8Av) (see Case 3,

below). The trajectory of the association pathways areschematically depicted in the inset diagram of Figure4B.

Figure 3 (Continued)



Fig. 4. Diagrammatic representation of the unfolded lateral(A) and medial (B) surfaces of the cerebral hemisphere in Case 2 withisotope injection in caudal area 8Ad and the resulting distribution ofterminal label. C: Coronal sections (1–9), taken at the levels indicatedin A, show the location of the injection site and the labeled pathwaysin the white matter. The inset in B summarizes schematically the

origin, trajectories, and terminations of the long association pathwaysobserved in this case. In A the principal sulcus, the upper and inferiorlimbs of the arcuate sulcus, the intraparietal sulcus, and the superiortemporal sulcus have been opened up to show the terminal label intheir banks. For abbreviations, see list.



From the injection site, a distinct cord of labeledfibers emerged. One segment of fibers coursed mediallyand entered the genu of the corpus callosum, whileanother segment entered the internal capsule (Fig. 4C,sections 2, 3). Some of these internal capsule fibersterminated in the dorsomedial nucleus of the thalamus,while others continued ventrally into the cerebral pe-

duncle to terminate in basis pontis. A significant num-ber of labeled striatal fibers (the MB) occupied a posi-tion medial to the internal capsule and terminated inthe head of the caudate nucleus, while others occupied amore ventral location (i.e., the external capsule) andterminated in the putamen and claustrum (Fig. 4C,sections 2, 3).




Case 3

In this case the isotope injections were placed in area8Av in the ventral portion of the arcuate concavity (Fig.5A). Rostrally, the labeled fibers terminated in the vicinityof the injection site in areas 8Ad, 8B, 6V, and 45. The longassociation fibers are conveyed by two fiber bundles: FOFand SLF II. The FOF fibers occupied a position above thehead and body of the caudate nucleus, dorsal to the MB.The SLF fibers occupied a position more lateral to the FOFand continued caudally in the white matter above thelateral fissure (Fig. 5B, sections 3, 4). Both these fiberbundles coursed parallel to each other for a considerable

distance, but around the intraparietal sulcus they mergedand terminated in areas POa and IPd. A large componentof the caudally directed long association fibers coursed inthe white matter above the lateral fissure in the form of adiscrete bundle in the superior longitudinal fasciculus(SLF II) (Fig. 5B, sections 2–8). These fibers occupied thewhite matter of the inferior parietal lobule and continuedcaudally and ventrally mingling with the fibers of the ILFto terminate in the caudal portion of the superior temporalsulcus in areas MST, FST, and MT (Fig. 5B, sections 5–8).The trajectory of the association pathways are schemati-cally depicted in the inset diagram of Figure 5B.

Fig. 5. Diagrammatic representation of the unfolded lateral (A)surface of the cerebral hemisphere in Case 3 with isotope injection inarea 8Av and the resulting distribution of terminal label. B: Coronalsections (1–8), taken at the levels indicated in A, show the location ofthe injection site and the labeled pathways in the white matter. Theinset in B summarizes schematically the origin, trajectories, and

terminations of the long association pathways observed in this case.In A the principal sulcus, the upper and inferior limbs of the arcuatesulcus, the intraparietal sulcus, and the superior temporal sulcushave been opened up to show the terminal label in their banks. Forabbreviations, see list.



From the injection site, a cord of labeled fibers emerged.A medial contingent of fibers from this cord entered thegenu of the corpus callosum and a ventrally directed con-tingent entered the internal capsule to terminate in sub-cortical structures (Fig. 5B, sections 1–3). Another groupof labeled fibers that entered the MB lay medial to theinternal capsule above the caudate nucleus and termi-nated in the head of the caudate nucleus, while otherfibers entered the external capsule and terminated in theputamen and the ventral part of the claustrum (Fig. 5B,section 4).

