The Journal of Neuroscience, November 1988, 8(11): 4049-4088

Common Cortical and Subcortical Targets of the Dorsolateral Prefrontal and Posterior Parietal Cortices in the Rhesus Monkey: Evidence for a Distributed Neural Network Subserving Spatially Guided Behavior

L. D. Selemon and P. S. Goldman-Rakic Section of Neuroanatomy, Yale University School of Medicine, New Haven, Connecticut 06510

Common efferent projections of the dorsolateral prefrontal project to the intermediate layers of the superior colliculus cortex and posterior parietal cortex were examined in 3 rhe- and to the midline reticular formation of the pons. sus monkeys by placing injections of tritiated amino acids The present study has uncovered a remarkably large num- and HRP in frontal and parietal cortices, respectively, of the ber of cortical and subcortical areas that receive input from same hemisphere. Terminal labeling originating from both both the dorsolateral prefrontal and posterior parietal as- frontal and parietal injection sites was found to be in ap- sociation cottices, indicating that these common efferent position in 15 ipsilateral cortical areas: the supplementary pathways constitute part of an elaborate anatomical circuit , the dorsal , the ventral pre- which could mediate many aspects of spatial function, in- motor cortex, the anterior arcuate cortex (including the fron- cluding spatial perception, attention, memory, and spatially tal eye fields), the , the anterior and pos- guided movement. terior cingulate cortices, the frontoparietal , the , the medial parietal cortex, the superior tem- The dorsolateral and the posterior parietal poral cortex, the parahippocampal , the presubiculum, cortex are perhapsthe most densely,reciprocally interconnected the caudomedial lobule, and the medial prestriate cortex. areasof associationcortex in the primate (Leichnetz, 1980; Convergent terminal labeling was observed in the contra- Goldman-Rakic and Schwartz, 1982; Schwartz and Goldman- lateral hemisphere as well, most prominently in the principal Rakic, 1982, 1984). Moreover, a recent detailed analysisof the sulcal cortex, the superior arcuate cortex, and the superior intracortical connections of theseareas has revealed that each temporal cortex. In certain common target areas, as for ex- of the subdivisionsof the posterior parietal cortex (areas7a, 7b, ample the cingulate cortices, frontal and parietal efferents 7ip, and 7m) is specifically connected with a distinct subregion terminate in an array of interdigitating columns, an arrange- of the principal sulcalcortex (Cavadaand Goldman-Rakic, 1985). ment much like that observed for callosal and associational Thus, multiple reciprocal corticocortical projections intercon- projections to the principal (Goldman-Rakic and nect the prefrontal and parietal cortices and provide an ana- Schwartz, 1982). In other areas, frontal and parietal terminals tomical substratefor transfer of information between these 2 exhibit a laminar complementarity: in the depths of the su- areasof higher associationcortex. perior temporal sulcus, prefrontal terminals are densely dis- The dorsolateral prefrontal cortex and the posterior parietal tributed within laminae I, Ill, and V, whereas parietal termi- cortex may be related functionally as well. Physiologicalstudies nals occupy mainly laminae IV and VI directly below the have shown that the posterior parietal cortex mediatesspatial prefrontal bands. Subcortical structures also receive ap- perception by transforming the retinotopic image into a map of posing or overlapping projections from both prefrontal and visual space(Andersen et al., 1985) and is involved in relating parietal cortices. The dorsolateral prefrontal and posterior body position to this map of visual space(Hyvarinen and Por- parietal cortices project to adjacent, longitudinal domains of anen, 1974; Mountcastle et al., 1975), while the dorsolateral the neostriatum, as has been described previously (Selemon prefrontal cortex plays a central role in tasksthat require spatial and Goldman-Rakic, 1985); these projections are also found memory, such as the delayed responseand delayedalternation in close apposition in the claustrum, the , the cau- tasks (Goldman and Rosvold, 1970; Goldman et al., 1971; Fu- domedial lobule, and throughout the anterior medial, medial nahashi et al., 1986). Furthermore, lesionsin presumably ho- dorsal, lateral dorsal, and medial pulvinar nuclei of the thal- mologousregions of the prefrontal or parietal cortex in humans amus. In the brain stem, both areas of association cortex result in altered spatial perception and often in sensoryneglect of spacecontralateral to the lesion (Holmes, 1918; Denny-Brown and Banker, 1952; Critchley, 1953;Htcaen et al., 1956;Heilman Received Aug. 14, 1987; revised Mar. 7, 1988; accepted Mar. 8, 1988. and Valenstein, 1972). This work was supported by USPHS Grants MH38546 and MH00298 (P.S.G.-R.) In the present study we have examined the common outflow and an NIA fellowship award AGO53 10 (L.D.S.). We wish to thank J. Cobum, M. Pappy, L. Ladewig, and J. Musco for excellent technical assistance and Dr. R. pathways of the dorsolateral prefrontal and posterior parietal Williiims for advice on Figure 3. corticesusing a double anterogradelabeling method that allowed Correspondence should be addressed to Dr. P. S. Goldman-Rakic, Section of Neuroanatomy, Yale University School of Medicine, 333 Cedar Street, Rm. C303 usto visualize the prefrontal and parietal projections in adjacent SHM, New Haven, CT 065 10. sections.While numerousstudies have traced the efferent con- Copyright 0 1988 Society for Neuroscience 0270-6474/88/l 14049-20%02.00/O nections of each of thesecortical areas(see Table l), the present 4050 Selemon and Goldman-Rakic l Prefrontal and Parietal Projections

Table 1. Anatomical evidence for prefrontal and parietal target areas based on single labeling of projections

Target areas Prefrontal Parietal Pandya and Kuypers, 1969. Pandya and Kuypers, 1969” (area 6) Pandya et al., 19710 Petrides and Pandya, 1984* Jlirgens, 1984* Jiirgens, 1984* Dorsal premotor cortex Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area 6cu) Pandya et al., 197 1 Chavis and Pandya, 1976 Barbas and Pandya, 1987b Petrides and Pandya, 1984 Ventral premotor cortex Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area 60) Pandya et al., 197 1 Chavis and Pandya, 1976 Matelli et al., 1986b Petrides and Pandya, 1984 Barbas and Pandya, 1987b Godschalk et al., 1984b Matelli et al., 1986b Anterior arcuate cortex Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area 8) Pandya et al., 197 1 Jones and Powell, 1970 Goldman and Nauta, 1977a Chavis and Pandya, 1976 Barbas and Mesulam, 198 1b Barbas and Mesulam, 198 1b Huerta et al., 1987b Petrides and Pandya, 1984 Huerta et al.. 1987b Orbitofrontal cortex Pandya et al., 1971 Cavada and Goldman-Rakic, 1986 (area 11) Goldman and Nauta, 1977a Anterior Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area 24) Pandya et al., 197 1 Jones and Powell, 1970 Goldman and Nauta, 1977a Baleydier and Mauguiere, 1980b Baleydier and Mauguiere, 1980b Petrides and Pandya, 1984 Posterior cingulate cortex Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area 23) Pandya et al., 197 1 Jones and Powell, 1970 Goldman and Nauta, 1977a Baleydier and Mauguiere, 1980b Baleydier and Mauguiere, 1980b Petrides and Pandya, 1984 Frontoparietal operculum Pandya et al., 197 1 Pandya and Kuypers, 1969 (areas 1,Z,SII) Preuss and Goldman-Rakic, Pandya and Seltzer, 1982 1985 Petrides and Pandya, 1984 Insular cortex (area IG) Pandya et al., 197 1 Mufson and Mesulam, 1982b Goldman and Nauta, 1977a Mufson and Mesulam, 1982b Medial parietal cortex Goldman and Nauta, 1977ac Pandya and Kuypers, 1969* (area 7m) Pandva and Seltzer. 1982 Superior temporal cortex Pandya and Kuypers, 1969 Pandya and Kuypers, 1969 (area IPa) Pandya et al., 1971 Jones and Powell, 1970 Goldman and Nauta, 1977a Seltzer and Pandya, 1978 Seltzer and Pandva. 1984 Presubiculum Goldman-Rakic et al., 1984 Seltzer and Van Hoesen, 1979 Seltzer and Pandya, 1984 Pandya and Kuypers, 1969 Jones and Powell, 1970 (area TF) Pandya et al., 197 1 Seltzer and Pandya, 1984 Goldman-Rakic et al., 1984 Caudomedial lobule Goldman-Rakic et al., 1984 Cavada and Goldman-Rakic, 1986 Medial prestriate cortex NPD Cavada and Goldman-Rakic, 1986 (area 19) Neostriatum Goldman and Nauta, 1977b Yeterian and Van Hoesen, 1978 Selemon and Goldman-Rakic, 1985 Amygdala AggIeton et al., 1980b Aggleton et al., 1980b Claustrum Pearson et al., 1982 Pearson et al., 1982 The Journal of Neuroscience, November 1988, 8(11) 4051

