thalamic projections to the posteromedial cortex in the macaque

Thalamic Projections to thePosteromedial Cortex in the Macaque

JOSEPH A. BUCKWALTER,1* JOSEF PARVIZI,1 ROBERT J. MORECRAFT,2

AND GARY W. VAN HOESEN1

1Department of Anatomy and Cell Biology and Department of Neurology, University ofIowa, Iowa City, Iowa 52242

2Division of Basic Biomedical Sciences, Laboratory of Neurological Sciences, University ofSouth Dakota School of Medicine, Vermillion, South Dakota 57069

ABSTRACTThe medial parietal, posterior cingulate, and retrosplenial cortices collectively constitute

a region of cortex referred to as the posteromedial cortices (PMC). In an effort to shed lighton the neuroanatomical organization of the PMC, we undertook a study to identify andanalyze the thalamocortical connections of these cortices. Retrograde tracer injections wereplaced in the posterior cingulate (PCC), retrosplenial (RSC), medial parietal cortices (MPC),and posterior cingulate sulcus (PCS), and the labeling patterns within the thalamus wereanalyzed. Three afferent projection patterns were observed to the PMC from the thalamus: aPCC/RSC pattern that involved the anterior thalamic nuclei, an MPC pattern that involvedthe lateral posterior and pulvinar nuclei, and a PCS pattern that involved the ventralthalamic nuclei. Additionally, a shared pattern of projections from the anterior intralaminarnuclei (AILN) and posterior thalamic nuclei (PTN) to all cortical regions of the PMC wasobserved. Our findings suggest that distinct regions within the PMC are supplied by distinc-tive patterns of thalamic input, but also share common projections from intralaminar andposterior thalamic sources. In addition, we relate our findings to functional abnormalities inaging and dementia, and address a domain-like pattern of thalamocortical labeling of thePMC that is drawn selectively and collectively from multiple thalamic nuclei. J. Comp.Neurol. 507:1709–1733, 2008. © 2008 Wiley-Liss, Inc.

Indexing terms: thalamus; medial parietal cortex; posterior cingulate cortex; retrosplenial

cortex; precuneus; neuroanatomy

The posteromedial cortices (PMCs) are comprised ofseveral cytoarchitectural regions, namely, Brodmann’s ar-eas 23 and 31 of the posterior cingulate cortex (PCC),areas 29 and 30 of the retrosplenial cortex (RSC), and area7m or PGm of the medial parietal cortex (MPC) and theirvarious subdivisions (Pandya and Seltzer, 1982; Vogt,1993; Vogt et al., 1995, 2005). Areas PEci and PEc occupythe posterior portion of the cingulate sulcus and the supe-rior medial parietal region, respectively. In both humanand nonhuman primates these cortical areas have a sim-ilar topography (Fig. 1). However, in cynomolgus and rhe-sus monkeys, the nonhuman primates examined in thisstudy, the RSC is confined mostly to the upper bank of thecallosal sulcus, whereas in the human this cortical regionextends onto the medial surface, dorsal and posterior tothe splenium of the corpus callosum (Brodmann, 1909;Braak, 1979). Individual regions within the PMC areknown to have varying cortical connections (Pandya andSeltzer, 1982; Cavada and Goldman-Rakic, 1989a,b; More-

craft et al., 1993, 2004; Yukie, 1995; Morris et al., 1999;Leichnetz, 2001; Kobayashi and Amaral, 2003) and sub-cortical connections (Vogt et al., 1979; Baleydier and Mau-guiere, 1985, 1987; Yeterian and Pandya, 1985, 1988,1993, 1995, 1997; Vogt and Pandya, 1987; Schmahmannand Pandya, 1990; Leichnetz, 2001; Shibata and Yukie,2003). However, this knowledge is drawn largely frominvestigations with diverse aims and not from experimen-

Grant sponsor: National Institutes of Health; Grant numbers: NS 19632and NS 14944 (to G.V.H.), NS 046367 (to R.J.M.).

*Correspondence to: Joseph A. Buckwalter, Center for Autism Research,UCSD, 8110 La Jolla Shores Dr., Suite 201, La Jolla, CA, 92037.E-mail: [email protected]

Received 16 February 2007; Revised 29 June 2007; Accepted 19 Decem-ber 2007

DOI 10.1002/cne.21647Published online in Wiley InterScience (www.interscience.wiley.com).

THE JOURNAL OF COMPARATIVE NEUROLOGY 507:1709–1733 (2008)

© 2008 WILEY-LISS, INC.

tal designs aimed at specifically exposing the thalamocor-tical afferents to the PMC in detail.

Multiple studies have consistently highlighted the PMCas an area of interest in a wide array of neural processes(Andreasen et al., 1995; Damasio, 1999; Ogiso et al., 2000;Mazoyer et al., 2001; Gusnard and Raichle, 2001; Lund-strom et al., 2003, 2005; Malouin et al., 2003; Shannonand Buckner, 2004; Vogt and Laureys, 2005; Wagner etal., 2005; Cavanna and Trimble, 2006), and the PMC hasthe highest level of glucose metabolism at rest when com-pared to other areas of the cerebral cortex (Gusnard andRaichle, 2001). These functional aspects of the PMC makethis region particularly interesting for studies of agingand dementia. Although it has been known for some timethat regional decreases in cerebral blood flow exist in bothaging and dementia, recent data suggest that the loss ofcerebral metabolism and cortical dysfunction may be lo-calized to specific cortical regions including the PMC(Buckner et al., 2000, 2005; Matsuda, 2001; Lustig et al.,2003).

To understand the possible functional correlates of thePMC, it is necessary to understand the differential andsimilar neural connectivity of the encompassed corticalareas. We recently presented a comprehensive report ofthe neuroanatomical connections of the PMC with theentire brain including cortical and subcortical connections(Parvizi et al., 2006). The current study was designed tospecifically address the details of the thalamic inputs tothe PMC.

The thalamus is considered to act in concert with thecerebral cortex, forming the substrates of cognitive func-tion. Therefore, we reasoned that thalamocortical projec-tions might reveal both unique patterns related to cytoar-chitectural differentiation, but commonality as well thatmight contribute to the functional observations of thePMC. We recognize that these connections may representonly one aspect of a neural system or systems that con-

tribute to the functions attributed to the PMC. Neverthe-less, an investigation using contemporary retrograde trac-ers to examine thalamocortical connectivity represents animportant endeavor to further elucidate the extrinsic neu-ral systems directly influencing the PMC. The aim of thisinvestigation was to examine the projections from thethalamus to individual cortical areas of the PMC. Thisarticle analyzes three distinct thalamocortical projectionpatterns and also addresses the mutual projections foundwithin each pattern.

MATERIALS AND METHODS

Seven cynomolgus (Macaca fascicularis) and three rhe-sus (Macaca mulatta) monkeys of both genders, weighing2.0–6.1 kg, were utilized for this study (Table 1). TheInstitutional Animal Care and Use Committees at theUniversity of Iowa and the University of South Dakotaapproved all experimental and surgical protocols. Thesealso conformed fully to AAALAC accreditation require-ments and to the Society for Neuroscience Policies on theUse of Animals in Neuroscience Research. Some of thecortical and subcortical connections of several of the ex-perimental cases in this study have previously been de-scribed (Morecraft et al., 2004, 2007; Parvizi et al., 2006;Buckwalter et al., 2007). Cases 1, 2, 3, 7, and 8 correspondto Cases M2-FB-23a/b, M3-FB-30/23a, M1-FB-31, M5-FB-7m, and M7-FB-7m, respectively, in Parvizi et al. (2006),Case 4 corresponds to Case 7 in Morecraft et al. (2007),Cases 4, 5, and 6 correspond to Cases 4, 3 and 7, respec-tively, in Morecraft et al. (2004), and Cases 1, 2, 3, and 7correspond to Cases 3, 1, 2, and 4, respectively in Buck-walter et al., (2007).