Case 4

In this case the isotope injections were placed in themedial part of the frontal lobe and involved medial area8B (Fig. 6A). Labeled grains were noted in areas 9, 32, and24 on the medial surface of the frontal lobe. On the lateralsurface of the frontal lobe, labeled grains were observed inareas 9, 46, 8B, 8Ad, 6DR, and 6DC. A distinct cluster oflabeled grains was noted in area 47/12 on the ventrolat-eral surface of the frontal lobe. The long association fiberswere conveyed caudally by the cingulate fasciculus and




Fig. 6. Diagrammatic representation of the unfolded lateral (A)and medial (B) surfaces of the cerebral hemisphere in Case 4 withisotope injection in the medial part of area 8B with some involvementof medial area 6 and the resulting distribution of terminal label. Theprincipal sulcus and the upper limb of the arcuate sulcus in A and the

cingulate sulcus in B have been unfolded to show the terminal label intheir banks. The inset in A summarizes schematically the origin,trajectories, and terminations of the long association pathways ob-served in this case. For abbreviations, see list.



the dorsal segment of SLF I. Fibers from the injection sitethat entered the cingulate fasciculus coursed caudally andterminated, first in area 24, then in area 23. Some of thesefibers terminated in the cingulate motor areas M3 and M4in the lower bank of cingulate sulcus. The SLF I associa-tion fibers coursed in the white matter adjacent to theupper bank of the cingulate sulcus and terminated in thepresupplementary motor area (preSMA) and the supple-mentary motor area (SMA) on the medial surface of thehemisphere and in dorsorostral area 6 (i.e., area 6DR) anddorsocaudal area 6 (i.e., area 6DC) on the lateral surface ofthe hemisphere. Further caudally, these fibers terminatedin areas 31 and PGm. The trajectory of the associationpathways are schematically depicted in the inset diagramof Figure 6A.

A cord of labeled fibers emerged from the injection siteand coursed through the adjacent white matter progress-ing ventrally. At the level of the cingulate sulcus this fiberbundle divided into a medial component that entered thegenu of the corpus callosum to terminate in the oppositehemisphere. The lateral component of fibers entered theinternal capsule progressing towards the thalamic andpontine nuclei. Another contingent of fibers was noted tocourse toward the head of the caudate nucleus. Thesefibers aggregated into the MB and terminated in the cau-date nucleus. Some of these fibers moved laterally, cross-ing the internal capsule to enter the external capsule andthen terminated in the claustrum and the putamen.

Case 5

The isotope injections in this case were placed in thedorsal bank of the caudal part of the sulcus principalisinvolving area 9/46d, encroaching on the adjacent rostralpart of area 8Ad (Fig. 7A). Rostral to the injection site,labeled fibers were seen in the dorsal white matter. Thesefibers terminated in the dorsal and ventral portions ofarea 46 and in area 9 both in its medial and lateral parts.Some terminations were also observed in the cingulatesulcus. All these terminations were in a columnar man-ner. Caudal and ventral to the injection site, local associ-ation fibers terminated into areas 8B, 8Ad, 8Av, 6DR, 45,44, and 47/12.

The labeled long association fibers entered SLF I andSLF II and the cingulate fasciculus (Fig. 7C, section 4).The labeled fibers in SLF I coursed through the whitematter of the frontal lobe and the superior parietal lobule(Fig. 7C, sections 4–8). These fibers terminated in areas31, PGm, PEc, and PEci (Fig. 7B,C, sections 6–8). Thelabeled fibers in SLF II coursed through the white matterabove the lateral fissure and terminated in the caudalinferior parietal lobule in areas PG, PGop, POa, and IPd(Fig. 7A–C, sections 4–7). A few fibers arched around thecaudal end of the lateral fissure as part of the arcuatefasciculus to terminate in area Tpt in the caudal part ofthe superior temporal gyrus. These latter fibers are prob-ably due to the involvement of area 8Ad in this case (seeCase 1, above). The labeled fibers that were directed to-ward the cingulate gyrus coursed around the ventral partof the cingulate sulcus and in the cingulate fasciculus (Fig.7C, sections 4–7). These fibers terminated in the caudalpart of area 24, cingulate motor areas M3 and M4, area 23,and retrosplenial area 30. Some of these fibers turnedaround the splenium of the corpus callosum and then intothe white matter around the calcarine fissure and termi-nated in the caudal part of the presubiculum (Fig. 7C,

sections 6, 7). The trajectory of the association pathwaysare schematically depicted in the inset diagram of Figure7C.

At the level of the injection site, heavily labeled fiberswere observed in the form of a cord running medially.These fibers divided into a medial and a lateral compo-nent, the medial component coursing through the genu ofthe corpus callosum (Fig. 7C, section 2). From the lateralcomponent, fibers entered the internal capsule directedtoward the thalamus and the pontine nuclei. The thalamicfibers terminated in the lateral part of the dorsomedialthalamic nucleus. The remaining fibers turned ventrallyand entered the cerebral peduncle to terminate in thepontine nuclei. Other fibers entered the subcallosal fasci-cle of MB and terminated within the caudate nucleus indiscrete patches. Some of these fibers crossed the internalcapsule and entered the external capsule (Fig. 7C, section3). These fibers terminated in the rostral part of the pu-tamen as discrete patches, as well as in the claustrum.