Table 1. Continued

Target areas Prefrontal Parietal Thalamus Jacobsen et al., 1978 Asanuma et al., 1985 Ktinzle, 1978 Yeterian and Pandya, 1985 Preuss and Goldman-Rakic, 1987 Superior colliculus Kuypers and Lawrence, 1967 Kuypers and Lawrence, 1967 Goldman and Nauta, 1976 Asanuma et al., 1985 Leichnetz et al., 198 1b Lynch et al., 1985 Pontine reticular formation Brodal, 1980 Kuypers and Lawrence, 1967 Leichnetz et al., 1984b NPD, not previously described. y Projections that were shown in published diagrams but not included in the descriptive passage of the text. b Evidence for projections based on placement of retrograde tracer in the target area. c Target area referred to as .

study has focusedmore specifically on the efferent target areas tration of 100 PCilpl. Multiple small injections of radiolabeled isotope that receive projections from both prefrontal and parietal cor- were made in the desired cortical area at depths of 3.0 and 1.5 mm from the cortical surface. The total amount of isotope injected in each tices. A double-labeling paradigm enabled us to identify the monkey equaled 360, 390, and 450 pCi, respectively. Frozen sections areasin which integration of prefrontal and parietal projections were mounted on glass slides and coated with tritium-sensitive emul- may occur and to examine the interrelationship of the dorso- sion, then exposed for 12-16 weeks at -20°C in the dark, and developed lateral prefrontal and posterior parietal terminal fields in these as described in detail by Goldman and Nauta (1977a). common target areas. HRP histochemistry. HRP pellets were prepared according to the method of Griffin et al. (1979). In cases 1 and 3,7-8 pellets were placed in the selected cortical site just below the pial surface. In case 2, 5 Materials and Methods injections totaling 1.6 ~1 in a volume of a 1.5% solution of WGA-HRP Injections. A double anterograde labeling paradigm was used to examine were placed 1.0 mm below the cortical surface. Sections were reacted the common efferent targets of the dorsolateral prefrontal cortex (Brod- for HRP with the tetramethylbenzidine method of Mesulam (1978). mann’s area 9, 10) and the posterior parietal cortex (Brodmann’s area Data analysis. Adjacent autoradiograms and HRP-reacted sections 7) in 3 rhesus monkeys. All injections were made in the left hemisphere. were examined, and selected pairs were photographed, under low power, In case 1 tritiated amino acids (‘H-AA) were injected into the dorsal dark-field illumination on a Leitz Orthoplan microscope; Nissl-stained bank of the principal sulcus, and HRP pellets were placed in the posterior sections were viewed under bright-field illumination. Localization of bank of the during the same surgery. In case 2, ‘H- terminal labeling to a specific cortical area or subcortical nucleus was AA were injected into both dorsal and ventral banks of the principal based on cytoarchitectonic analysis of each area in conjunction with an sulcus; 10 d later multiple small injections of wheat germ agglutinin- evaluation of the sulcal patterning of the section. Autoradiographic horseradish peroxidase (WGA-HRP) were made in the posterior parietal silver grains and HRP labeling in adjacent sections were drawn with cortex. Placement oftracers was reversed in case 3: ‘H-AA were injected the aid of a Wild zoom stereomicroscope equipped with a camera lucida in the posterior parietal cortex and HRP pellets were implanted 1 week attachment. Use of the zoom stereomicroscope permitted us to vary later in the dorsolateral prefrontal cortex. The reversal of tracers in this the magnification of the HRP sections to match the adjacent autora- case served as a control for the spread of tracer into the white matter diograms in order to compensate for differences in size due to differential underlying the parietal cortex in the previous 2 cases. Since tritiated processing. These drawings then were superimposed to create composite amino acids are not taken up by cut axons, we could eliminate from drawings of the parietal and prefrontal labeling at each level. consideration any parietal projections that were observed only with The flattened reconstruction of prefrontal and parietal labeling of the HRP tracers. As it turned out, however, the 2 methods produced the arcuate premotor cortex in Figure 3 is based on drawings of adjacent same findings for comparable prefrontal and parietal injections, and the sections through this region from case 2. For each pair of sections, the results obtained with both techniques were entirely consistent with pre- outer cortical surface was traced on the graphics tablet of a Macintosh vious reports based on smaller injection sites in the prefrontal or parietal computer. The fundus of the principal sulcus arbitrarily was designated cortex (see Table 1). Monkeys were sacrificed 2 d following HRP in- as zero, or in sections posterior to the sulcus, the midpoint between the jection br implants; the interval between injection of 3H-AA and sacrifice ventral lip of the superior arcuate sulcus and the dorsal lip of the inferior ranged from 2-l 2 d. arcuate sulcus was assigned the zero value. The distance between the Perfusion. Following deep barbituate anesthesia, monkeys were per- zero point and the fundus of the superior arcuate sulcus, as well as the fused with l-2 liters of PBS followed by a mixed aldehyde fixative in approximate location of the dorsal and ventral rims, was measured and phosphate buffer (1 .O% paraformaldehyde + 2.5% glutaraldehyde for assigned a positive value. Distances between zero and analogous land- cases 1 and 3; the concentration ofglutaraldehyde was reduced to 1.25% marks of the inferior arcuate sulcus were assigned negative values. Sub- in case 2). Postfixation rinses consisted of a series of graded sucrose sequently, the location of parietal and prefrontal terminal labeling in solutions in phosphate buffer. The pH of all perfusate solutions was 7.4. layer I was determined by measuring the distance between the label and Saline rinses and fixatives were warmed to 37°C; postfixation sucrose the nearest fundus, i.e., of the principal sulcus, superior arcuate sulcus, rinses were cooled to 4°C. or inferior arcuate sulcus. All measurements were then graphed to show Histology. The were sectioned at 40 or 50 pm on a freezing- the distribution of prefrontal and parietal label in the arcuate cortex. stage microtome, and adjacent sections were processed for autoradio- Reconstructions were made of layer I, rather than of layer IV, because graphic localization of )H-AA and HRP histochemistry, respectively. terminal labeling was more consistently found in layer I and because In cases 1 and 3 autoradiograms were counterstained with thionin. In much of the cortex in this region was cut tangentially in frontal section, case 2 a separate set of sections, adjacent to those processed for auto- making the identification of deeper layers difficult. While we recognize radiographic localization of 3H-AA, were Nissl-stained with cresyl vi- that basing the reconstructions on layer I introduces distortion into the olet. map such that the cortex deep within each sulcus is compressed and Autoradiography. Equal amounts of tritiated leucine (specific activity the cortex on the rims and convexities is expanded, we feel that the > 110 Ci/mmol) and proline (specific activity 20-40 Ci/mmol) were reconstructions accurately depict the interrelationship of prefrontal and evaporated and then reconstituted in distilled water to a final concen- parietal terminal labeling in the arcuate cortex. 4052 Selemon and Goldman-Rakic * Prefrontal and Parietal Projections