Surgical procedures

Each monkey was immobilized with an intramuscularinjection of ketamine (10 mg/kg) before being anesthetized

Abbreviations

AD Anterodorsal nucleusAILN Anterior intralaminar nucleiAM Anteromedial nucleusAV Anteroventral nucleusbsc Brachium of the superior colliculuscal Calcarine fissureCC Corpus callosumCd CaudateCeM Central medial nucleuscgs Cingulate sulcusCL Central lateral nucleusCM Centromedian nucleusCSL Central lateral nucleus, superior partDY Diamidino yellow tracerFB Fast blue tracerGP Globus pallidusH HabenulaIC Internal capsuleips Intraparietal sulcusLD Lateral dorsal nucleusLGN Lateral geniculate nucleusLim Limitans nucleusLP Lateral posterior nucleusLPC Lateral parietal cortexMD Mediodorsal nucleusMDdc Mediodorsal nucleus, densocellular partMDpc Mediodorsal nucleus, parvocellular partMGN Medial geniculate nucleus

MPC Medial parietal cortexNeu-N Anti-neuronal nuclei antibodyOT Optic tractots Occipital temporal sulcusPB Phosphate bufferPC Paracentral nucleusPCC Posterior cingulate cortexPEc Parietal area PEcPEci Parietal area PEciPGm Parietal area PGmPMC Posteromedial cortexPo Posterior nucleusPTC Posterior thalamic complexPu PutamenPul PulvinarPul.A Anterior pulvinarPul.I Inferior pulvinarPul.L Lateral pulvinarPul.M Medial Pulvinarr Reticular nucleusRe Reuniens nucleusRSC Retrosplenial cortexV VentricleVA Ventral anterior nucleusVL Ventral lateral nucleusVLc Ventral lateral nucleus, caudal partVP Ventral posterior nucleus1–47 Brodmann areas 1–47

The Journal of Comparative Neurology

1710 J.A. BUCKWALTER ET AL.

with an intravenous injection of Nembutal (30 mg/kg/hr)or isoflurane inhalation (1.25–2% total volume), the latterof which required intubation and assisted mechanical res-piration. The target injection sites were identified by prox-imity to the corpus callosum and in position relative to the

visible hemispheric sulcal patterns. All injections wereviewed with a surgical microscope to ensure pial penetra-tion between cortical arterioles and veins.

Injections were made with a 31G stainless steel needleattached to a 1-�L Hamilton microsyringe. Retrogradetracers, either Fast blue (FB) (Dr. Illing Plastics,Breuburg, Germany) or Diamidino yellow (DY) (Sigma-Aldrich, St. Louis, MO) were injected at a cortical depth of�2 mm by pressure injection. Each injection consisted of0.25–0.7 �L of a 3–4% in 0.1 M phosphate-buffered (PB)saline solution of the chosen tracer. Digital pictures weretaken to document the cerebral topography in direct rela-tion to the injection site and to assist in accurate recon-struction of the location of the injection during data anal-ysis.

After a survival period of 24–27 days, each monkey wasanesthetized with Nembutal (50 mg/kg) and perfusedtranscardially with 1 L 0.9% saline, followed by 2 L of cold4% paraformaldehyde in 0.1 M PB (pH 7.4). The brain wasflushed with 1 L of 10% sucrose in 0.1 M PB, followed by1 L of 30% sucrose in 0.1 M PB. After removal, the brainwas placed in 30% sucrose in 0.1 M PB and allowed toequilibrate for 2–4 days for cryoprotection at 4°C. Theremaining meninges were then removed and the brainwas photographed from all angles, including the medialsurface, to ascertain sulcal and gyral patterns, the planeof sectioning, and surface location of the injection siteswhen visible.

Tissue processing

After removal the brain hemispheres and brainstemwere frozen with dry ice and cut in the coronal plane at athickness of 50 �m using a sliding microtome. The sec-tions were divided into 10 series, which effectively spacedeach section used for fluorescent visualization of the affer-ent connections by 500 �m. These sections were mountedon gelatin-subbed slides, dried overnight, coverslippedwith DPX neutral mounting medium (Aldrich Chemicals),and stored in a refrigerator (4°C) in light-tight boxes. Theremaining series were used for cytoarchitectural and im-munohistochemical analyses.

Data analysis

At the injection site the outline of the section and ana-tomical landmarks such as sulci, ventricles, and gray andwhite matter interface were traced using darkfield illumi-nation that delineates the internal structures. The follow-ing guidelines were used to estimate the effective uptakearea for each injection site. The site of tracer deposit wasdefined as the small necrotic zone of tissue at the tip of thecannula penetration where tracer remained during thepostsurgical survival period (Conde, 1987). Under fluores-cence illumination the FB deposit appeared yellow or or-ange, whereas for DY it appeared intensely yellow clearlyFig. 1. A: Medial view of macaque brain with PMC outlined with

a dashed line. B: Cytoarchitectural map depicting cortical areas of themedial surface (Morecraft et al., 2004). C: Medial view of human brainwith PMC outlined with a dashed line.

TABLE 1. Summary of Individual Cases and Procedural Information

Case No. 1 2 3 4 5 6 7 8 9 10

Animal ID IM 152 IM 153 IM 150 SDM 27 SDM 30 SDM 29 IM 155 IM 160 IM 162 IM 163Sex M F F F M F M M M MWeight 2.0 kg 2.0 kg 4.5 kg 5.2 kg 6.1 kg 4.5 kg 3.8 kg 4.6 kg 4.2 kg 3.2 kgHemisphere R R L L R L R R R LInjection site 23a/b 30/23a 31 23c PEci 31/PGm PGm PGm PEc PEcTracer used FB FB FB FB FB DY FB FB FB FBAmount of tracer 0.5 �L 0.5 �L 0.8 �L 0.3 �L 0.3 �L 0.3 �L 0.7 �L 0.6 �L 0.7 �L 0.3 �L


1711THALAMIC PROJECTIONS TO THE PMC

demarcating these areas from surrounding tissue (Fig. 2).The cortical injection site and region of tracer deposit wasverified using adjacent Nissl sections stained with thionin(Fig. 2) as well as homotypical commissural retrogradelabeling in the contralateral hemisphere.

Retrograde fluorescent material was studied using epi-fluorescent illumination and viewed under a NikonOptiphot-2 Microscope. The cell bodies of FB-labeled cellsappear bright and the nuclei of DY-labeled cells appearyellow or white when viewed under fluorescent illumina-tion (Fig. 3). Data from all tissue sections were collectedwith the use of the 2003 updated Neurolucida System(MicroBrightField, Colchester, VT). This software wasloaded onto a Micron Millenia LXA computer connected toa Nikon Optiphot-2 microscope with a motorized stagecontroller and Optronics DEI 750 digital camera. Photo-graphic montages of the injection sites and labeled cellbodies were created using Adobe PhotoShop 7.0 (AdobeSystems, San Jose, CA). Brightness and contrast wereadjusted in the images. In addition, background spotsoutside of the tissue section were removed in the low-magnification Nissl photomicrographs.

In each thalamic section the outline of the thalamus,distinct thalamic nuclei, as well as anatomical landmarkssuch as ventricles, were charted using darkfield illumina-tion. After anatomical outlining, fluorescence illuminationwas used to determine the location of labeled cells withineach nuclei of the thalamus (Fig. 3) and they were markedfor the descriptive purpose of this report. Every tissuesection through the thalamus was charted in this mannerand representative sections were chosen to illustrate thetopographical distribution of labeling patterns. Line draw-ings were made to demonstrate labeling patterns (Figs.4–13) using Adobe Illustrator CS.

Cytoarchitectural analysis

Initially, each cortical injection site was approximatedusing sulcal patterns and various brain atlases and laterverified using adjacent Nissl sections stained with thionin.Cytoarchitectural classifications of the cortical areaswithin the PMC have previously been established (Brod-mann, 1909; von Bonin and Bailey, 1947; Vogt, 1976;Pandya and Seltzer, 1982; Vogt and Pandya, 1987; Ca-vada and Goldman-Rakic, 1989a; Kobayashi and Amaral,2003; Morecraft et al., 2004). In addition to basic cytoar-chitectural analyses, adjacent sections stained forcalcium-binding proteins aided in unique phenotypic iden-tification of cortical injections sites (Nimchinsky et al.,1997). Briefly, each cortical area was identified using thefollowing morphological characteristics.

Posterior cingulate cortex. Area 23 is positioned be-tween the cingulate and callosal sulci, occupying a largeportion of the posterior portion of the crown of the cingu-late gyrus (Vogt et al., 1995). There are several currentperspectives on the organization of this brain region, andfor this project we adopted the view of area 23 beingformed by four major subdivisions. They include areas23a, 23b, 23c, and 23d, which extend dorsally from theventral part of the cingulate gyrus into the lower bank andfundus of the cingulate sulcus, respectively. Area 23a isproisocortex with a thin layer IIIc and medium-sized py-ramidal cells in layer Va and is primarily separated from23b by a less conspicuous layer II with a subtle transitionto layer III. Area 23b has a more discernable layer II withconspicuous large pyramidal neurons in layer IIIc and Va.

Area 23c occupies the ventral bank of the cingulate sulcusand is distinguished from area 23b by a denser layer IVand thinning of deep layer VI. Area 23d lines the fundus ofthe sulcus and its laminar definition is less distinct thanadjacent areas, where infragranular layer V thicknessdiminishes significantly.