Case 6

In this case the isotope injections were placed in area9/46v on the ventral bank of the sulcus principalis withsome involvement, rostrally, of the rostrolateral part ofarea 47/12 (Fig. 8A). Rostral to the injection site, terminallabel was noted in rostral area 47/12 in a columnar man-ner. Some terminal label was noted in the dorsal edge ofthe principal sulcus (area 9/46d). At the level of the injec-tion site, the bulk of the label in the white matter occurredin the ventral part of the frontal lobe and some of thesefibers terminated in areas 47/12, 11, and 13. One group ofassociation fibers coursed in the white matter subjacent tothe principal sulcus and the lower limb of the arcuatesulcus. Some of these fibers terminated in areas 8Av, 45,44, ventral area 6, and the proisocortical motor cortex(proM) (Fig. 8A). Some fibers coursed in the white matterof the superior part of the frontal lobe, entered the cingu-late fasciculus, and terminated in the depth of the cingu-late sulcus in the cingulate motor area M3. Other fiberscontinued further dorsally to reach areas 8B and 6DR.

Further caudally, the long association fibers traveledvia the ventral segment of SLF III in the white matter ofthe frontoparietal operculum, the extreme capsule, andthe uncinate fasciculus. The fibers that coursed withinSLF III terminated predominantly within the frontopari-etal opercular cortex involving the gustatory cortex andthe second somatosensory area SII (Fig. 8C, sections 2–5).Further caudally, these fibers terminated in ventral areas1 and 2 and in the inferior parietal lobule in areas PF,PFG, and PG. These terminations were in a columnarmanner, with emphasis on layer I. The trajectory of theSLF III pathway is schematically depicted in the insetdiagram of Figure 8C.

The long association fibers that coursed through theextreme capsule terminated in the dysgranular part of theinsula and in areas TEa and IPa within the lower bank ofthe superior temporal sulcus and in area TE2 of the in-ferotemporal region in a columnar manner (Fig. 8C, sec-tions 3–5). A small contingent of fibers entered the unci-nate fasciculus at the lower part of the extreme capsuleand turned ventrally in the limen insulae coursing withinthe white matter under the rostral part of the superiortemporal sulcus. These fibers terminated, in a columnarmanner, in the visual proisocortex in the rostralmost partof the lower bank of the superior temporal sulcus and in



area TE1 (Fig. 8C, section 2). These fibers that entered theextreme capsule and the uncinate fasciculus were notobserved in Case 7 (see below) in which the injection wasalso placed in area 9/46v but without spreading into the

rostrolateral part of area 47/12 as in Case 6. Thus, theextreme capsule and uncinate fibers seen in Case 6 mayhave been due to the rostrolateral extension of the injec-tion in area 47/12.

Fig. 7. Diagrammatic representation of the unfolded lateral(A) and medial (B) surfaces of the cerebral hemisphere in Case 5 withisotope injection in area 9/46d and the resulting distribution of ter-minal label. C: Coronal sections (1–8), taken at the levels indicated inA, show the location of the injection site and the labeled pathways inthe white matter. The inset in C summarizes schematically the origin,

trajectories, and terminations of the long association pathways ob-served in this case. The principal sulcus, the upper and inferior limbsof the arcuate sulcus, and the intraparietal sulcus in A and thecingulate sulcus in B have been opened up to show the terminal labelin their banks. For abbreviations, see list.



A dense cord of labeled fibers was seen in the centralpart of the white matter running medially. Further cau-dally, this dense cord separated into fibers that enteredthe dorsal part of the corpus callosum and those that weredirected to subcortical structures, namely, the striatum,thalamus, and pons (Fig. 8C, sections 1, 2). The fibers

directed toward the striatum first surrounded the rostralpart of the caudate nucleus. At the level of the anteriorlimb of the internal capsule, these fibers divided into twocomponents: the dorsal one entered the MB and termi-nated within the head and body of the caudate nucleus ina patchy manner, whereas the ventral one entered the




external capsule and terminated in the claustrum and theventral part of the putamen in discrete patches through-out its rostrocaudal extent. The fibers that were directed

to the thalamus and pons entered the anterior limb of theinternal capsule (Fig. 8C, section 2). The major bulk ofthese fibers entered the anterior pole of the thalamus and