into the adjacent dorsal and ventral cortex and rostrally to in- clude the ventral lip of the sulcus.In case3, the HRP injection site covered much of the dorsolateral frontal cortex with the exclusion of the banks and depths of the rostra1 third of the principal sulcus. The halo of the injection site involved the ventral bank ofthe superiorarcuate sulcus (area 6) and the cortex posterior to the principal sulcus(area 8); in addition, there was spreadof HRP through the white matter to involve the cortex surrounding the lateral (area 11) and the rostra1 (areas 6, 32) (not shown in Fig. 1). In all cases, the parietal injection siteswere centered in the lateral parietal cortex bordering the posterior bank of the intraparietal sulcus (area 7). However, the 3 injection sitesdiffered with respectto the relative involvement of the various subdivisions of Brod- mann’s area7, designated7a, 7b, 7ip by Cavada and Goldman- Rakic (1985). In case 1, the injection site included the cortex dorsal and ventral to the intraparietal sulcus along nearly its entire length (areas 5, 7a, b); HRP reaction product filled the banks and fundus of the posterior half of the sulcusas well (area 7ip). The HRP injection site in case 2 was more limited in- volving only the cortex bordering the posterior two-thirds of the sulcus (areas 7a, caudal 7b). In case 3, silver grains were concentrated in the posterior parietal cortex bordering the mid- dle of the intraparietal sulcus(areas 7a, b), but there was sub- stantial involvement of the posterior bank of the sulcus(area 7ip) and spreadof tritiated amino acids into the cortex dorsal to the sulcusat rostra1levels (area 5). Technical considerations wCASE2 The following description of common efferent targets is based largely on the most optimal case(case 2) in which the frontal injection site was restricted to areas9 and 10 and the parietal inejction site to area 7. Only about half of theseprojections were observed in case1. In part, this wasdue to technical limitations: for example, HRP-reacted sectionswere not collectedrostra1 to the anterior limit of the arcuate sulcus becausethe casewas originally processedto examine common corticostriatal projec- tions; likewise, a portion of the rostromedial was excisedfor another study. However, the absenceof frontal pro- jections in and around the inferior arcuate sulcusand to the frontoparietal operculum and superior temporal cortex in case 1 may indicate that theseprojections ariseeither from the depths of the principal sulcusor from the cortex ventral to the sulcus. Although the frontal injection site in case3 was not restricted (/J/ CASE 3 to areas9 and 10, very few additional common projections were observed,notably to the superiorcolliculus and the caudomedial Figure 1. Prefrontaland parietalinjection sites. In cases1 and 2, lobule. Sincethese projections were present in case1 as well, it tritiated aminoacids (‘H-AA), designatedby cross-hatching, werein- is possible that they originate from the cortex dorsal to the jected into the cortex surroundingthe principal sulcus,while HRP, principal sulcusand from the posterior bank of the intraparietal indicatedby stippling, wasplaced in the posteriorbank of the intra- sulcus(area 7ip), areasthat were not injected in case2. parietalsulcus. Placement of tracerswas reversed in case3. Some mention of the nonconvergent projections of the dor- solateral prefrontal and posterior parietal cortices should be made, although thesewere not analyzed in detail in the present Results study. In general, frontal projections to other frontal areaswere Injection sites more extensive than comparable parietal projections. For ex- Frontal injection siteswere centeredin the caudal two-thirds of ample, in cases2 and 3 (no data are available for case l), pro- the principal sulcusspanning Brodmann’sareas 9 and 10 (Fig. jections from the prefrontal cortex to the cingulate and dorso- 1). In case 1 tritiated amino acids were most densely concen- medial premotor cortices extended much farther rostrally than trated over the dorsal lip of the middle third of the principal thoseoriginating in the posterior parietal cortex. Conversely, in sulcuswith lighter grain density observed in the ventral lip and all casesparietal projections to the temporal and occipital cor- in the cortex dorsal to the sulcus.Dense autoradiographic label tices were more widespreadthan projections from the frontal in case2 was observed throughout the banks and depths of the cortex. Parietal projections extendedonto the dorsaland ventral caudal half of the principal sulcuswith lighter label extending banks of the superior temporal sulcus, although the common The Journal of Neuroscience, Novemaer 1988, 8(11) 4053

Figure 2. Common target areas of the prefrontal and parietal cortices shown in 9 coronal sections through the rhesus monkey brain. All of the projections depicted were observed in case 2 (injection sites shown on a lateral view of the brain) with the exception of the projections to the caudomedial lobule, the medial prestriate cortex, the superior colliculus, and the pontine reticular formation, which were observed in case 3. Nonconvergent projections are not shown on this semischematic diagram. Autoradiographic label representing prefrontal terminal labeling is indicated by cross-hatching HRP reaction product representing parietal terminal labeling is illustrated by stippling. Abbreviations: AC, anterior cingulate cortex; ARC, arcuate cortex; Cd, caudate nucleus; CZ, claustrum; CML, caudomedial lobule; CS, central superior nucleus; DPM, dorsal premotor cortex; FPO, frontoparietal operculum; INS, insular cortex; ZPS, intraparietal sulcus; LD, lateral dorsal nucleus of the thalamus; MD, medial dorsal nucleus of the thalamus; MPC, medial parietal cortex; MPSt, medial prestriate cortex; NRTP, nucleus reticularis tegmenti pontis; OFC, orbitofrontal cortex; PARA, parahippocampal cortex; PC, posterior cingulate cortex; PRE, presubiculum; PS, principal sulcus; Pul, pulvinar nucleus of the thalamus; Put, putamen; SC, superior colliculus; SMA, supplementary motor area; STC, superior temporal cortex; VPM, ventral premotor cortex; VLc, ventral lateral nucleus of the thalamus, pars caudalis. efferent target of the 2 cortices was restricted to the depths of However, comparison of the patterns of projection among the the sulcus.Parietal cortex also projected to the occipital cortex 3 casesenabled us to identify and dismissthose projections that surrounding the lunate and occipitotemporal sulci, areas that did not originate in the intended injection areas.Thus, in case were not innervated by frontal terminals in thesecases. In this 1 with extensive involvement of area 5, terminal labelingfrom regard,projections to the contralateral hemispherealso warrant the parietal injection site was present in the primary somato- consideration.The dorsolateralprefrontal cortex projected pref- sensory and motor cortices but was not observed in case 2, erentially to homotopic and many heterotopic areasof the fron- whoseinjection was confined to area 7. Furthermore, asknown tal cortex, and widespreadprojections throughout the contra- from the literature, the dorsolateralprefrontal cortex doesnot lateral hemispherewere observed from the posterior parietal project to either the primary motor or somatosensorycortex cortex. On the whole, thesecontralateral projections were non- and henceconvergence with parietal terminals was neither ex- convergent. However, a few areasof convergencewere observed pected nor observed in these2 areas. in the opposite hemisphere:Dual terminal labeling from the prefrontal and parietal injection siteswas observed in the con- Projections tralateral principal sulcal and arcuateprefrontal cortices and in Cortical targets the depths of the superior temporal sulcus. Fifteen cortical areasreceived projections from both prefrontal As the injection sitesin this study were made intentionally and parietal injection sitesin the ipsilateral hemisphere(Fig. 2). large to expose the full extent of the efferent circuitry of the Brodmann’s area1designations are used in the following de- dorsolateral prefrontal and posterior parietal cortices, some of scription except where otherwise indicated. In the , them impinged on adjacent areas of cortex, and in all cases, common targetsincluded the supplementarymotor cortex (area spread into the underlying white matter to varying degrees. 6), the dorsal premotor cortex (area 6a of Vogt), the ventral 4054 Selemon and Goldman-Rakic l Prefrontal and Parietal Projections

q parietal SAd , q prefrontal

SAf I ...... - ..*....*...... --__-...... *...... s ...... *.. SAv PSd

PSf

PSV I Ad

2 IAf

IAv mm

3 0.5 mm Figure 3. Composite 2-dimensional reconstruction of prefrontal and parietal terminal fields in layer I of the arcuate cortex, including the , from case 2. The prefrontal and parietal injection sites are shown on a lateral brain view above, and drawings of labeling in 3 frontal sections are illustrated below. Cross-hatching represents the autoradiographic label from the frontal injection site; stippling indicates HRP terminal labeling from the parietalprojection. Note that the prefrontaland parietalprojections form parallelsets of stripesacross the corticalsurface with someoverlap at bordersbetween adjacent stripes. The overlapis moreprominent in layer I than in otherlayers. Abbreviations: IA, inferior arcuate sulcus;PS, principal sulcus; SA, superiorarcuate sulcus; dl, dulcus;vl, ventral;J; fundus.