Area 31 is located on the medial surface between pari-etal area PGm and area 23. Area 31 is often positionedbetween the cingulate and splenial sulci at the coronallevel above the splenium. It occupies the zone between thePCC and MPC and has well-differentiated layers II, III,and IV (Vogt et al., 2005). For example, it has a particu-larly broad layer III with large, scattered pyramidal neu-rons in layer IIIc (Morecraft et al., 2004) which distin-guishes this area from area PGm.

Retrosplenial cortex. Areas 29 and 30 are identifiedby their position on the upper bank of the callosal sulcus,lateral and medial, respectively. A transition from allocor-tex of the indusiem griseum to proisocortex of area 30occurs within the retrosplenial cortices (Sanides, 1972;Vogt, 1976; Kobayashi and Amaral, 2000). Area 29 isperiallocortex and has an undifferentiated layer III that isdifficult to distinguish from layers II and IV, and is di-vided into medial and lateral segments (Vogt, 1976; Vogtet al., 1995; Ding et al., 2003). In contrast, layer III can bedistinguished from layer IV in dysgranular area 30, al-though distinction from layer II is poorly defined. Area 30abuts area 23a of the PCC; the transition is recognized bythe subtle differentiation of layer II, and the presence ofmedium-sized pyramidal neurons in layer Va in 23a.

Medial parietal cortex. Medial areas PEc, PEci, andPGm are easily distinguished from PCC and RSC by theirindisputable isocortical cytoarchitecture. Area PEc is thecaudal division of area PE extending over the dorsal apexof the hemisphere onto its medial surface. This area has apoorly differentiated layer II, large pyramidal neurons inlayer IIIc, and medium-sized pyramidal cells in layer Va(Pandya and Seltzer, 1982). Area PEci is the extension ofarea PE into the caudal cingulate sulcus and is distin-guished by less conspicuous pyramidal neurons in layerIIIc when compared to other parietal areas (Pandya andSeltzer, 1982), and a noticeable thinning of cortexthroughout the extent of the cingulate sulcus. Area PGmoccupies a large part of the medial surface of the parietallobe, and hence, much of what is known as the precuneus.It has conspicuous layers II and IV and a noticeable thin-ning of cortex as a whole. It is identified by larger pyra-midal neurons in layer III and well-developed layers Vand VI (Pandya and Seltzer, 1982), characteristic featuresof parietal cortex.

Delineation of thalamic nuclei

Thalamic nuclei were defined using a combination ofJones (1985), Olszewski (1952), and Paxinos et al. (2000).The anterior thalamic nuclei refer to anterior dorsal (AD),anterior medial (AM), anterior ventral (AV), and lateraldorsal (LD) nuclei. The anterior intralaminar nuclei(AILN) include central medial (CeM), central lateral (CL),superior central lateral (CSL), which courses superior tothe mediodorsal nucleus (MD), and the paracentral (PC)nuclei. The ventral anterior (VA), ventral lateral (VL),dorsal caudal segment of VL (VLc), and the caudal andoral segments of the lateral ventral posterior (VPLc andVPLo) nuclei form the ventral thalamus. MD and reuniensnuclei (Re) comprise the medial group of thalamic nuclei;



Fig. 2. Epifluorescent photographs of coronal sections through theinjection sites of all 10 cases with adjacent Nissl or Neu-N stains. Thecase number and determined injection sites follows: (A) Case 1: FBinjection of Area 23a/b, (A�) Nissl-stained section corresponding toinjection site in Case 1; (B) Case 2: FB injection of Area 30/23a,(B�) Nissl-stained section corresponding to injection site in Case 2;(C) FB injection of Area 31, (C�) Nissl-stained section corresponding toinjection site in Case 3; (D) Case 4: FB injection of Area 23c,(D�) Nissl-stained section corresponding to injection site in Case 4;(E) Case 5: FB injection of Area PEci, (E�) Nissl-stained sectioncorresponding to injection site in Case 5; (F) Case 6: DY injection of

Area 31/PGm, (F�) Nissl-stained section corresponding to injectionsite in Case 6; (G,H) Cases 7, 8: FB injections of Area PGm,(G�,H�) Neu-N and Nissl-stained section corresponding to injectionsites in Cases 7 and 8, respectively; (I,J) Cases 9 and 10: FB injectionsof Area PEc (I�,J�) Nissl-stained section corresponding to injectionsites in Cases 9 and 10. White arrows identify the injection site inepifluorescent photographs (A–J), while black arrows represent cyto-architectonic boundaries in Nissl and Neu-N-stained sections(A�–J�). Scale bar � 2.0 mm. Portions of this figure were adapted fromFigure 3 of Buckwalter et al., (2007).



Fig. 3. A: Representative Neurolucida charting of Case 2 withinjection in RSC illustrating retrogradely labeled neurons in the an-terior nuclei accompanied by a fluorescent image showing the actualblue fluorescing labeled neurons. Note the high density of labeled cellsin the anterior nuclei (see white arrows). B: Representative Neurolu-cida charting of Case 7 with an injection in PGm illustrating retro-gradely labeled cells dispersed in LP, LD, CL, and MD accompaniedby a fluorescent image showing actual blue fluorescing labeled neu-

rons (see white arrows). Note that neuronal size increases and lowerdensity of labeled cells when compared to (A). Also, note the domain oflabels cells that appears to transcend cytoarchitectural boundaries.The red box in the Neurolucida chartings represents the area depictedin each fluorescent image. The white dotted line identifies thalamicnuclear boundaries. Neurolucida chartings scale bar � 2.0 mm; fluo-rescent images scale bar � 0.25 mm.



MD is further subdivided into a caudal densocellular di-vision (MDdc) and a lateral parvocellular division (MDpc).Posterior nuclei include the lateral posterior nucleus (LP)and the anterior, medial, and lateral divisions of the pulv-inar (Pul.A, Pul.L, and Pul.M). Finally, the limitans-suprageniculate (Li/SG) and posterior (Po) nuclei collec-tively comprise the posterior thalamic complex (PTC).

RESULTS

Thalamocortical connections from 10 cases of injectionsof FB or DY within the PMC were studied (Table 1). Caseswere selected based on accuracy and precision of the in-jections and robust thalamic labeling. The injection depthin all cases presented was �2 mm, involving layers II–VI.Results are presented here in a progression from ventraland caudal PCC to dorsal and rostral MPC. Percentageslisted in Table 2 and following each nucleus in the testrepresent the estimated percentage of labeled cells withineach nucleus as compared to the entire thalamus.

Case 1 (IM 152)

In Case 1 an FB injection was located in the rightposterior cingulate gyrus involving area 23. The site oftracer deposit was judged as confined to area 23a withslight infringement into area 23b (Fig. 4A,B).

In the anterior portions of the thalamus, labeling wasfound in the anterior group of nuclei, including AM (3.2%),AV (8.4%), and LD (5.7%); however, AD contained no

labeled neurons (Fig. 4C–E). Retrograde labeling was alsonoted in AILN, including CeM (12.0%), CL (7.2%), CSL(5.0%), and PC (6.8%) (Fig. 4C–E). The labeling in theanterior nuclei was near the border with the internalmedullary lamina, thus making the labeling in AILN andthe anterior nuclei a seemingly noninterrupted strip (Fig.4C). Anterior nuclear labeling was restricted to AV inmore caudal sections; however, labeling in AILN contin-ued through most of the anteroposterior extent of thethalamus including the more caudally positioned CSL(Fig. 4F). Additionally, a few labeled cells were noted in Re(3.8%) (Fig. 4D) and the most dorsal segments of VLc(3.8%) (Fig. 4E,F).

In posterior portions of the thalamus, labeling was ob-served in the dorsal portion of LP (6.1%) (Fig. 4G), Pul.A(2.1%), the dorsal and ventral portions of Pul.L (4.3%), andPul.M (13.6%) (Fig. 4H). MDpc (2.7%) (Fig. 4G) and caudalsegments of MDdc (7.2%) (Fig. 4H) also contained labeledneurons. Labeling was present in PTC; including denselabeling in Li/SG (6.8%) and Po (1.4%) forming a densestrip of labeled cells along the thalamo-mesencephalicjunction (Fig. 4H). Overall, labeling in this case was evi-dent in: the anterior nuclei, excluding AD, AILN, LP,dorsal portions of PTC, and Pul (Fig. 4).