Fig. 8. Diagrammatic representation of the unfolded lateral (A) andmedial (B) surfaces of the cerebral hemisphere in Case 6 with isotopeinjection in area 9/46v and the resulting distribution of terminal label. Inthis case, the isotope injection spread a little to adjacent rostral part ofarea 47/12. C: Coronal sections (1–6), taken at the levels indicated in A,show the location of the injection site and the labeled pathways in the

white matter. The inset in C summarizes schematically the origin, tra-jectories, and terminations of the long association pathways observed inthis case. The principal sulcus, the inferior limb of the arcuate sulcus, thesuperior temporal sulcus, and the lateral fissure in A and the cingulatesulcus in B have been opened up to show the terminal label in theirbanks. For abbreviations, see list.



terminated in the ventral portion of the dorsomedial nu-cleus, the midline, and the intralaminar nuclei. Furthercaudally, the thalamic fibers terminated in the pulvinarnucleus. The fibers that were directed to the pontine nu-clei coursed ventrally and entered the cerebral peduncle(Fig. 8C, section 3).

Case 7

The isotope injections were placed at the edge of theventral bank of the sulcus principalis and involved area9/46v (Fig. 9A). In this case the isotope injection was morerestricted than in Case 6. Within the frontal lobe, terminallabel was observed in ventral area 46, 9/46d, area 47/12,8Av, 45, 44, 6v, and ProM. On the medial surface of the

frontal lobe, sparse terminal label was observed in area 24and MII, as well as in the cingulate motor area M3. On theorbital surface of the frontal lobe, terminal label was ob-served in areas 47/12, 11, and 13. The labeled long asso-ciation fibers coursed in the dorsal Sylvian operculum aspart of SLF III and terminated in the gustatory area, theprecentral part of areas 1 and 2, SII, as well as in theinferior parietal lobule involving areas PF, PFG, and ros-tral PG. In this restricted 9/46v case we did not observelabeled fibers in either the extreme capsule or the unci-nate fascicle, as in Case 6 (see above). Thus, it seems thatthe extreme capsule and uncinate fascicle fibers observedin case 6 may have been due to the rostrolateral extensionof the injection in area 47/12.




Fig. 9. Diagrammatic representation of the unfolded lateral(A) and medial (B) surfaces of the cerebral hemisphere in Case 7 withisotope injection in area 9/46v and the resulting distribution of ter-minal label. The principal sulcus, the inferior limb of the arcuate

sulcus, and the lateral fissure in A and the cingulate sulcus in B havebeen opened up to show the terminal label in their banks. For abbre-viations, see list.



From the injection site in area 9/46v, a dense cord oflabeled fibers was observed to course medially in the whitematter. A group of fibers separated from this cord andentered the genu of the corpus callosum to terminate inthe opposite hemisphere. From the remainder of the cord,one group of fibers surrounded the head of the caudatenucleus terminating in it. Further caudally, these fibersentered the external capsule to terminate in the putamenand claustrum. Another group of fibers entered the inter-nal capsule anteriorly to terminate mainly in the anteriorthalamic nuclei, the dorsomedial thalamic nucleus, andthe intralaminar thalamic nuclei.

Overall organization of cortical fibers

Before discussing the long association fiber pathways,we should make some general comments on the organiza-tional scheme of the fibers as they enter the white matterfrom a particular prefrontal cortical area and as they getorganized into different fiber bundles. These commentsapply to all prefrontal cortical areas that we examined andappear to be true of the cortex in general (Schmahmannand Pandya, 2006). Immediately below the gray matter ofa cortical area lie the local association fibers. Underneaththese fibers, in coronal sections, the long association fibersoriginating from a given area appear diffusely distributedin the underlying white matter, while the commissuraland subcortical fibers are organized in a compact cord-likebundle (Figs. 3C, 4C, 5B, 7C, 8C). From this cord-like fiberbundle the commissural fibers separate and are directedmedially towards the genu and the rostrum of the corpuscallosum. The subcortical fibers, on the other hand, arefurther separated into various segments. One such seg-ment of fibers enters the subcallosal fascicle (MB) and theexternal capsule and is directed to the striatum (e.g.,Yeterian and Pandya, 1991). Another segment of subcor-tical fibers enters the internal capsule and is directed tothe diencephalon (e.g., Siwek and Pandya, 1991) and thebasis pontis (e.g., Schmahmann and Pandya, 1997). Thelong association fibers, as they course caudally, are grad-ually organized into the specific association fasciculi to bediscussed below.

