trajectories of cholinergic pathways within the cerebral - brain

Brain (1998),121,2249–2257

Trajectories of cholinergic pathways within thecerebral hemispheres of the human brainNathan R. Selden,1,2 Darren R. Gitelman,1 Noriko Salamon-Murayama,1 Todd B. Parrish1 andM.-Marsel Mesulam1

1Cognitive Neurology and Alzheimer Disease Center, Correspondence to: M.-Marsel Mesulam, CognitiveNorthwestern University Medical School, Chicago, Illinois Neurology and Alzheimer Disease Center, Northwesternand 2Section of Neurosurgery, Department of Surgery, University, 320 E. Superior Ave, Searle 11-453, Chicago,University of Michigan Medical Center, Ann Arbor, IL 60611, USA. E-mail: [email protected], USA

SummaryAll sectors of the human cerebral cortex receive densecholinergic input. The origin of this projection is locatedin the Ch4 cell group of the nucleus basalis of Meynert.However, very little is known about the location of thepathways which link the cholinergic neurons of the nucleusbasalis to the human cerebral cortex. This question wasaddressed in whole-hemisphere sections processed for thevisualization of multiple cholinergic markers. Two highlyorganized and discrete bundles of cholinergic fibresextended from the nucleus basalis to the cerebral cortexand amygdala and were designated as the medial andlateral cholinergic pathways. These bundles containedacetylcholinesterase, choline acetyltransferase and nervegrowth factor receptors, confirming their cholinergicnature and origin within the basal forebrain. The medialpathway joined the white matter of the gyrus rectus,

Keywords: nucleus basalis; cerebral hemispheres; choline acetyltransferase; nerve growth factor receptor;acetylcholinesterase

Abbreviations: ACh 5 acetylcholine; AChE5 acetylcholinesterase; ChAT5 choline acetyltransferase; nbM5 nucleusbasalis of Meynert; NGFr5 nerve growth factor receptor

IntroductionMagnocellular neurons of the primate basal forebrain providea massive and widespread cholinergic input to thetelencephalon and influence nearly all aspects of corticalfunction, especially in the domains of attention, memory andemotion (Mesulam, 1996; Everitt and Robbins, 1997). Theseprojections originate from the four overlapping Ch1–Ch4 cellgroups of the basal forebrain. Cholinergic neurons of themedial septal nucleus (also known as the Ch1 cell group)and the vertical limb nucleus of the diagonal band (Ch2)provide the major cholinergic input of the hippocampus;cholinergic neurons of the horizontal limb nucleus of thediagonal band (Ch3) provide the major cholinergic input ofthe olfactory bulb; and cholinergic neurons of the nucleus

© Oxford University Press 1998

curved around the rostrum of the corpus callosum toenter the cingulum and merged with fibres of the lateralpathway within the occipital lobe. It supplied theparolfactory, cingulate, pericingulate and retrosplenialcortices. The lateral pathway was subdivided into acapsular division travelling in the white matter of theexternal capsule and uncinate fasciculus and a perisylviandivision travelling within the claustrum. Branches of theperisylvian division supplied the frontoparietaloperculum, insula and superior temporal gyrus. Branchesof the capsular division innervated the remaining partsof the frontal, parietal and temporal neocortex.Representation of these cholinergic pathways within a 3DMRI volume helped to identify white matter lesion sitesthat could interfere with the corticopetal flow ofcholinergic pathways.

basalis of Meynert (nbM–Ch4) provide the principalcholinergic input of the remaining cerebral cortex andamygdala (Mesulamet al., 1983; Everittet al., 1988; Alonsoet al., 1996).