Case 2 (IM 153)

In Case 2 an FB injection was confined to cortex imme-diately posterior and dorsal to the splenium of the corpuscallosum. The tracer deposit for this case was judged to

TABLE 2. Summary of Labeled Cells in the Thalamus

Projection Pattern PCC/RSC Pattern PCS Pattern MPC Pattern

Case Number 1 2 3 4 5 6 7 8 9 10

Injection Site 23a/b 30/23a 31 23c PEci 31/PGm PGm PGm PEc PEc

AnteriorNuclei

AD — 1.3% — — — — — — — —

AM 3.2% 10.6% 1.4% — — — — — — —AV 8.4% 16.1% 4.4% — — — — — — —LD 5.7% 21.9% 5.4% 2.5% 1.7% 2.5% — 2.3% 0.9% 1.0%Total 17.2% 50.0% 11.2% 2.5% 1.7% 2.5% 0.0% 2.3% 0.9% 1.0%

AnteriorIntralaminarNuclei

CeM 12.0% 9.3% 5.9% 2.9% 5.2% 1.0% 11.8% 8.8% 6.2% 6.6%

CL 7.2% 4.0% 2.5% 2.8% 1.7% 5.5% 0.7% 5.9% 4.8% 2.8%CSL 5.0% — 1.7% — 1.7% — — 2.9% 4.1% —PC 6.8% 9.5% 3.7% 5.0% 3.9% 2.4% 6.3% 2.4% 5.8% 5.1%Total 31.0% 22.7% 13.7% 10.8% 12.5% 8.9% 18.8% 20.1% 20.9% 14.5%

VentralNuclei

VA — — 0.4% 10.9% 5.2% — — — — —

VL — — — 9.9% 5.0% — — — — —VLc 3.8% 2.4% 7.3% 9.4% 4.8% 5.6% 5.9% 9.4% 10.0% 10.8%VPLc — — — 0.8% 2.9% — — — — —VPLo — — — 3.9% 4.6% — — — — —Total 3.8% 2.4% 7.7% 34.8% 22.5% 5.6% 5.9% 9.4% 10.0% 10.8%

MedialNuclei

MDdc 7.2% 3.2% 1.7% 2.7% 4.9% 8.2% 3.1% 8.0% 3.3% 2.2%

MDpc 2.7% — 5.0% 7.0% 0.9% 2.1% — 4.0% — —Re 3.8% — — — 0.7% — — 0.5% — —Total 13.8% 3.2% 6.6% 9.8% 6.5% 10.3% 3.1% 12.6% 3.3% 2.2%

PosteriorNuclei

LP 6.1% 0.8% 30.5% 11.8% 10.7% 21.9% 19.5% 20.1% 22.9% 18.7%

Pul.A 2.1% 0.6% 5.7% 11.3% 3.9% 11.8% 9.5% 10.7% 12.8% 11.8%Pul.M 13.6% 7.9% 7.4% 9.1% 8.5% 8.2% 5.9% 8.0% 10.6% 12.2%Pul.L 4.3% 6.9% 11.0% 1.6% 24.7% 22.2% 31.7% 6.7% 12.9% 20.8%Total 26.1% 16.2% 54.6% 33.8% 47.9% 64.1% 66.6% 45.5% 59.2% 63.4%

PosteriorThalamicNuclei

Li/SG 6.8% 4.0% 3.8% 5.7% 5.6% 5.1% 2.8% 4.8% 3.2% 5.8%

Po 1.4% 1.6% 2.4% 2.7% 3.4% 3.5% 2.8% 5.4% 2.5% 2.3%Total 8.1% 5.6% 6.1% 8.4% 9.0% 8.7% 5.6% 10.2% 5.7% 8.1%

Thalamus Total 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%

Relative percentages of labeled cells are listed for each nucleus and for each group of nuclei (in bold). Dash represents no observed labeling. Note the relative percentage differencesof observed labeling in the anterior nuclei in Cases 1–3, in the ventral nuclei in Cases 4 and 5, and in the posterior nuclei in Cases 6–10.



Fig. 4. Diagram illustrating Case 1 placement of retrograde tracer(black oval) in area 23a/b on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through thethalamus from anterior to posterior demonstrating the distribution of

labeled neurons. Note the dorsal pattern of labeling observed through-out the thalamus from AV to dorsal Pul. The numbers in parentheses,shown here and in Figures 5–13, correlate to the approximate coronallevel reported by Olszewski (1952).


Fig. 5. Diagram illustrating Case 2 placement of retrograde tracer(black oval) in area 30/23a on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through thethalamus from anterior to posterior demonstrating the distribution of

labeled neurons. Note the dorsal pattern of labeling observed through-out the thalamus from AV to dorsal Pul and the high density oflabeling in the anterior nuclei. This figure was adapted from figure 4of Parvizi et al. (2006).


involve primarily area 30 with a smaller portion of theuptake zone located in posterior area 23 (Fig. 5A,B). Area29, also of the RSC, was not within the injection uptakesite.

Retrograde labeling was noted in all nuclei of the ante-rior thalamic group, including AD (1.3%), AM (10.6%), AV(16.1%), and LD (21.9%) (Fig. 5C–G). In anterior portionsof the thalamus, labeled cells formed a dense cluster en-compassing many neurons of these nuclei (Fig. 5C). Also,AILN, including CeM (9.3%), CL (4.0%), and PC (9.5%)contained labeled neurons (Fig. 5C–G). Again, a denselabeling pattern existed between the AILN and the ante-rior nuclei that seemed to form a bridge between thesestructural subsectors, similar to Case 1. However, unlikeCase 1 the majority of labeling was in the anterior nuclei.The labeling in AILN did not continue posteriorly as inCase 1, as it ceased when the anterior complex ended.Also, no labeled cells were found in CSL. A few labeledcells were scattered throughout VLc (2.4%) (Fig. 5E,F).

Very few cells were found in LP (0.8%). A few labeledcells were identified in Pul.A (0.6%) and the superior seg-ments of Pul.L (6.9%) and Pul.M (7.9%) (Fig. 5H), al-though this cell group appeared to be continuous withlabeling in LD. MDdc (3.2%) contained a few labeled cellsin the very posterior and dorsal segments (Fig. 5H). As inCase 1, PTC was intensely labeled on the thalamo-mesencephalic border, including labeling in both Li/SG(4.0%) and Po (1.6%) (Fig. 5H). Overall, the pattern oflabeling in this case was primarily restricted to the ante-rior and dorsal segments of the thalamus (Fig. 5).

Case 3 (IM 150)

Case 3 had an FB injection into the posterior aspect ofthe PCC, located between the ascending branch of thecingulate sulcus and the splenial sulcus (Fig. 6A,B). Cy-toarchitectural analysis placed the injection in area 31.

Labeled cells were observed in the anterior thalamicnuclei, including AM (1.4%), AV (4.4%), and LD (5.4%),but not AD (Fig. 6C–F). These cells seemed to be located inspecific regions of the nuclei and not distributed through-out their entirety as seen in Case 2. Labeling was presentin AILN including CeM (5.9%), CL (2.5%), CSL (1.7%), andPC (3.7%) (Fig. 6C–F). As in Cases 1 and 2, it was difficultto distinguish clear borders between the anterior nucleiand AILN, as the labeled cells occupied both cytoarchitec-turally determined nuclear territories, as well as the an-atomical territory between the two. Labeling was alsoobserved in the dorsal region of VLc (7.3%) (Fig. 6E,F) anda small number of cells were found in VA (0.4%).

The retrograde labeling in VLc was continuous, withlabeled cells in LP (30.5%) and Pul.A (5.7%) forming amassive projection site in the dorsal posterior thalamicregion (Fig. 6F,G). This injection also yielded a uniquepattern of labeling throughout the posterior part of thethalamus. Labeling in MD encompassed both MDdc (1.7%)and MDpc (5.0%) (Fig. 6F–H). Furthermore, Pul.L (11.0%)and Pul.M (7.4%) displayed a number of labeled cells andlabeling was also observed in PTC, i.e., Li/SG (3.8%) andPo (2.4%) (Fig. 6G,H).

Case 4 (SDM 27)

In Case 4 an FB injection was placed in area 23c alongthe ventral bank of the cingulate sulcus. The estimatedtracer deposit zone was �2 mm from the medial face of the

interhemispheric fissure within the cingulate sulcus (Fig.7A,B).

No labeled neurons were observed within the confines ofthe anterior thalamic nuclei, with the exception of a fewscattered cells in LD (2.5%) (Fig. 7F). Labeled neuronswere observed in AILN including CeM (2.9%), CL (2.8%),and PC (5.0%) (Fig. 7C,D,F). These cells were widelyspaced and very sparse, unlike the previous two cases. Anew pattern of labeling revealed labeled neurons in thelateral segments of the VA (10.9%) and VL (9.9%) forminga crescent-shaped band that outlined the lateral bound-aries of the nuclei in close proximity to the external med-ullary lamina (Fig. 7C,D). A small cluster of labeled cellswas also observed in the inferolateral segment of VPLo(3.9%) (Fig. 7F) and a small number of cells were observedin VPLc (0.8%). Labeling was also observed in the dorsalregion of VLc (9.4%).