premotor cortex (area 68 of Vogt), the anterior bank of the At the juncture between frontal and parietal lobes,prominent arcuate sulcus (area 8), the anterior cingulate cortex (area 24) terminal labeling from both injection siteswas present in the and the orbital prefrontal cortex (area 11). In area 8, dual ter- upper bank of the Sylvian fissure(the frontoparietal operculum) minal labelingwas observedthroughout the anterior banks and and in the insular cortex proper (area IG of Jones and Burton, depths of the superior and inferior arcuate sulci and in the 1976). In the frontoparietal operculum, prefrontal and parietal intervening cortex, including the frontal eye fields (Figs. 2, 3). terminal labeling extended from nearly its anterior limit to well In addition, labelingwas observedin the dorsal premotor cortex beyond the level of its intersection with the .[Note in the posterior banks of the arcuatesulci (Figs. 2,3). Prefrontal that this projection probably encompassedmore than one cy- and parietal terminal labeling also extended into the ventral toarchitectonic area, i.e., SI (Brodmann’s areas 1, 2) and SII.] premotor cortex in the posterior bank of the inferior arcuate The common target area within the operculum was located ap- sulcusand onto the convexity of the hemispherejust ventral to proximately midway betweenthe dorsal lip of the Sylvian fissure this sulcus(Figs. 2, 3). On the medial surfaceof the hemisphere, and the insular cortex (Figs. 2; 5, A, B). Labeling was lessex- the 2 projection fields were closely apposedin a limited portion tensive in the insular cortex and located near the level of the of the premotor cortex roughly correspondingto the area that central sulcus (Figs. 2; 9, C, D). On the medial surfaceof the has been physiologically defined as the supplementary motor parieto-, the common efferent targets of the pre- area(Figs. 2; 4, A, B). Ventral to the cingulate sulcus,prefrontal frontal and parietal projections included the entire posterior and parietal terminal fields were interrelated in the caudal half cingulate gyrus (area 23) and the medial parietal cortex (area of the anterior cingulate gyrus (Figs. 2; 4, C, D). In the orbito- 7m) (Figs. 2, 6). frontal cortex, the common projection area was confined to the In the temporal lobe, dual terminal labelingwas most prom- superficial cortex between the medial and lateral orbital sulci inent in the depths of the superior temporal sulcus(area IPa of (Fig. 2). Seltzer and Pandya, 1978) where it was confined to the middle The Journal of Neuroscience, November 1988, @II) 4055

Fig-t m 4. Paired dark-field photomicrographs of adjacent sections through the dorsomedial and anterior cingulate cortices in case 2. A, In the ;omedial cortex, parietal terminals form a dense, broad column on the medial surface of the hemisphere. B, In an adjacent section, a de nse mn of prefrontal terminal labeling is situated ventral to the parietal column, and a smaller, weaker prefrontal column is present dorsally. C,” In tl le anterior cingulate cortex, broad columns of parietal terminals flank (0) a smaller prefrontal column. Arrowheads point to surface landma irks that aid in comparison of adjacent sections. Abbreviation: CS, cingulate sulcus. Magnification: A and B, x 9.5; C and D, x 12.8.

third of the sulcus(Figs. 2; 5, C, 0). Caudally within the tem- 1 and 3, prefrontal and parietal terminals were present in a poral lobe, prefrontal and parietal projections were observed in small outpouching of cortex adjacent to the posterior hippo- the presubiculum (Figs. 2, 7A) and in the parahippocampal campusdesignated the caudomediallobule (Goldman-Rakic et cortex, areaTF of von Bonin and Bailey (1947) (Fig. 2). In cases al., 1984) (Figs. 2, 7B). Finally, a smaller common projection 4056 Selemon and Goldman-Rakic * Prefrontal and Parietal Projections

Figure 5. Dark-field photomicrographs of the frontoparietal operculum and the superior temporal sulcus in case 3. A, In the frontopaxietal operculum, parietal terminals are most densely distributed in layer IV, where 3 dense patches of label are found, and in layer VI. B, In an adjacent section, prefrontal terminals form a dense band in layer I with patches of terminal labeling located directly below in layers III and V. C, Parietal terminal labeling is also concentrated in layers IV and VI in the depths of the superior temporal sulcus; 0, prefrontal terminal labeling is most extensive in layers I, V, and III, respectively. Note that a subtle columnar patterning is superimposed on the more prominent laminar segregation as dense clusters of prefrontal labeling in layers III and V are aligned in a vertical column that is flanked by dense clusters of parietal labeling in layers IV and VI. Abbreviations: STS, superior temporal sulcus; Syl F, Sylvian fissure. Magnification: A and B, x 9.6; C and D, x 8.

area was observed posterior to the caudomedial lobule in the We cannot exclude the possibility that a few additional areas medial prestriate cortex of the occipital lobe (area 19) in case 3 of the ipsilateral hemisphere may receive prefrontal and parietal (Fig. 2). input, as well. One area that is known to receive input from Parietal and prefrontal projections converged to a more lim- both cortices is the in the depth of the rhinal ited extent in the contralateral hemisphere. For example, in case sulcus (Jones and Powell, 1970; Goldman-Rakic et al., 1984; 2 parietal terminal labeling was observed in the ventral bank Seltzer and Pandya, 1984). Although technical difficulties and and rim of the contralateral principal sulcus, which also received considerations limited our evaluation of the rostromedial tem- a dense homotopic projection from the prefrontal injection site poral lobe, prefrontal terminal labeling was observed in the in this case. Farther posterior in the frontal lobe in case 2, of case 3, and parietal terminal labeling was found columns of prefrontal and parietal terminal labeling were ap- in this same area in case 1. It seems unlikely that any other posed in the anterior bank ofthe superior arcuate sulcus. Beyond common target areas in the ipsilateral hemisphere would have the central sulcus, a small prefrontal projection to the cortex in been missed in the present study since all other areas of the the depths of the contralateral superior temporal sulcus, an area brain were analyzed in detail in at least 2 of the 3 cases. More- which receives bilateral innervation from the posterior parietal over, the projections described in the present study are in agree- cortex, was seen in case 3. Although dual terminal labeling was ment with the results of previous single-labeling studies (see not observed in the insular cortex in any case, a frontal projec- Table 1). tion to the insular cortex was present in case 3, and a parietal Columnar interdigitation of prefrontal and parietal terminal projection was noted in case 2. It is therefore possible that the jelds. In most cortical target areas, columns of terminal labeling insular cortex, and perhaps other areas ofthe contralateral hemi- originating from the frontal injection site alternated spatially sphere, might be added to the list of common efferent targets if with similar columns of parietal labeling. Although overlap of more sections were collected and analyzed. prefrontal and parietal terminal labeling was observed, inter- The Journal of Neuroscience, November 1988, 8(11) 4057