DISCUSSION

The present investigation demonstrates that the longassociation fibers originating in the various architectonicareas of the caudal lateral prefrontal region (areas 8Ad,8Av, and 8B) and of the adjacent mid-lateral prefrontalcortex (areas 9/46d and 9/46v) are organized into severaldistinct fiber pathways: three distinct components of thesuperior longitudinal fasciculus (SLF I, SLF II, and SLFIII), the cingulate (CING F), the fronto-occipital (FOF)and the arcuate (AF) fasciculi, and the extreme capsulefiber bundle (Extm C). It should be noted that a particularprefrontal cortical area may utilize more than one of thesedistinct fasciculi to convey frontal cortical control to vari-ous posterior cortical regions.

Association fibers from different sectors ofarea 8 (8Ad, 8Av, 8B)

Fibers from both the rostral (Case 1) and caudal (Case2) parts of area 8Ad course, initially, in the FOF and SLFII pathways (Figs. 3C, 4C, 10). The FOF fibers occupy aposition above the head and body of the caudate nucleus,

just dorsal to the MB, whereas the SLF II fibers occupy aposition more lateral to the FOF, and continue caudally inthe white matter lateral to the corona radiata and justabove the insula (Fig. 10). Both these fiber bundles courseparallel to each other for a considerable distance. Onecontingent of the FOF fibers moves further caudally in amedial direction to terminate in the medial parieto-occipital region in areas PGm and PO (Figs. 3C, 10).Another contingent of the FOF fibers merges with the SLFII in the white matter of the caudal inferior parietal lob-ule. These SLF II/FOF fibers terminate in areas IPd andPOa within the intraparietal sulcus and continue caudallyto terminate in area PG and the occipitoparietal cortex(area Opt) (Figs. 3C, 4C).

A distinct contingent of fibers from the rostral part ofarea 8Ad courses with the SLF II fibers in the whitematter of the inferior parietal lobule and arches aroundthe caudal end of the lateral fissure, forming the arcuatefasciculus (Figs. 3C, 11). These efferent frontal fibers thatenter the arcuate fasciculus terminate in areas Tpt andpaAc in the caudal part of the superior temporal gyrus andadjacent portion of area TPO in the superior temporalsulcus (Case 1). Some fibers from the rostral part of area8Ad are conveyed via the extreme capsule and continuefurther caudally in the white matter of the middle part ofthe superior temporal gyrus (middle longitudinal fascicu-lus, MdLF) to terminate in areas TPO and PGa of thesuperior temporal sulcus and area paAlt of the superiortemporal gyrus (Fig. 3C). In addition, fibers originating inrostral area 8Ad course through the cingulate fasciculus toterminate in the caudal cingulate gyrus (areas 23 and 31)(Fig. 3C).

Fibers originating in area 8Av (i.e., the ventral area 8A)(Case 3) course in FOF and SLF II, for a considerabledistance, parallel to each other (Fig. 5B, sections 3 and 4).These fibers merge within the white matter of the inferiorparietal lobule and terminate in areas POa and IPd in theintraparietal sulcus (Fig. 5B, sections 5–8). Some of thesemerged fibers running in the white matter of the inferiorparietal lobule turn, further caudally in the parietal lobe,in a ventral direction and continue as part of the inferiorlongitudinal fasciculus (ILF) coursing under the fundus ofthe superior temporal sulcus to terminate in the extrastri-ate visual areas MST, MT, and FST in the caudal superiortemporal sulcus (Fig. 5B, sections 6–8, inset, Fig. 12).

Long association fibers originating in medial area 8Btravel via the dorsal component of SLF I, the cingulatefasciculus, and to a lesser extent in FOF (Case 4, Figs. 6,10). The SLF I fibers terminate in the supplementarymotor region (MII) and, further caudally, in area 31 (Case4). Fibers running in the FOF, just above the MB, coursecaudally as far as the parietal lobe and merge with thefibers of the SLF I to terminate in area PGm. Finally,fibers from area 8B course through the cingulate fascicu-lus to terminate in area 24 and the cingulate motor areasM3 and M4 (Fig. 6).