LP (11.8%), MDdc (2.7%), MDpc (7.0%), Pul.A (11.3%),and Pul.L (1.6%) all had labeled cells (Fig. 7F–H). PTChad a somewhat different pattern of labeling in that thesecells formed a strip at the thalamo-mesencephalic border,occupying most of Li/SG (5.7%) and Po (2.7%). However, incontrast to Cases 1 and 2, the field of labeled cells ex-panded to include posterior segments of Pul.M (9.1%) (Fig.7H). In addition, this case demonstrated heavier labelingin posterior regions, LP, Pul.A, and Pul.M, than seen inprevious cases and as emphasized above there was a no-ticeable absence of labeling from AM and AV (Fig. 7).

Case 5 (SDM 30)

In Case 5 an FB injection was placed on the ventralbank of the extreme caudal tip of the cingulate sulcus,corresponding to the rostral portion of PEci. The region oftracer deposit was restricted to the lower bank of thesulcus (Fig. 8A,B). The pattern of labeling was very sim-ilar to that seen in Case 4 in which the injection waslocated in area 23c.

No labeled cells were observed in the anterior thalamicnuclei, except for a few cells in the inferomedial LD (1.7%).Labeling was observed in AILN, including CeM (5.2%), CL(1.7%), CSL (1.7%), and PC (3.9%) (Fig. 8C–F). As in Case4, labeled cells were observed in the anterolateral seg-ments of VA (5.2%) and VL (5.0%) nuclei forming a linethat outlined the lateral subsector near the boundary ofthe external medullary lamina (Fig. 8C,D). Labeled cellswere also found in VLc (4.8%) and the superior and infero-lateral portions of VPLc (2.9%) and VPLo (4.6%) (Fig.8D–F). A few cells were observed in Re (0.7%) (Fig. 8C).

More posteriorly, labeled neurons in MDdc (4.9%) ap-peared to interdigitate with labeled cells in extreme pos-terior parts of CL due to the indistinct boundary betweenthese two nuclei. These cells, together with labeled cellswithin CSL, and LD formed an ostensibly singular clusterof labeled cells (Fig. 8E,F). A few labeled cells were alsoobserved in MDpc (0.9%) (Fig. 8G). Labeled cells werefound in both LP (10.7%) and Pul.A (3.9%) (Fig. 8E,F).Pul.L (24.7%) and Pul.M (8.5%) demonstrated a uniquelabeling pattern; the cells formed a tier-like configurationwithin the pulvinar nuclei in which there was an absenceof labeling between the tiers (Fig. 8G). A large number oflabeled cells occupied the PTC, occupying both Li/SG(5.6%) and Po (3.4%). Again, these cells formed a strip thatspread over the surface on the interface between the di-encephalon and mesencephalon (Fig. 8G).



Fig. 6. Diagram illustrating Case 3 placement of retrograde tracer(black oval) in area 31 on (A) medial surface and (B) coronal section.C–H: Neurolucida chartings of coronal sections through the thalamus

from anterior to posterior demonstrating the distribution of labeledneurons. Note the dorsal pattern of labeling and the high density oflabeling in posterior nuclei LP and Pul.



Fig. 7. Diagram illustrating Case 4 placement of retrograde tracer(black oval) in area 23c on (A) medial surface and (B) coronal section.C–H: Neurolucida chartings of coronal sections through the thalamus

from anterior to posterior demonstrating the distribution of labeledneurons. Note the lateral pattern of labeling observed in VA, VL, andVPL.



Fig. 8. Diagram illustrating Case 5 placement of retrograde tracer(black oval) in area PEci on (A) medial surface and (B) coronal section.C–H: Neurolucida chartings of coronal sections through the thalamus

from anterior to posterior demonstrating the distribution of labeledneurons. Note the lateral pattern of labeling that appears in VA, VL,and VPL similar to the pattern observed in Case 4, Figure 7.



Case 6 (SDM 29)

In Case 6 a DY injection was placed �2 mm inferior tothe ascending ramus of the cingulate sulcus involvingprimarily dorsal area 31 with some tracer uptake in ros-tral PGm (Fig. 9A,B). In most DY injections the site oftracer deposit is more focused than that of FB (Conde,1987); however, in this case the deposit and uptake zonewas comparable to FB injections.

No labeled cells were observed in the anterior thalamicnuclei, except some labeled cells were found in the infero-lateral portion of LD (2.5%) (Fig. 9D,E). As in other cases,labeling was observed in AILN, including CeM (1.0%), CL(5.5%), and PC (2.4%) (Fig. 9C,F), although the density ofcells was much less than noted in other injections used inthis study, and no labeled cells were found in CSL. La-beled cells were noted in VLc (5.6%) (Fig. 9D,E).

The labeled cells in LD and adjacent VLc formed asmall, continuous cluster that crossed the architectoni-cally delineated thalamic boundaries (Fig. 9E). MDdc(8.2%) and MDpc (2.1%) showed a sparse pattern of label-ing (Fig. 9F,G). A heavy cluster of labeling in Pul.L(22.2%) and Pul.M (8.2%) seemed continuous with thelabeled cells in LP (21.9%) (Fig. 9F,G). As seen in all othercases, labeling was observed in PTC (Fig. 9G), Li/SG(5.1%), and Po (3.5%). The overall results of this experi-ment showed that labeling was present in the AILN, LD,LP, MD, PTC, and Pul (Fig. 9).

Case 7 (IM 155)

In Case 7 an FB injection was placed �2 mm below themost posterior segment of the ascending ramus of thecingulate sulcus and slightly posterior to the injectionlocation in Case 6, encompassing rostral PGm (Fig.10A,B). Labeling was similar to that seen in Case 6, withone major exception. In Case 7 no labeled cells were ob-served in LD as they were in Case 6.

In anterior segments of the thalamus no labeling wasseen in any of the anterior thalamic nuclei, in contrast toCase 6, which had labeling in LD. AILN labeling wasconfined to the anterior regions of CeM (11.8%), CL (0.7%),and PC (6.3%) (Fig. 10C,D) and no labeling was seen atmore posterior levels. Occasional labeling was observed inthe dorsal region of VLc (5.9%) (Fig. 10D–F).

Very light labeling was observed in MDdc (3.1%) (Fig.10G). Labeled cells were observed in LP (19.5%) and Pul.A(9.5%) (Fig. 10F,G), and a pattern of labeling like previouscases was seen in the PTC, in both Li/SG (2.8%) and Po(2.8%) (Fig. 10H). Labeled cells were scattered throughoutboth Pul.L (31.7%) and Pul.M (5.9%) (Fig. 10H). The in-jection site in Case 7 was slightly posterior to Case 6 andthe absence of labeling in LD in this case highlights theconnectional idiosyncrasies that exist for adjacent corticalareas.

Case 8 (IM 160)

In Case 8 FB was injected �4 mm below the ascendingramus of the cingulate sulcus in dorsal PGm. This injec-tion was similar to Case 7, only slightly inferior (Fig.11A,B).

Anteriorly, no labeled cells were seen in any of theanterior nuclei, with the exception of a few labeled cells inthe inferomedial (Fig. 11E) and inferolateral portions ofLD (2.3%) (Fig. 11F). Labeled cells were present in AILNincluding, CeM (8.8%), CL (5.9%), CSL (2.9%) and PC

(2.4%) (Fig. 11C–G). As in Case 7, labeled cells were ob-served in the dorsal portion of VLc (9.4%) (Fig. 11E,F).Also, a few labeled cells were observed in Re (0.5%), di-rectly inferior to the labeled cell in CeM (Fig. 11D).

A dense distribution of labeling occupied LP (20.1%) andPul.A (10.7%) , which formed an arch in the posterior anddorsal part of the thalamus (Fig. 11G). Labeled neuronswere also located in MDdc (8.0%) and MDpc (4.0%), whichformed a continuous population with the labeled cells inLP (Fig. 11G,F). Labeled cells were present in PTC form-ing a projection pattern similar to that seen in all othercases (Fig. 11H), Li/SG (4.8%) and Po (5.4%). Pul.L (6.7%)and Pul.M (8.0%) displayed a number of labeled cells thatoccupied both divisions of the nuclei (Fig. 11H). Overall,the pattern of labeling in Case 8 was very similar to Case7, different only in the relative amount of labeled cellsobserved in individual nuclei and a few labeled cells ob-served in the inferolateral portion of LD in Case 8.