Figure 6. Dark-field photomicro- graphs showing interdigitation of pre- frontal and par&al columns in area 7m in case 2. A, Three faint columns of parietal terminals are located along the medial surface of the hemisphere. B, In an adjacent section, multiple columns of prefrontal terminal labeling are pres- ent, and these appear to be interposed between the parietal columns. In C, three widely spaced columns of parietal terminals are shown in area 7m, while in D, a pair of prefrontal columns are located between 2 of the parietal col- umns in an adjacent section. Arrow- heads serve as points of reference for comparison of the 2 sections. Note that a portion of the parietal injection site is visible in A and C. IPS, intraparietal sulcus. x6.8. digitation of prefrontal and parietal columns appeared to be the tation of prefrontal and parietal columns extended from the preponderant arrangement of these projections. Very little lam- middle of area 24 throughout the entire extent of area 23 to inar specificity was discernible in the columnar projections with well beyond the splenium of the and therefore the exception that layer I often was more densely labeled than including the medial portion of area 7 (Figs. 2, 6). In many other layers in both prefrontal and parietal columns. Columnar instances, adjacent prefrontal and parietal columns traversed patterning was particularly prominent in the anterior (Figs. 2; several sections, which were 400 Mm apart. This same columnar 4, C, D) and posterior cingulate gyrus (Fig. 2) where interdigi- relationship was observed in a limited portion of the supple- 4058 Selemon and Goldman-Rakic - Prefrontal and Parietal Projections

labelingwere superimposedon the more salient pattern of lam- inar alternation. Denseclusters of prefrontal label in layers III and V were alignedwithin a vertical column and often located adjacent to denseclusters of parietal terminals in layers IV and VI. Furthermore, within “parietal” columnsprefrontal terminal labeling appeared to be increasedabove background levels in layers IV and VI, and faint parietal terminal labelingwas present in layers I, III, and V of adjacent “prefrontal” columns. This samelaminar specificity was evident in the contralateral hemi- sphere, though only the layers most denselylabeled in the ip- silateral hemisphere were innervated contralaterally. For ex- ample, in the hemisphereopposite to the injection sitesin case 3, prefrontal terminal labeling was restricted to layer I in the fundus of the sulcus,while parietal terminals were confined to layer IV. In summary, 2 distinct patterns of termination were observed in the common cortical projections of the prefrontal and parietal cortices (Fig. 8). In certain cortical target areas,prefrontal and parietal terminal fields formed an array of interdigitating col- umns, while in other areas,prefrontal and parietal projections converged on the samecolumn or cluster of adjacent columns but terminated within different laminae. However, exceptions to these 2 general patterns were found. For example, a variant B of the laminar patterning found in the frontoparietal operculum and superior temporal sulcuswas observed in the insular cortex Figure 7. Drawing of prefrontal and parietal projection to the temporal (Figs. 2; 9, C, D). Prefrontal terminals were located in layers I, lobe in case 3. A, In the presubiculum, prefrontal and parietal terminals overlap in the molecular layer at posterior levels of the hippocampal III, and V, while the parietal projection terminated in all layers gyrus. B, A column of prefrontal terminals (stippling) is adjacent to a but wasleast densein layer I. Similarly, in the parahippocampal columnar projection from the parietal cortex (crowhatching) in the cortex (area TF), prefrontal terminals were concentrated in caudomedial lobule. Abbreviations: CA, Ammons horn; CC, corpus layer I, whereasparietal terminals were located in deeperlayers callosum; CML, caudomedial lobule; DG, ; Paw, para- (III, V , and VI) (Fig. 2). Finally, the terminal patterning of the hippocampal cortex; PC, posterior cingulate cortex; Pre, presubiculum; PSt, prestriate cortex; Pul, pulvinar. projections of the prefrontal and parietal cortices to the pre- subiculumdiffered from that observed in any other cortical area. In the presubiculum,both prefrontal and parietalterminals were present in layer I of the very sameregion of the posterior pre- mentary motor cortex on the medial surfaceof the hemisphere subiculum; therefore, extensive overlap of prefrontal and pa- (Figs. 2; 4, A, B). In the cortex posterior to the principal sulcus, rietal terminals was observed in this cortical area (Figs. 2, 7A). i.e., the dorsal and ventral premotor cortex and the frontal eye fields,columns of frontal terminals were most prominent in the convexity of cortex between the superior and inferior limbs of Subcortical targets the arcuate sulcus, whereas parietal columns were most nu- Prefrontal and parietal terminal fields were observed in close merous in the banks and depths of the superior and inferior apposition in several subcortical areas(Fig. 2). These included sulci (Figs. 2, 3). Columns of prefrontal and parietal terminal the neostriatum, claustrum, thalamus, superior colliculus, and fields also interdigitated in the premotor cortex just ventral to brain-stem reticular formation. Here again, it should be noted the inferior arcuate sulcus (Fig. 2). In the orbital prefrontal that this list of subcortical target areasmay not be exhaustive. cortex between the lateral and medial orbital sulci, a single Particularly at brain-stem levels, where individual nuclei are column or cluster of columns originating from the prefrontal small, dual innervation of some sites may have been missed cortex was flanked by adjacent parietal columns (Fig. 2). The since only every 5th or 10th section was collected through this projection of the posterior parietal cortex to the caudomedial region. While few nonconvergent projections were observed at lobule waslimited to a singlecolumn of terminals that adjoined the subcorticallevel, one noteworthy exception is the projection a column of prefrontal terminals (Figs. 2, 7B). of the prefrontal cortex to the mesencephaliccentral gray, an Laminar complementarity ofprefrontal andparietal terminal area that apparently does not receive cortical input from the fields. A completely different pattern was noted in prefrontal posterior parietal cortex (Amsten and Goldman-Rakic, 1984). and parietal projections to the frontoparietal operculum and to Neostriatum. The neostriatal projections of the prefrontal and the superiortemporal cortex (Figs. 2, 5). In theseareas, terminal parietal cortices have been describedin detail previously (Se- labeling from the 2 cortices was present in the same columns lemon and Goldman-Rakic, 1985) and therefore will not be or cluster of adjacent columns but exhibited a laminar comple- repeatedhere. In the presentcontext, the main finding was that mentarity. In both regions,prefrontal terminal labelingwas con- prefrontal and parietal cortices project to adjacent territories centrated in layer I, with a moderate distribution in layers III within the neostriatum throughout the longitudinal extent of and V, whereasparietal terminals occupied mainly layer IV but this subcortical structure (Figs. 2; 9, A, B). also layer VI directly beneath the prefrontal terminal labeling. Claustrum. Prefrontal and parietal projections terminated It is interesting to note, however, that faint columns of terminal throughout the entire A-P extent of the claustrum(Fig. 2); how- The Journal of Neuroscience. November 1988, 8(11)

INTERDIGITATION PDDE anterior cingulate prefronta

I parietal II & III

IV

V

VI

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CXklE'-YUmmE superior temporal sulcus