Association fibers from areas 9/46dand 9/46v

Fibers originating in dorsal area 9/46 (i.e., 9/46d) areconveyed via SLF I, SLF II, and the cingulate fasciculus(Case 5, Fig. 7C). The SLF I fibers course in the whitematter of the superior frontal lobe and the superior pari-etal lobule and project to areas PGm, PEc, and PEci in thedorsal and medial part of the parietal lobe. The long as-



sociation fibers in SLF II course in the white matter lat-eral to the corona radiata, just above the Sylvian fissure,and project to areas PG, PGop of the inferior parietal

lobule, and areas POa and IPd in the intraparietal sulcus(Case 5, Fig. 7C). Fibers in the cingulate fasciculus origi-nating in dorsal area 9/46 project to areas 24, 23, and 31 of

Fig. 10. Three-dimensional reconstruction of the MRI of a ma-caque monkey brain to illustrate the course of the three parts of thesuperior longitudinal fasciculus (SLF I, SLF II, SLF III) and thefronto-occipital fasciculus (FOF) on the lateral and medial hemi-

spheric surfaces. The accompanying coronal sections (A–G) weretaken at the levels indicated at the top of the lateral hemisphere toshow the relative course of these pathways as seen in coronal planes.Color codes: SLF I, blue; SLF II, red; SLF III, yellow; FOF, green.



Fig. 11. Three-dimensional reconstruction of the MRI of a ma-caque monkey brain to illustrate the course of the arcuate fasciculus(AF) on the lateral hemispheric surface. A part of the cortex in theinferior parietal lobule has been cut out so that the arching fibers ontheir way to the caudal part of the superior temporal gyrus and sulcus

can be appreciated. The accompanying sections (A–D) were taken atthe levels indicated at the top of the hemisphere to show, on coronalsections, the location of the fibers as they are turning ventrally to-wards the superior temporal region.


the cingulate gyrus and area 30 of the retrosplenial cortex,as well as to the caudal part of the presubiculum (Fig.7B,C). In contrast, fibers originating in the ventral part ofarea 9/46 (i.e., 9/46v) course via the ventral component ofSLF III, the extreme capsule, and the cingulate fasciculus(Cases 6 and 7, Figs. 8C, 10). The SLF III fibers course inthe dorsal part of the white matter of the frontoparietaloperculum and are relayed to the gustatory area, thesecond somatosensory area (SII), ventral somatosensoryareas 1 and 2, and areas PF, PFG, and the rostral part ofPG (Figs. 8C, 10). The fibers from ventral area 9/46 run-

ning in the cingulate fasciculus terminate in area 24 in therostral cingulate gyrus, as well as in the adjacent motorcingulate area M3 (Figs. 8B, C inset, 9B).

Fronto-occipital fasciculus

There has been considerable confusion in the anatomi-cal literature regarding the precise location of fibers thatlink the frontal cortex with the occipital cortex, namely,the fronto-occipital/occipito-frontal fasciculus. In the hu-man brain, Dejerine (1895) described the occipito-frontalfasciculus as being located just dorsal to the caudate nu-

Fig. 12. Three-dimensional reconstruction of the MRI of a ma-caque monkey brain to illustrate the course of those fibers of thefronto-occipital fasciculus that blend with the superior longitudinalfasciculus (FOF/SLF II) and then at the caudal part of white matter ofthe inferior parietal lobule turn ventrally to course within the inferiorlongitudinal fasciculus (ILF) under the fundus of the superior tempo-ral sulcus. A part of the cortex in the inferior parietal and superiortemporal region has been cut out to show the course of these ventrally

directed fibers that run underneath the white matter of the superiortemporal sulcus (see sections A–C). These axons terminate in thecaudal superior temporal sulcus in areas MT, MST, and FST. Thefundus of the caudal superior temporal sulcus in the 3D reconstruc-tion is shown in orange where the terminations occur. The accompa-nying coronal sections (A–C) were taken at the levels indicated at thetop of the hemisphere.