Case 9 (IM 162)

In Case 9 FB was injected into the rostral segment ofPEc on the dorsomedial surface. This cytoarchitecturalregion courses onto the dorsolateral crest of the hemi-sphere extending slightly in the lateral posterior parietalregion. The zone of tracer deposit in this case was localizedto a cortical territory posterior to the termination of thecingulate sulcus on the medial surface, �2 mm inferior tothe dorsal convexity (Fig. 12A,B).

There were no labeled cells in any of the anterior tha-lamic nuclei, except for a few cells in ventral LD (0.9%)(Fig. 12E). As in other cases, labeled cells were observed inAILN, consisting of the CeM (6.2%), CL (4.8%), and PC(5.8%) (Fig. 12C–G). In this case, there were many labeledcells in CSL (4.1%) as well (Fig. 12E,F). A large number ofcells were also observed in VLc (10.0%) (Fig. 12E,F).

MDdc (3.3%) and LP (22.9%) contained labeled cells,and a few labeled cells were noted on the border of theventrolateral portion of LD (Fig. 12E–G). This cluster ofcells appeared continuous with the labeled cells observedin VLc. Labeling was found in Pul.A (12.8%), Pul.L(12.9%), and Pul.M (10.6%) (Fig. 12G,H). There were la-beled cells present in PTC with a number of cells in Li/SG(3.2%) and Po (2.5%) (Fig. 12H).

Case 10 (IM 163)

In Case 10 FB was injected into the very caudal seg-ments of PEc on the dorsal surface (Fig. 13A,B). Thisinjection site was posterior and lateral to the injection siteof Case 9 but the tracer deposit zone was still withincytoarchitectural area PEc, as this cortical area occupiesmost of the caudal parietal lobe on both the medial andlateral surfaces. The thalamocortical inputs were similarto those seen in Case 9, with a few slight differences.

No labeling was observed in the anterior thalamic nu-clei, with the exception of a few labeled cells that lined theventral border of LD (1.0%) (Fig. 13F). The AILN includ-ing CeM (6.6%), CL (2.8%), and PC (5.1%) contained la-beled cells (Fig. 13C–E). Labeled cells were observed inVLc (10.8%) (Fig. 13E,F).

Labeling in MDdc (2.2%) was sparse and confined to theposterior centrolateral region (Fig. 13H). Labeling wasalso noted in the PTC, both Li/SG (5.8%) and Po (2.3%)(Fig. 13H). Labeling in LP (18.7%), Pul.A (11.8%), Pul.L(20.8%), and Pul.M (12.2%) was comparable to Case 9 inboth location and number of labeled cells (Fig. 13F–H).



Fig. 9. Diagram illustrating Case 6 placement of retrograde tracer(black oval) in area 31/PGm on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through the

thalamus from anterior to posterior demonstrating the distribution oflabeled neurons. Note the lack of labeling in the anterior nuclei exceptLD.



Fig. 10. Diagram illustrating Case 7 placement of retrogradetracer (black oval) in area PGm on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through the

thalamus from anterior to posterior demonstrating the distribution oflabeled neurons. Note the lack of labeling in the anterior nuclei withmore considerable labeling in the posterior nuclei.



Fig. 11. Diagram illustrating Case 8 placement of retrogradetracer (black oval) in area PGm on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through thethalamus from anterior to posterior demonstrating the distribution of

labeled neurons. Note the lack of labeling in the anterior nuclei andthe robust labeling in the posterior nuclei that crosses cytoarchitec-tural boundaries.


Fig. 12. Diagram illustrating Case 9 placement of retrogradetracer (black oval) in area PEc on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through the

thalamus from anterior to posterior demonstrating the distribution oflabeled neurons. Note the absence of labeling in the anterior nucleiand heavy labeling in the posterior nuclei.



Fig. 13. Diagram illustrating Case 10 placement of retrogradetracer (black oval) in area PEc on (A) medial surface and (B) coronalsection. C–H: Neurolucida chartings of coronal sections through the

thalamus from anterior to posterior demonstrating the distribution oflabeled neurons. Note the lack of labeling in the anterior nuclei andthe heavy labeling observed in the posterior nuclei.



The pattern observed in Case 10 was very similar to Case9, differing only in the relative number of labeled cells inindividual nuclei.

General Summary of Results

In each case the pattern of connections demonstrateddistinctive thalamocortical input to the different cytoar-chitectural areas of the PMC. Comparatively, PCC andRSC received more projections from the anterior thalamicnuclei, including AV and AM, whereas MPC received in-put predominately from more posterior nuclei, such as LPand Pul. Cortex within the posterior region of the cingu-late sulcus, including areas 23c and PEci, received inputfrom anterolateral segments of VA, VL, and VPL. Despitethe differences in thalamic projections to all cortical areasanalyzed, a common pattern of projections also existed;namely, all cortical areas investigated within the PMCreceived input from the AILN, LP, MDdc, dorsal Pul, andPTC (Table 2), although the relative density and percent-age of retrogradely labeled cells varied with each case.

DISCUSSION

The extrinsic neural connectivity of the PMC has re-mained largely underexplored due to its surgical inacces-sibility and the presumption of connectional and func-tional commonality to neighboring cingulate and parietalassociation cortices. A major aim of this investigation wasto examine the thalamocortical input to the different sub-regions forming the PMC with the working hypothesisthat connectional patterns may parallel the diverse cyto-architectural and functional correlates affiliated with thisbrain region. Although the thalamocortical connectionsrepresent only part of a larger neural network, we believethat these projections reveal systematic differences withinthe PMC that may assist in interpreting functional obser-vations in previous as well as future studies. These differ-ences, as well as observed connectional commonalities,form the core of the discussion that follows.

Thalamocortical projections to the PMC

The thalamocortical connections evaluated in this studyreveal three distinct patterns of connectivity to the PMC:a PCC/RSC pattern, an MPC pattern, and a PCS, each ofwhich is characterized by a distinct set of afferents fromthe thalamus. In addition, area 31 of the MPC demon-strates labeling characteristics of both the PCC/RSC andMPC patterns and is unique in this respect as it appearsto represent, based on connectional grounds, a transi-tional region interposed between the two systems.

Posterior cingulate and retrosplenial thalamocorti-

cal inputs. Cases 1 and 2 represent connections of thePCC and RSC, respectively. The PCC receives robust pro-jections from anterior nuclei, AM, AV, and LD, but notAD. In addition, PCC receives input from posterior asso-ciation nuclei, LP and Pul, as well as lesser input fromVLc and Re. In comparison, the RSC receives projectionsfrom essentially the same thalamic areas with the addi-tion of projections from AD and CSL and the absence ofprojections from Re. Both PCC and RSC receive afferentsfrom PC, CeM, and CL of the AILN, MDdc, and PTC.

Our results confirm previous findings of thalamocorticalprojections to the PCC (Rose and Woolsey, 1948; Vogt etal., 1979) and RSC (Shibata and Yukie, 2003), with theadditional observation of projections from the PTC, which

have not been described. Our observations also show thatthe RSC receives input from the anterior thalamic nucleiAM and AV, which is in contrast to Rose and Woolsey(1948). Finally, we could not confirm the finding of aprojection from AD to the PCC as previously reported(Vogt et al., 1979). It is possible that the differences be-tween our observations and these previous reports couldbe due a number of factors, including injection site size,injection location, choice of neuronal tracer, tissue pro-cessing applications, and possibly species differences inthe case of Rose and Woolsey’s (1948) report.

The most notable feature in our RSC/PCC cases is thatthe overall pattern of labeling was very similar, with vari-ation in the percentage of labeled cells observed in eachcase. In the rostral thalamus of both cases, nearly identi-cal networks of dense patches of labeled cells were foundin the anterior nuclei and AILN (Figs. 4, 5). However, theprojections from the anterior nuclei to the RSC comprised�50% of the total thalamic input, whereas the anteriornuclei projections to the PCC, although still substantial,were much less, at 17.2%. In the caudal thalamus, labeledcells lined the dorsal Pul along the third ventricle and theventral PTC, with slight differences in the percentages oflabeled cells within each nucleus. Despite the similarity inthe thalamocortical labeling pattern, the PCC and RSCare usually described as participating in differential func-tional systems. The PCC is thought to contribute to anumber of cognitive functions such as attention (Mesu-lam, 1981; Vogt et al., 1992b) and reward evaluation (Mc-Coy et al., 2003), whereas the RSC processes informationrelated to spatial navigation (Maguire, 2001), memory(Vogt et al., 1992b), and possibly in integrating emotionalinformation with episodic memory (Maddock, 1999). Thesimilarity in thalamocortical connectivity of the PCC andRSC presented herein would not necessarily support thenotion of differential functional systems for these twocortical areas, as both cortical areas were found to receivevery similar thalamic afferents. This suggests that thesource of observed differences in function of the PCC andRSC may be due to afferents other than the thalamus,such as corticocortical or other subcortical inputs (Morriset al., 1999; Kobayashi and Amaral, 2003; Morecraft et al.,2004; Morecraft and Tanji, 2008). For example, corticocor-tical connections including the rich inputs from the pre-frontal region to the PCC (Morecraft et al., 2004) andthose from the entorhinal cortex to the RSC (Morris et al.,1999) may contribute to some of the observed functionaldiversity. However, the slight connectional differences,like input from AD to the RSC and not to the PCC, mayalso contribute to some observed functional differences.