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II & III

Figure 8. Schematicillustration ofthe 2 patternsof corticaltermination ob- IV servedin the presentstudy. In most corticalregions (e.g., in the anteriorcin- V gulate cortex), prefrontal and parietal terminal labeling forms an interdigitat- ing array of columns. A second, less commonpattern was observed (e.g., in VI the superior temporal sulcus) in which prefrontal terminals occupy layers I, III, and V with parietal terminals filling v\rM complementary layers IV and VI. ever, at anterior levels of the claustrum the relationships of these throughout virtually the entire A-P expanse of the thalamus 2 terminal fields was obscured by the presence of large numbers with very little overlap between parietal and prefrontal fields of prefrontal fiber bundles. More posteriorly within the claus- (Figs. 2, 11). Moreover, the relative size of the 2 projections trum, prefrontal and parietal terminal fields were adjacent with- shifted suchthat the prefrontal projection was much larger than in the ventral portion of the nucleus (Figs. 2; 9, C, D; 10). In the parietal projection at rostra1levels of the thalamus,and the some paired sectionsthe parietal terminal field appearedto be reverse was true caudally in the thalamus. interposed between dorsally and ventrally adjacent territories In the rostra1thalamus, the prefrontal cortex projected bilat- of prefrontal terminal labeling (Fig. 9, C, D). erally to the anterior medial (AM) and midline nuclei (Fig. 11). Amygdala. A weak projection from the parietal injection site The prefrontal projection to AM formed a continuous, dorsally to the basolateralnucleus of the amygdalawas observed in case located band that extendedfrom the lateral border of AM across 2, and a prefrontal projection to this same nucleus was found the midline to the contralateral border zone as reported pre- in case 3. Therefore, although projections from prefrontal and viously (Goldman, 1979; Preussand Goldman-Rakic, 1987). parietal cortices to the amygdala were not seen in the same In contrast, the parietal projection to AM was situated more animal, it seemslikely that the basolateralnucleus of the amyg- ventrally within AM, had a patchy appearanceand was largely dala is a common efferent target of theseareas. restricted to the ipsilateral hemisphere.The prefrontal projec- Thalamus. In many respectsthe interrelationship of prefron- tion to the midline nuclei consistedof 2-4 discrete patchesof tal and parietal projections in the thalamus resembledthat ob- terminal label. The parietal projection to AM extended into the servedin the neostriatum. In the thalamus, prefrontal and pa- ventrally adjacent midline nuclei, where clusters of prefrontal rietal projections occupied adjacent territories that extended and parietal terminals appearedto avoid one another. The pre- Figure 9. Projections of the prefrontal and parietal cortices to the neostriatum, claustrum, and insular cortex in case 2. A, In the rostra1 neostriatum, parietal terminal labeling is located in the dorsolateral caudate nucleus and extends ventrally into the medial rostra1 putamen. B, Prefrontal terminal labeling is located more medially within the rostral caudate and ventrally adjacent putamen. C, Parietal terminal labeling within the claustrum, as well as a single column of label in the insular cortex, are shown. D, In an adjacent section, 2 clusters of prefrontal terminal labeling in the claustrum are present; comparison of the 2 sections reveals that the prefrontal projection borders the parietal terminal field dorsally and ventrally. A single column of prefrontal terminals overlaps the parietal column in the insular cortex; however, prefrontal terminal labeling is primarily located in layer I, the layer in which parietal labeling is sparse. Arrows and arrowheads point to the same blood vessels in the claustrum and insular cortex, respectively, to facilitate comparison of adjacent sections. Abbreviations: Cd, caudate; ZC, internal capsule; Put, putamen; Syl F, Sylvian fissure. Magnification: A and B, x 6; C and D, x 5. frontal and parietal projections also were coextensive through- projection (Figs. 2; 12, A, B). In LD, the prefrontal terminal out the medial dorsal (MD) and lateral dorsal (LD) nuclei (Figs. field was located dorsomedially; parietal terminal labelingwas 2, 11). While the prefrontal projection densely innervated the situated ventromedially (Figs. 2, 11). Terminal labeling from parvicellular subdivision of MD, parietal terminals formed a both cortices was presentdorsally within the ventrolateral (VL) thin arc at the lateral border of MD. A few clusters of parietal nucleus(Figs. 2, 11). Prefrontal terminal labelingwas restricted terminals extended medially into the prefrontal domain where to a narrow strip of labeling at the dorsal margin of the nucleus they appearedto fit into holesor fenestrationsin the prefrontal adjacent to the capsulesurrounding LD, whereasparietal ter- The Journal of Neuroscience, November 1988, 8(11) 4061

A +25

A+15

A+13

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Figure 10. Drawing of the superimposed projections of the prefrontal and parietal cortices to the claustrum in case 3. Parietal (cross-hatching) and prefrontal (stippling) terminal fields are shown at 5 rostrocaudal levels (A+25-A+ 13) of the claustrum. At rostra1 levels, parietal terminal labeling is located lateral to the prefrontal projection. At more caudal levels, the parietal field shifts to a position dorsal to the prefrontal terminal zone.

minal labelingwas more diffusely distributed over a wide dorsal formation just dorsal to the parietal projection to the ventral band of VL. Prefrontal and parietal projection zones were ap- tegmental nucleus (Fig. 2). posedthroughout the medial pulvinar nucleus as well (Figs. 2; 11; 12, C, D). The large parietal projection occupied a dorsal Discussion territory within the lateral part of the medial pulvinar. The much The dorsolateral prefrontal cortex and the posterior parietal smaller prefrontal projection was contiguous with the medial cortex project to at least 15 distinct areasof the ipsilateralcortex edgeof the parietal terminal field at all A-P levels of the nucleus. (seeSummary diagram, Fig. 14) to at least 3 contralateral cor- Superior colliculus. The intermediate layers of the superior tical areasand to many of the samesubcortical targetsas well. colliculus received projections from the prefrontal and parietal The existenceof an extensive common efferent circuitry suggests corticesin cases1 and 3 (Figs. 2, 13).Both projections exhibited that the prefrontal and parietal corticesare part of a largerneural a discontinouspatterning such that approximately 4 patchesof system that mediatesbehavior in a specific cognitive domain. prefrontal terminal labeling and 4 or 5 patchesof parietal ter- At the cortical level this neural network includespremotor cen- minal labelingwere presentin any given coronal section. While ters, in particular the frontal eye fieldsand supplementarymotor the relationship betweenthe prefrontal and parietal patcheswas cortex, limbic areas,other associationcortices, and a region of not clear-cut, there was someindication of interdigitation of the the somatosensorycortex in the frontal-parietal operculum. 2 terminal fields. Prominent subcortical areas that receive both prefrontal and Pontine reticular formation. In case 3, prefrontal terminals parietal inputs are the neostriatum, thalamus,and claustrum at were found within the central superior nucleus of the reticular telencephalic levels and the superior colliculus and pontine re- 4062 Selemon and Goldman-Rakic - Prefrontal and Parietal Projections

Figure II. Corticothalamicprojections from the prefrontaland parletal cortices at 4 rostrocaudallevels of the thalamusin case3. At rostra1levels, the prefrontalprojection is much largerin sizethan the moreventrally locatedprojection of the parietalcortex. At caudallevels, the parietal projectionenlarges and movesto lie lateral to the smallerprefrontal terminal field. Abbreviations:AD, anterior dorsalnucleus; Al, alaris;AM, anteriormedial nucleus; AV, anterior ventral nucleus;can, capsuleof the anteriornuclei; Cdc, centralnucleus, pars densocellularis; Clc, central nucleus,pars latocellularis; Cl, centrolateralnucleus; Cif; centralnucleus, pars inferior; Cim, centralnucleus, pars intermedialis; Cs, central nucleus, parssuperior; CnMd, centromecliannucleus; LD, lateraldorsal nucleus; le, laminaextema; mtt, mammillothalamictract; MDmJ medialdorsal nucleus,pars multiformis; MDmc, medialdorsal nucleus, pars magnocellularis; MDpc, medialdorsal nucleus, pars parvicellularis; Pa, paraventricular nucleus;Pen, paracentralnucleus; Pul m, medialpulvinar nucleus;Pul I, lateralpulvinar nucleus;Re, nucleusreuniens; Ret, reticularnucleus; Ro, nucleusrotundus; sm, stria medullaris;VA, ventral anterior nucleus;VAmc, ventral anterior nucleus,pars maguocellularis; VLc, ventral lateral nucleus,pars caudalis; VLm, ventral lateralnucleus, pars medialis; VLo, ventrallateral nucleus, pars oralis; VPZ, ventroposteriorinferior nucleus; T/PLO, ventroposterlorlateral nucleus, pars oralis; VPM, ventroposteriormedial nucleus; VPMpc, ventroposteriormedial nucleus, pars parvicellularis; X, areaX.

ticular formation in the brain stem. While it is relatively easy than segregationin all common cortical and subcortical sites to speculatethat prefrontal and parietal input to the frontal eye with the exception of the presubiculum.The segregationof pre- fields and superiorcolliculus may direct eye movementsto spa- frontal and parietal terminal fields suggeststhat the brain utilizes tially coded targets, it is more difficult to assigna specificfunc- the spatial dimension to code incoming information. At the tion to each of the other areas. However, the present findings cortical level, prefrontal and parietal projections were segregated suggestthat areassuch as the superiortemporal sulcusmay play either vertically into spatially distinct columns of terminal la- a role in spatially guided behavior: Physiologic study of these beling or horizontally into different cortical laminae within a regions will provide further insight into their functional rela- seriesof columns. Subcortically, prefrontal and parietal termi- tionship to the dorsolateral prefrontal and posterior parietal nals most often were located in adjacent, longitudinally exten- cortices. sive territories within a given nucleus, as in the neostriatum, claustrum, and pulvinar nucleus of the thalamus but in some Convergenceof prefrontal and parietal terminaljields regionswere located in adjoining nuclei as in the pontine retic- Double labeling of prefrontal and parietal projections in the ular formation and LD/VL nuclei of the thalamus.Thus, at the samemonkey enabledus to examine the preciserelationship of subcortical level, the pattern of prefrontal and parietal termi- the 2 terminal fields. In virtually all areasexamined, prefrontal nation suggeststhat the 2 corticesproject in apposition to most and parietal terminal fields occupieddistinct territories. Overlap subcortical targets. The closenessof their efferent terminations of prefrontal and parietal projections was much lessprevalent is all the more impressive becauseof the wide separationbe- The Journal of Neuroscience, November 1988.8(11) 4063