cleus between the base of the corona radiata (“pied de lacouronne rayonnante”) and the callosal fibers. This path-way that Dejerine called the occipito-frontal fasciculus (orthe subcallosal fasciculus of Muratoff) was considered byhim to comprise association fibers that link the occipito-temporal cortical region with the frontal cortical region.Later investigators have referred to this fasciculus as thesuperior fronto-occipital or the superior occipito-frontal orthe subcallosal fasciculus (e.g., Crosby, 1982) and againreiterated that it contains association fibers linking occipi-totemporal cortical regions with the frontal cortex, butwith the caveat that it may also contain frontostriatalfibers (Crosby, 1982). Recent diffusion tensor imagingstudies have perpetuated the notion of a superior fronto-occipital fasciculus that runs just above the caudate nu-cleus and below the callosal fibers, although this pathwaycould not be traced beyond the end of the body of thecaudate nucleus in the parietal lobe and no informationabout its origin or termination is available (see Mori et al.,2005). The present autoradiographic material shows thatthe fronto-occipital fasciculus (FOF) is a fiber bundle thatarises from the different sectors of area 8 in the caudalprefrontal region and courses posteriorly dorsal and lat-eral to the caudate nucleus, remaining always dorsal toand clearly distinct from the subcallosal fasciculus of Mu-ratoff (Figs. 3C, 4C, 5C). Note that the subcallosal fascic-ulus of Muratoff, which had been confused with the FOFin the past, is a corticostriatal pathway, as suggested byYakovlev and Locke (1961) and Mufson and Pandya(1984). By contrast, the FOF is a distinct association fiberpathway linking the caudal prefrontal cortex (variousparts of area 8) with the medial and lateral occipitopari-etal junction region. Rostral to the intraparietal sulcus,the fibers running in the FOF and SLF II pathways areclearly distinct. Those in the FOF run above the caudatenucleus (but distinct from the MB) and those in SLF II runjust above the circular sulcus of the insula (Figs. 3C, 4C,5B, 10). At the rostral end of the intraparietal sulcus, acontingent of the FOF starts moving medially to end in themedial occipitoparietal region (areas PO and PGm) (e.g.,Fig. 3C inset and Fig. 10). Another contingent of the FOFfibers blends with those of SLF II and is directed to thelateral occipitoparietal region (caudal PG and Opt) (Fig.4B inset, 4C). Some of these fibers turn ventrally to blendwith fibers of the inferior longitudinal fasciculus (ILF) toend in areas MST, MT, and FST (Fig. 5B inset and Fig.12).

Recent experimental anatomical studies in the monkeyhave shown that fibers originating in the medial and lat-eral extrastriate visual areas are directed to the caudalprefrontal region via the FOF and, therefore, there areboth efferent and afferent fibers in this fasciculus (Yete-rian and Pandya, unpubl. obs.).

Superior longitudinal, arcuate, and inferiorlongitudinal fasciculi

The term superior longitudinal fasciculus (SLF) hasoften been used interchangeably with the term arcuatefasciculus (AF) (Dejerine, 1895). Previous experimentalanatomical studies in the monkey have shown that thesuperior longitudinal fasciculus contains fibers originat-ing within the parietal cortex (Petrides and Pandya,1984), whereas the arcuate fasciculus contains fibers orig-inating from the caudal superior temporal region andarching around the posterior part of the lateral fissure as

they course to the frontal cortex (Petrides and Pandya,1988). Furthermore, it was shown that the SLF can bedivided into three components: SLF I, SLF II, and SLF III(Petrides and Pandya, 1984). SLF I fibers stem from thesuperior and medial parietal cortical region and are di-rected to the dorsal and medial premotor and adjacentprefrontal region. SLF II fibers originate from the caudalinferior parietal lobule and are directed to the dorsal pre-motor and the caudal prefrontal region. SLF III fibersstem from the rostral inferior parietal lobule and termi-nate in ventral premotor and prefrontal cortex.

The present material demonstrates that the arcuatefasciculus and all three components of the SLF also con-tain efferent association fibers that originate from thecaudal prefrontal region (Figs. 10, 11). Efferent frontalfibers that enter the arcuate fasciculus arise from therostral part of area 8Ad and terminate in the caudalsuperior temporal gyrus (area Tpt) and the multimodalarea TPO of the caudal superior temporal sulcus. SLF Ifibers stem from area 8B and caudolateral prefrontal area9/46d and are directed to the superior and medial parietalregion, whereas SLF II fibers originate in areas 8A and9/46d and proceed toward the caudal inferior parietal lob-ule (areas PG and Opt) and adjacent intraparietal sulcus(areas POa and IPd). In addition, a contingent of fibersfrom area 8Av that are coursing in SLF II turn ventrallyin the white matter of the caudal parietal lobule and enterthe ILF to terminate in the extrastriate visual areas FST,MST, and MT in the caudal superior temporal sulcus (Fig.12). Finally, fibers from area 9/46v course in SLF III (Fig.10) and terminate in the frontoparietal operculum in thegustatory area, SII, ventral somatosensory areas 1 and 2,and areas PF, PFG, and rostral PG.