Posterior cingulate sulcus thalamocortical inputs.

Two injections, Case 4 and Case 5, were placed within theposterior cingulate sulcus. In Case 4 the injection site wasin area 23c and in Case 5 the injection site was located inthe neighboring, more caudal part of area PEci. Althoughboth areas are located on the lower bank of the posteriorcingulate sulcus, they are cytoarchitecturally distinct(Morecraft et al., 2004). These caudal cortical areas, whichare buried within the depths of the cingulate sulcus, arealso part of the caudal cingulate motor area or M4 (i.e.,area 23c) (Morecraft et al., 1996; Morecraft and VanHoesen, 1998) and the supplementary sensory area (i.e.,area PEci) (Bowker and Coulter, 1981; Murray andCoulter, 1981).



The common thalamocortical relationship found inthese two cases, which effectively dissociates these areasusing connectional criteria from other areas of the PMC, isa unique pattern of projections from VA, VL, and VPL,which are classically recognized sensorimotor nuclei.Cases 4 and 5 demonstrated labeling within the lateralsegments of VA, VL, and primarily the anterior region ofVPL forming a strip of labeled cells that outline theirlateral boundaries near the external medullary lamina.This pattern was different from all other cases examinedin this study.

Traditionally, VA and VL are considered peri-rolandicsensorimotor nuclei of the thalamus because they heavilyinnervate the sensorimotor areas of the cerebral cortex(Jones, 1985). Moreover, VPLo is a component in thalamicmotor processing and VPLc is a somatosensory nucleus ofthe thalamus (Jones, 1985). The location of labeled cells inour cases further supports the idea that cortical regionswithin the cingulate sulcus are structurally equipped to besensorimotor-related processing centers (Morecraft andVan Hoesen, 2003; Morecraft et al., 2004) and demarcatesunique locations within the thalamus for input to thecaudal cingulate motor area (i.e., M4, area 23c). The la-beling pattern observed in VA and VL continued into VPL,classically designated as the primary sensory nucleus ofthe thalamus (Jones, 1985). The projections from VPL toarea PEci (Case 5) would support the designation of areaPEci as a supplementary sensory area (Murray andCoulter, 1981).

Based on the thalamocortical data, and in conjunctionwith cortical-cortical data (Morecraft and Van Hoesen,1992; Morecraft et al., 2004), it appears that areas 23c andPEci are indeed part of a sensorimotor neural network.This assertion is also supported by unit recording studiesin nonhuman primates (Murray and Coulter, 1981; Shimaet al., 1991) and the fact that this region of cortex alsoprojects to the spinal cord (Murray and Coulter, 1981;Hutchins et al., 1988; Nudo and Masterton, 1990; Dumand Strick, 1991; Luppino et al., 1994; Morecraft et al.,1997).

Finally, the pattern of labeling observed in these twocases demonstrates that the cortex located on the lowerbank of the caudal cingulate sulcus is systematically dis-tinct from the systems of the PCC/RSC described aboveand the MPC described below.

Medial parietal thalamocortical inputs. Cases 6, 7,and 8 represent injections of MPC area PGm and Cases 9and 10 represent injections involving the caudal dorsalmedial area PEc. Predominantly, we found MPC regionsto receive robust input from posterior association nuclei,LP and dorsal Pul, representing over 45% of the totalthalamic input in each case. Both areas of the MPC re-ceived input from VLc as well. No labeled cells were foundin the anterior nuclei, with the exception of a small per-centage of labeled cells observed in LD, in contrast toearlier findings (Schmahmann and Pandya, 1990) inwhich the anterior nuclei were labeled. The absence oflabeled cells in the anterior nuclei and ventral nuclei inour cases indicates that cortical areas of the MPC are partof a distinct functional system that differs from the PCC/RSC and PCS thalamic afferentation patterns describedabove. Similar to thalamic projections to PCC/RSC, theMPC receive afferents from the AILN, MDdc, and PTC.

Previous anatomical studies of the posterior parietalcortex have shown that this cortex has extensive connec-

tions with the posterior portions of the thalamus, includ-ing LP and Pul (Robertson, 1976, 1977; Schmahmann andPandya, 1990). However, those studies focused mostly onthe region of the superior lateral parietal cortices (LPC).The LPC receives projections from more medial nuclei,such as medial VP (VPM), and from different regionswithin common nuclei, such as ventral portion of Pul.A(Schmahmann and Pandya, 1990). Neither PEc nor PGmreceives projections from VPM or the ventral portion ofthe Pul.

Our results, along with those published previously (Ci-polloni and Pandya, 1999; Morecraft et al., 2004), showthalamocortical connectional differences between the LPCand MPC. However, the results presented here fail toshow that within MPC there are distinct thalamocorticalinput differences between PEc and PGm. In comparison,the overall location and patterns of thalamic labeling withinjections to PEc and PGm are very similar, as both areasreceive robust projections from dorsolateral segments ofposterior nuclei, such as LP and Pul, while not receivingany input from the anterior nuclei.

Cortical connection studies of areas medial PEc (Pet-rides and Pandya, 1984; Marconi et al., 2001) and PGm(Pandya and Seltzer, 1982; Petrides and Pandya, 1984;Cavada and Goldman-Rakic, 1989b; Leichnetz, 2001; Par-vizi et al., 2006) reveal that they have differential corticalconnectivity, and functional imaging studies suggest thatthey are also involved in discrete functions. Area PEc istraditionally associated with coordination of eye and handmovements during reaching motions (Caminiti et al.,1999; Marconi et al., 2001; Wenderoth et al., 2005),whereas PGm has been the subject of studies correlatedwith more cognitive functions, such as motor imagery andnavigation (Ogiso et al., 2000; Malouin et al., 2003; Sato etal., 2006), memory retrieval (Lundstrom et al., 2003,2005), and generation of self (Gusnard and Raichle, 2001).

From a functional standpoint, as described above, thesetwo cortical areas seem to be involved in different neuralsystems, but the thalamic input to these areas is verysimilar. This suggests, similar to the PCC/RSC, that thedifferent activity-dependent neural systems may be morereliant on other connections such as cortical–cortical con-nectivity than thalamic inputs. However, our results doshow distinctly that cortical areas of the MPC have adifferential thalamic input pattern from both the PCC/RSC and LPC (Schmahmann and Pandya, 1990), indica-tive of distinguished neural systems.

Area 31 thalamocortical inputs. Case 3 representsan injection of area 31 and Case 6 represents an injectionat the cytoarchitectural interface between areas 31 andPGm. The thalamic pattern of labeling exhibited in Case 6was very similar to Case 3, but lacks considerable labelingin the anterior nuclei, with the exception of labeled cells inLD. Interestingly, anterior thalamic labeling in the lateralpart of the anterior nuclei in Case 3 was similar in topog-raphy to Case 1, which has an injection in the dorsocaudalregion of area 23. However, the thalamic projections fromthe anterior nuclei to the inferior part of area 31 in Case3 was much weaker than the projections found to end inarea 23, as evidenced in Case 1. Collectively, these casesshow a gradational trend that suggests the anterior tha-lamic projections to PMC gradually diminish in the dorsaldirection.

The labeling in LD of the anterior thalamic group ofnuclei demonstrates another example indicating that area



31, although similar to PGm in some respects, has relatedconnectional characteristics of the PCC as well. Therefore,the thalamocortical input pattern to area 31 possessescomponents from both the PCC/RSC and MPC systemsand does not have a unique pattern of thalamocorticalinput that is unshared by all three regions. In general,PCC/RSC receives projections from primarily anterior nu-clei; MPC receives input from predominately LP and Pul;and area 31 receives input similarly from all of thesethalamic regions. Additionally, area 31 Cases 3 and 5receive afferents from AILN, MDdc, and the PTC, as dis-cussed below.