Figure 12. Dark-fieldphotomicrographs illustrating the projectionof the prefrontaland parietal cortices to the medialdorsal and medial pulvinar nucleiof the thalamusin case3. A, Parietalterminals are situatedat the lateralborder of the medialdorsal nucleus with a few patchesof label foundventrally within the nucleus.B, The prefrontalprojection nearly fills the parvicellulardivision of the medialdorsal nucleus, although unlabeled holesare present in the otherwisedense terminal plexus. In C, the parietalprojection to the pulvinarnucleus occupies au extensive territory within the lateralportion of the medialpulvinar nucleus,whereas in D, the prefrontalterminal field is muchsmaller and more mediallysituated within the pulvinar.Abbreviations: LD, lateraldorsal nucleus; MD, medialdorsal nucleus; Pul, pulvinar.Magnification: A andB, x 15.4;C andD, x 9.25. tween prefrontal and parietal cortices on the cerebral surface. of 2 inputs of the sameneuron, would seemto be rather limited Moreover, there were subcortical nuclei in which some hint of in the caseof prefrontal and parietal inputs. Whether prefrontal interdigitation of prefrontal and parietal projections was ob- and parietal projections terminate on the same neuron at the served: Thesewere the claustrum, the MD nucleusof the thal- cortical level will remain uncertain until appropriate ultrastrnc- amus,where small patchesof parietal terminals appearedto fill tural data areavailable. At leastin thoseregions where prefrontal holes in the much larger prefrontal projection, and in the su- and parietal terminals occupy different laminaewithin a vertical perior colliculus, where patchesof prefrontal and parietal ter- column, it seemshighly probable that the 2 inputs converge minals werealigned along the mediolateralaxis of the colliculus. onto different portions of the dendritic trees of pyramidal neu- Convergencein the strict senseof the term, that is, termination rons (Fig. 8), much as hippocampal inputs are distributed on 4064 Selemon and Goldman-Rakic l Prefrontal and Parietal Projections

gated in part by having adjacent terminal domains inhibit one another (Groves, 1983). In contrast, prefrontal and parietal in- puts to different laminae within a single column may interact cooperatively to reinforce a particular perception or affect a behavior. For instance, the cortex in the depths of the superior temporal sulcus may be an area in which incoming spatial in- formation from the parietal cortex is compared and summated with an internal trace of the spatial world supplied by the frontal input. While the significance of these 2 patterns of termination is obscure at this time, the existence of diverse anatomical re- lationships must in some manner reflect a duality of cortical processing mechanisms. Prefrontal-parietal efferent Circuitry in relation to forward/ feedback schema Recent analyses of cortical pathways in the visual system have shown that forward and feedback projections have distinct lam- inar patterns of termination: that is, forward projections ter- minate primarily in layer IV, whereas feedback pathways ter- minate mainly in layer I (Rockland and Pandya, 1979; van Essen and Maunsell, 1983). Many of the prefrontal and parietal pro- jections described in the present study do not fit either classi- fication because they terminate in a columnar fashion extending throughout all 6 layers, though possibly terminating in different densities in different layers. While we have considered the pos- sibility that columnar patterning might actually represent la- beling of fibers of passage en route to their terminal destination in layer I, the presence of clear-cut laminar patterning, as for example in the projection of the prefrontal cortex to layers I, III, and V of the superior temporal cortex, illustrates that fiber labeling does not obscure discrete terminal labeling within spe- cific layers. In target areas that exhibit discrete laminar pat- Figure 13. Dark-field photomicrographs of the superior colliculus in terning, such as the frontoparietal operculum and superior tem- case 3. The projections of the prefrontal (A) and parietal cortices (B) to poral cortex, the forward and feedback designations may be the intermediate layers of the colliculus are shown. Patches of prefrontal and parietal terminals span the medial-lateral axis of the intermediate applicable. The parietal projections to these areas terminate layers. Arrowspoint to the same 3 blood vessels in these adjacent sec- primarily in layer IV and as such are analogous to forward tions. X 18.8. pathways of the visual system; the prefrontal projections ter- minate largely in layers I, III, and V and therefore have a laminar patterning that may be considered feedback. Thus, the laminar proximal and distal segments of pyramidal neurons in Ammons specificity of prefrontal and parietal terminations may give some horn. indication of the direction of information flow in the cortical circuitry involved in spatial perception. Accordingly, one might suppose that the parietal cortex relays visual information that Dual patterns of prefrontal-parietal termination in the cortex is relevant for spatial perception to temporal and opercular cor- In many cortical target areas, prefrontal and parietal projections tices, which in turn relay spatial percepts to the prefrontal cortex. terminate in adjacent, spatially alternating columns. Columnar The prefrontal cortex, which receives spatial information di- interdigitation of cortical terminal fields was originally described rectly via its corticocortical connections with the parietal cortex for association and callosal inputs to the principal sulcal cortex and indirectly via relays in the temporal and opercular cortices, (Goldman-Rakic and Schwartz, 1982). In areas receiving co- feeds highly processed information back to all of these cortices. lumnar projections, prefrontal and parietal terminals contact Perhaps in regions like the superior temporal cortex, input from primarily separate sets of neurons, that is, neurons in adjacent the prefrontal cortex represents an internal memory trace for columns. A very different pattern of interaction is found in the spatial information which could be compared against incoming, frontoparietal operculum and the superior temporal sulcus where spatial coordinates from the external world via the parietal cor- prefrontal and parietal fields are located in alternating laminae tex. within the same column. The presence of 2 distinct patterns of Previous studies of cortical connectivity have suggested that cortical termination suggests that the integration of prefrontal the prefrontal cortex is the final destination and point of con- and parietal information differs accordingly. Perhaps, prefrontal vergence for multisynaptic relays from the primary visual, au- and parietal inputs act competitively at sites in which they oc- ditory, and somatosensory cortices (Pandya and Kuypers, 1969; cupy adjacent columns such that, for example, either the pre- Jones and Powell, 1970; Chavis and Pandya, 1976). It is inter- frontal or parietal cortex may activate the cingulate cortex at esting in this regard that prefrontal projections throughout the any given moment. An analogous situation may exist in the cortex terminate in layer I; even in regions innervated by a neostriatum, where cortical access to the motor system may be columnar prefrontal projection, terminal density appears to be The Journal of Neuroscience, November 1999,8(11) 4085

Figure 14. Schematicsummary ofthe common cortical targets of the dorso- lateral prefrontal and posterior parietal cortices. The targets depicted are the orbitofrontal cortex, premotor areas in- clusive ofthe supplementary motor area, the frontal eye fields, the anterior and posterior cingulate cortices, the fron- toparietal operculum, the insula, the su- perior temporal sulcus, the medial pa- rietal cortex, the parahippocampal and presubicular cortices, the caudomedial lobule, and the medial prestriate cortex. ZPS, intraparietal sulcus; PS, principal sulcus.