Functional considerations

The above results demonstrate that all the pathwaysthat had previously been shown to convey informationfrom posterior cortical areas to the caudal prefrontal re-gion also contain reciprocal fibers that convey prefrontalcontrol influences on these posterior cortical areas.Behavioral/lesion studies (Koski et al., 1998; Mesulam,1999; Barcelo et al., 2000; Daffner et al., 2000; Petrides,2005), single neuron recording studies in the monkey(Goldberg and Segraves, 1989), and functional neuroim-aging work (Corbetta, 1998; Nobre et al., 2004) have allconsistently shown that the caudal lateral prefrontal re-gion is critical for visual and auditory attentional mecha-nisms. It is traditionally thought that the prefrontal cor-tex exerts control over the parieto-occipital and caudalsuperior temporal regions that are critically involved invisual and auditory processing, respectively (Petrides,1994, 2005; Desimone and Duncan, 1995; Mesulam, 1999).The present anatomical study has shown that the frontalcortical attentional control is conveyed via distinct whitematter fascicles targeting specific posterior cortical re-gions. The arcuate fasciculus, which links the rostral partof area 8Ad with the caudal superior temporal gyrus,where neurons respond to the location of a sound source(e.g., Leinonen et al., 1980), may provide frontal controlover auditory spatial processing. By contrast, the FOF andSLF II can be viewed as fiber systems that enable area 8and adjacent dorsal area 9/46 to exert control over visuo-spatial processing occurring in prestriate and caudal pos-terior parietal cortex. Furthermore, prefrontal controlover visual motion processing may be conveyed via a con-



tingent of efferent frontal fibers that are running as partof the merged FOF/SLF II pathway and enter the ILF toreach the extrastriate visual motion areas within the cau-dal superior temporal sulcus (areas MT, MST, FST) (e.g.,Desimone and Ungerleider, 1986). It should be noted thatthe motion areas of the caudal superior temporal sulcusproject to area 8 (e.g., Boussaoud et al., 1990), indicatingthat the interaction between prefrontal area 8 and motionareas in the superior temporal sulcus is reciprocal.

Although frontal attentional control has traditionallybeen discussed in terms of visual and auditory processing,it can also be extended to the somatosensory field. In sucha framework, the frontal fibers that enter the SLF I andSLF III pathways can be viewed as the conduit for motor/somatosensory control. SLF I fibers arise from caudodor-sal prefrontal cortex (areas 8B and 9/46d) and are directedto premotor, supplementary motor, superior and medialparietal regions, namely areas involved with the control ofreaching and, more generally, movement in space (e.g.,Mountcastle et al., 1975; Lacquaniti et al., 1995). SLF IIIfibers enable the ventral part of area 9/46 to exert controlover the body-centered multimodal processing within therostral inferior parietal lobule that is related to action andaction interpretation (e.g., Leinonen et al., 1979; Taira etal., 1990; Murata et al., 2000; Gallese et al., 2002) andsomatosensory processing within the frontoparietal oper-cular cortex, i.e., the SII region (Ridley and Ettlinger,1976; Murray and Mishkin, 1984). The bidirectional con-nections between the dorsal and ventral areas 9/46 withthe superior parietal and rostral inferior parietal regionsvia the SLF I and SLF III pathways, respectively, may becritical for the monitoring of body actions since this area ispart of the mid-dorsolateral prefrontal region that hasbeen shown to play a critical role in the monitoring ofinformation in working memory (Petrides, 1994, 2005).

The present anatomical findings, by demonstrating theprecise trajectory of association fibers originating fromparticular caudal prefrontal areas and terminating in par-ticular posterior cortical regions, open up the possibility ofdisconnection studies to understand the effects of the lossof specific frontal control over posterior cortical areas.Technically, such precise disconnection studies are nowpossible because of modern methodological developmentsthat allow the incorporation of detailed information ob-tained from preoperative MRI of the brain of a particularmonkey into a frameless stereotaxic system that can guidea probe precisely into any part of the brain (Frey et al.,2004).

Modern studies with diffusion tensor imaging can dem-onstrate the large pathways of the human brain. However,neither the precise origin nor the precise termination ofthese pathways can be unambiguously shown withpresent diffusion tensor imaging. Experimental anatomi-cal studies in the monkey in which the precise origin,trajectories, and termination of fiber pathways can beshown provide strong hypotheses about comparable path-ways in the white matter of the human brain. Detailedknowledge of white matter pathways provided from exper-imental anatomical studies in the monkey combined withdiffusion tensor imaging in the human brain can be ex-tremely valuable to interpret behavioral/cognitive deficitsobserved in various disease states.

ACKNOWLEDGMENTS

We thank Helen Papageorgiou, Jurgen Germann, andVeronika Zlatkina for preparing the illustrations.

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