Area 31 is considered the most posterior portion of thePCC because of its anatomical proximity to area 23 (Vogt,1993; Vogt et al., 1995) and its specific chemoarchitectonicfeatures (Vogt et al., 2005). However, area 31 can also beviewed as an interface between PCC and MPC based onthe gradual change in cytoarchitecture that occurs towardthe isocortical parietal cortex and our findings onthalamocortical projections. As noted earlier, area 31 re-ceives substantial input from the anterior nuclei like PCC/RSC, but also receives robust input from the posteriornuclei LP and Pul. The LP and Pul projections to area 31are more robust than those to PCC/RSC, demonstratingthat the LP and Pul projections gradually increase in thedorsal direction.

Summary of thalamocortical PMC projections. Amajor aim of this study was to investigate projections fromthe thalamus to the multiple cortical areas found in thePMC. The results reveal a diverse and extensive relation-ship between the thalamus and regions of the PMC char-acterized by differences in thalamic projections that delin-eate cytoarchitectonic areas within the PMC. Ourinvestigation of the different cytoarchitectural regions ofthe PMC yields three distinct patterns of input from thethalamus: a PCC/RSC system, an MPC system, and acaudal cingulate sensorimotor area system. In addition tothese differential patterns, we note that thalamocorticalinput to area 31 includes properties of both the PCC/RSCsystems and the MPC systems, suggesting that area 31may be a functional as well as cytoarchitectural interfacebetween the PCC/RSC and MPC and may integrate infor-mation from both systems. However, it should be notedthat the connections of area 31 could be related to itslocation between area 23 and PGm.

Common thalamocortical inputs

As described in our studies, each region within the PMCreceives a distinct pattern of thalamic input that distin-guishes that system from other subsystems of the PMC.However, each of the thalamocortical systems of the PMCalso receives input from several common thalamic regionsincluding AILN, MDdc, LP, PTC, and Pul. In addition tothe PC, CL, CeM, and CSL projections of the AILN, thosearising from the posterior segments of MD and PTC mayalso be considered as an extended part of the AILN group.The similarity of projections shared in all cases binds thecortical areas within the PMC in a connectional and per-haps functional fashion. From a functional perspective,the shared inputs from the AILN may be involved in themaintenance of general arousal often attributed to thisregion (Mesulam, 1981). Indeed, some consider these pos-terior cell groups to be part of the same intralaminararrangement (Jones, 1985). In all cases presented here,cortical regions receive projections from the AILN, which,

in addition to midline nuclei, are thought to be involved inmodulating cortical arousal (Lorente de No, 1938; Morisonand Dempsey, 1942; Jones and Leavitt, 1974). Specificinput to the AILN from the brainstem (Krout et al., 2002;Van der Werf et al., 2002) has led to the notion that theAILN participate in the processes of arousal and aware-ness by influencing cortical activity (Groenewegen andBerendse, 1994; Kinomura et al., 1996; Van der Werf etal., 2002).

Our study also showed that all cortical areas of the PMCreceived input from posterior association nuclei LP andPul. The labeling in LP was consistent and robust,whereas the labeled cells within segments of Pul appearedto gradually increase as the injection site moved moredorsal and posterior within the PMC. The patterns ob-served in these posterior thalamic nuclei are consistentwith the idea that LP and Pul are associated with theparietal (Robertson, 1977; Schmahmann and Pandya,1990) and neighboring cortex and modulating inherentfunctions.

Domain-like labeling patterns in the dorsalthalamus

We described recently a continuous bar-like pattern ofanterograde projections from the PCC, RSC, and area 31to the dorsal thalamus (Parvizi et al., 2006). These antero-grade projections were found to be continuous and alignedin a horizontal bar-like manner extending from the poste-rior to the anterior tip of the thalamus uninterruptedlytraversing the dorsal nuclei AV, AD, AM, LD, VL, VA, LP,and lateral aspect of the pulvinar. It is interesting to notethat the same longitudinal bar-like pattern extendingfrom the posterior to the anterior tip of the thalamus is notseen after retrograde injections in the PMC. However, aconsistent observation in our study was the finding ofretrogradely labeled cells in the dorsal thalamus thatcross the boundaries of multiple adjacent thalamic nuclei(Figs. 4–13), as if the cortical areas of the PMC are receiv-ing thalamic afferents from a domain of thalamus. This isdifferent than the band-like pattern originally attributedto thalamo-frontal connections by Kievit and Kuypers(1977), and is most apparent in cases that involved area23, RSC, and area 31. Cases involving the MPC showed asimilar pattern, albeit in a more lateral location of thedorsal thalamus (Figs. 9, 10). Thus, individual areaswithin the PMC appear not to receive input from onenucleus or a series of separate nuclei, but from complex,three-dimensional thalamic arrays, or domains, that in-volve adjacent subsets of thalamic neurons supercedingthalamic nuclear cytoarchitecture. The extent to whichthese domains interdigitate, interlock, or overlap cannotbe discerned from the data and design of our experiments,but should be testable with multiple double-labelingtracer experiments.

Comparing the continuous bar-like pattern of antero-grade corticothalamic projections from the PMC to thepatchy domain-like pattern of thalamocortical projectionto the PMC suggests that there are thalamic neurons thatreceive unidirectional information from the PMC withoutreciprocating back to it. These thalamic neurons may berelaying the PMC inputs to other neural structures thatthe PMC can or cannot reach directly. This should also betestable with multiple double-labeling tracer experimentsin the future.



Correlation to aging and dementia

Multiple studies suggest that the PMC may play a rolein higher-order associative tasks such as visuo-spatialimagery and navigation (Ogiso et al., 2000; Malouin et al.,2003) memory retrieval (Andreasen et al., 1995; Lund-strom et al., 2003, 2005; Shannon and Buckner, 2004;Wagner et al., 2005), and self-referential processing(Damasio, 1999; Gusnard and Raichle, 2001; Mazoyer etal., 2001; Vogt and Laureys, 2005; Cavanna and Trimble,2006). Taken together, these putative functional roles ofthe PMC are of particular interest due to their dysfunctionin normal aging and dementia.

The PMC shows baseline hypometabolism in functionalstudies of patients with dementia (Minoshima et al., 1994,1997; Buckner et al., 2000, 2005; Matsuda, 2001; Scahill etal., 2002; Lustig et al., 2003; Nestor et al., 2003a,b; Buck-ner, 2004; Drzezga et al., 2005). Moreover, the task-independent decrease of activity seen in the PMC inyounger adults disappears with the onset of dementia(Buckner et al., 2000, 2005; Lustig et al., 2003). Thesefindings are not surprising given that the PMC is one ofthe brain regions that exhibits selective Alzheimer’s re-lated pathological changes in the course of the disease(Vogt et al., 1992a, 1998).

It has also been suggested that the PMC dysfunction indementia may be the result of damage to the major pro-jection pathways from the entorhinal cortex to the PMC(Giannakopoulos et al., 2000; Lustig et al., 2003; Buckneret al., 2005), given that pathological damage to the ento-rhinal cortex is a hallmark of Alzheimer’s disease (VanHoesen et al., 1991). These entorhinal-PMC pathwaysmay in some way modulate the functional processes of thePMC and may account for observed functional differencesseen in aging and dementia. The projections from thethalamus to the PMC described in this report may also bean additional factor in the normal, putative functions ofthe PMC, and damage to these thalamocortical pathways,in addition to damage of medial temporal lobe projectionsto the PMC, may collectively contribute to the observedbehavioral dysfunction in elderly and demented popula-tions.

Some have suggested that this altered activation pat-tern may be the result of damage to the major projectionpathways from the entorhinal cortex to the PMC (Lustiget al., 2003; Buckner et al., 2005), given that pathologicaldamage to the entorhinal cortex is a hallmark of Alzhei-mer’s disease (Van Hoesen et al., 1991). These entorhinal-PMC pathways may in some way modulate the functionalprocesses of the PMC and may account for observed func-tional differences seen in aging and dementia. The projec-tions from the thalamus to the PMC described in thisreport, in particular, projections from the AILN to allregions of the PMC, will likely additionally be a factor inthe normal putative functions of the PMC, and that dam-age to these thalamocortical pathways, in addition to dam-age of medial temporal lobe projections to the PMC, maycollectively contribute to the observed behavioral dysfunc-tion in the elderly and demented populations. The findingthat the AILN are progressively affected by DAT-relatedcytoskeletal pathology (Rub et al., 2002) strengthens theidea that damage to the AILN direct thalamocortical pro-jections to the PMC may be a contributor to the observedfunctional imaging abnormalities in the PMC.

ACKNOWLEDGMENT

We thank Tina Knutson, Diana Lei, Kim Stilwell-Morecraft, and Paul Reimann for technical assistance.

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