greatest in layer I. This suggests that prefrontal projections are centers may be interconnected in a network such that function relaying highly processed information to areas in which infor- is distributed among the interconnected areas.We proposethat mation processing is more closely attuned to primary sensory the elaborate network of efferent connections uncovered in the perceptions. Thus, in terms of cortical hierarchy, the present present study representsa neural circuit that is functionally findings are consistent with the notion that the prefrontal cortex specialized for spatially guided behavior. This doesnot imply represents the apex of the pyramid, with all other areas feeding functional redundancy but rather indicates that each link in the information forward to and receiving feedback projections from circuit mediates a single aspect of the multifaceted processing the prefrontal cortex. involved in spatially related behavior. Perceptionof the spatial dimension probably is relegated to the occipital and superior Prefrontal-parietal efferent circuitry: a distributed neural temporal cortices, while the cingulate and limbic cortices may net work attach emotional significance or coloring to spatial percepts. Classically, the brain was thought to be composed of function- Certainly, spatially dependent movement would involve pre- ally specialized centers, with each brain center mediating a uni- motor cortices, the basal ganglia, and superior colliculus. In- tary function distinct from that subserved by all other centers. terposedbetween perceptual and motor portions of the circuit However, the concept of focal centers of function does not ex- are the parietal and prefrontal associationcortices. Both of these plain the clinical observation that lesions in many different areas areasorchestrate spatially relatedbehavior; yet even at this level of the brain produce similar deficits. More contemporary views there may be division of labor such that the parietal cortex of functional localization in the brain suggest that several brain constructs spatial coordinates and maps from incoming visual 4066 Selemon and Goldman-Rakic * Prefrontal and Parietal Projections information (Mountcastle et al., 1984), while the dorsolateral prefrontal cortex accesses these representations to govern be- Functional pairing of pre- and post-Rolandic cortices havior requiring memory of spatial position (Goldman-Rakic, The present findings show that 2 widely separated areas of cortex 1987). are tightly linked throughout the neural circuit which governs Recently, Pandya and Yeterian (1984) described a neural cir- spatial perception and behavior. Whether other areas of the cuit for spatial perception with the posterior parietal cortex at prefrontal cortex are linked with post-Rolandic cortices in me- the hub sending efferents to many different areas of the cortex. diating different functions remains to be seen. However, Gold- The present study, which has shown that the prefrontal cortex man-Rakic (1987, 1988) recently has speculated that this may projects to virtually all of these same cortical areas, reveals the be true: She proposes that the prefrontal cortex as a whole per- parallel role that the prefrontal cortex plays in spatially related forms a unitary function, that of holding information gathered behavior. Moreover, the present study shows that the parietal by the more posterior cortices “on-line” in short-term memory. and prefrontal cortices innervate an array of subcortical target Thus, while the dorsolateral prefrontal and posterior parietal areas which should be included in this functionally specialized cortices may be paired via reciprocal corticocortical connections circuit. On the basis of parietal afferent circuitry, Mesulam (198 1) (and via common outflow pathways) in mediating visuospatial proposed that the parietal, frontal eyefields, and cingulate cor- function, the orbitofrontal and inferotemporal cortices may be tices, in conjunction with subcortical reticular areas, form a linked in an analogous circuit to govern auditory-related be- network that controls directed attention. While the connections havior and behavior dependent on detection of specific features described in the present study are efferent, it should be noted of objects, such as their size and shape. Additional double- that with the exception of the presubiculum, all the cortical labeling studies are required to determine whether other pre- projections we observed were reciprocal. Therefore, the circuitry frontal areas are linked with post-Rolandic cortices via a net- we have uncovered represents a much broader and reciprocal work of common efferent targets. If so, the prefrontal-parietal network in which the prefrontal association cortex is a promi- network described here may be paradigmatic of a large number nent and integral part. Furthermore, we suggest that this network of functionally diverse neural circuits. is involved in all aspects of spatial perception and behavior, including attention, perception, memory, and motor control References (Goldman-Rakic, 1987, 1988). Aggleton, J. P., M. J. Burton, and R. E. Passingham (1980) Cortical and subcortical afferents to the amygdala of the rhesus monkey (Mu- Parallel subsystems within the prefrontal-parietal eflerent caca mulatta). Brain Res. 190: 347-368. network Andersen, R. A., G. K. Essick, and R. M. Siegel (1985) Encoding of spatial location by posterior parietal neurons. Science230: 456&X. A recent study from our laboratory has shown that each cy- Amsten. A. F. T.. and P. S.Goldman-Rakic (1984) Selectivenrefrontal toarchitectonic subdivision of the posterior parietal cortex is cortical projections to the region of the iocus ‘coeruleus and raphe reciprocally connected with a distinct region of the prefrontal nuclei in the rhesus monkey. Brain Res. 306: 9-l 8. Asanuma. C.. R. A. Andersen. and W. M. Cowan (198% The thalamic cortex surrounding the principal sulcus (Cavada and Goldman- relations oi’the caudal infer& parietal lobule and-the lateral prefrontal Rakic, 1985). This finding raises the possibility that there is a cortex in monkeys: Divergent cortical projections from cell clusters comparable parcellation of the common efferent circuitry. In in the medial pulvinar nucleus. J. Comp. Neurol. 241: 357-38 1. support of this hypothesis, Cavada and Goldman-Rakic (1986) Baleydier, C., and F. Mauguiere (1980) The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis. have shown that, while each of the subdivisions of the parietal Brain 103: 525-554. cortex (areas 7a, 7b, 7ip, and 7m) project to a dozen or more Barbas, H., and M.-M. Mesulam (198 1) Organization ofafferent input of the common efferent targets, each terminates in a different to subdivisions of area 8 in rhesus monkeys. J. Comp. Neurol. 200: part of the target area. A few target areas do not receive input 407-431. from all subdivisions of the posterior parietal cortex. For ex- Barbas, H., and D. N. Pandya (1987) Architecture and frontal cortical connections of the premotor cortex (area 6) in the rhesus monkey. J. ample, the frontoparietal operculum receives parietal input spe- Comp. Neurol. 256: 21 l-228. cifically from area 7b (Petrides and Pandya, 1984; Cavada and Brodal, P. (1980) The cortical projection to the nucleus reticularis Goldman-Rakic, 1986), whereas the superior temporal sulcus tegmenti pontis in the rhesus monkey. Exp. Brain Res. 38: 19-27. (area IPa of Seltzer and Pandya, 1978) is innervated mainly by Cavada, C., and P. S. Goldman-Rakic (1985) Parieto-prefrontal con- nections in the monkey: Topographic distribution within the pre- areas 7a and 7ip (Seltzer and Pandya, 1984; Cavada and Gold- frontal cortex of sectors connected with the lateral and medial parietal man-Rakic, 1986); likewise, the parahippocampal and presu- cortex. Sot. Neurosci. Abstr. 11: 323. bicular cortices are innervated mainly by area 7a and not by Cavada,C., and P. S. Goldman-Rakic(1986) Subdivisionsof area7 area 7b (Seltzer and Van Hoesen, 1979; Cavada and Goldman- in the rhesusmonkey exhibit selectivepatterns of connectivitywith Rakic, 1986). However, areas 7a, 7b, and 7ip project indepen- limbic,visual and somatosensory cortical areas. Sot. Neurosci.Abstr. 12: 262. dently to a distinct subregion of every other target area described Chavis,D. A., and D. N. Pandya (1976) Further observationson in the present study. Therefore, it appears that areas 7a, 7b, and corticofrontalconnections in the rhesusmonkey. Brain Res. I I: 369- 7ip are each part of a large network of interconnected areas and 386. that the separate networks may be organized in parallel. Ad- Critchley,M. (1953) The ParietalLobe, Edward Arnold, London. Denny-&own, D., and B. Q. Banker (1952) Amorphosynthesisfrom ditional experiments in which small amounts of tracers are placed left varietal lesion.Arch. Neurol.Psvchiatrv 71: 302-313. in reciprocally connected areas of the parietal and prefrontal Funah-ashi,S., C. J. Bruce,and P. S. Goldman-kakic(1986) Perimetry cortices are needed to determine with certainty that intercon- of spatialmemory representation in primateprefrontal cortex: Evi- nected areas project to the same topographic zone within any dencefor a mnemonichemianopia. Sot. Neurosci.Abstr. 12: 554. given target region. If this were so, it might be more accurate Godschalk,M., R. N. Lemon,H. G. J. M. Kuypers,and H. K. Ronday (1984) Corticalafferents and efferentsof monkeypostarcuate area: to think of the circuitry involved in spatial perception as a set An anatomicaland electrophysiologicalstudy. Exp. BrainRes. 56: of parallel circuits, each controlling a particular aspect of spatial 410-424. perception or spatially guided behavior. Goldman,P. S. (1979) Contralateralprojections to thedorsal thalamus The Journal of Neuroscience, November 1988, 8(11) 4087

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