Basal forebrain cholinergic neurons are the only CNSneurons that continue to express high levels of the p75 nervegrowth factor receptor (NGFr) during adulthood (Heftiet al.,1986; Mesulamet al., 1992b). The presence of NGFr thereforeleads to the inference that a cholinergic axon originateswithin the Ch1–Ch4 complex of the basal forebrain (Heckerset al., 1994). The neuroanatomy, cytochemistry, connectionaltopography and cortical distribution of cholinergic pathwaysoriginating in the basal forebrain have been investigated in

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Fig. 1 (A) AChE histochemistry in the insula demonstrates a dense network of AChE-rich cholinergic axons. (B) Photomacrograph ofthe region of the external capsule and claustrum revealing dense AChE reaction product over the putamen (P) and a thick network ofAChE-rich fibres in the insular cortex (IN). The two components of the lateral cholinergic pathway are shown by the arrowhead(perisylvian division) and the double arrowhead (capsular division). The microscopic fields shown in (C) and (D) include the part of thecapsular division located at the tip of the double arrowhead in (B) but immunostained in adjacent sections for ChAT in (C) and NGFr in(D). The correspondence of the AChE-rich fibre bundle with ChAT- and NGFr-immunoreactive fibres demonstrates that the pathway isdefinitively cholinergic and that it originates in the Ch1–4 cells of the NbM. ec5 external capsule; LII, LIII5 cortical layers II and III;P 5 putamen. Medial is towards the left and dorsal towards the top. Magnifications:A, 3186; B, 311.3;C andD, 3371.

Cholinergic fibre pathways 2251

Fig. 2 (A) AChE histochemistry in the frontal lobe reveals two tracts of AChE-rich (cholinergic) fibres coursing through the white matter(arrows). The medial pathway (M) is closely associated with the adjacent cingulate gyrus (CG) and rostrum of the corpus callosum (R).This anatomical section was used to generate the diagram in Fig. 3A. (B) A higher power photomicrograph of the same sectiondemonstrating individual AChE-rich fibres streaming from the lateral pathway to the cortex of the inferior frontal gyrus (arrows). Thearrowheads in (A) and (B) serve as a reference marker for the identical anatomical area. L5 lateral pathway; OF5 orbitofrontal cortex.Magnifications:A, 31.56;B, 36.86.

considerable detail in the macaque monkey with the help ofaxonally transported tracers, enzyme assays andimmunohistochemistry (Mesulamet al., 1983, 1986; Satohand Fibiger, 1985; Everittet al., 1988; Kordoweret al., 1989;Geulaet al., 1993).

The human brain displays an analogous topographic andcytochemical organization of cholinergic cells in the basalforebrain, with perhaps an even greater degree of anatomicaldifferentiation, especially within the nbM (Mesulam andGeula, 1988). Furthermore, the density of cholinergic axons inthe human cerebral cortex displays orderly regional variationswhich obey the systems-level organization of informationprocessing streams (Mesulamet al., 1992a). Although directaxonal tracing experiments are not possible in the humanbrain, the study of patients with Alzheimer’s disease suggeststhat the topography of the projections connecting the Ch1–Ch4 cell groups to the cerebral cortex is similar to thatidentified in the monkey (Mesulam and Geula, 1988).

Some of the cholinergic pathways emanating from thebasal forebrain travel within easily identifiable fibre tracks.For example, cholinergic pathways extending from Ch1–2 tothe hippocampus travel predominantly within the fornix(Green and Mesulam, 1988; Alonsoet al., 1996), those thatreach the olfactory bulb within the olfactory tract (Kittet al.,1987; Luitenet al., 1987) and those to the amygdala withinthe ventral amygdalofugal pathway and the stria terminalis(Carlsenet al., 1985; Heckers and Mesulam, 1994). Thetrajectories of connections between the nbM and the cerebralcortex are less well understood.

Using injections of tritiated amino acids into the midportionof the nbM and surrounding structures in rhesus monkeys,Kitt et al. (1987) described a medial projection to thecingulate cortex that travelled within the cingulum, a lateralprojection to the frontoparietal and insular cortices thattravelled within the external and extreme capsules and aventral projection to the temporal cortex and the amygdalathat travelled within the uncinate fasciculus. However, thesestudies did not include specific histochemical or immuno-histochemical markers to ascertain the cholinergic nature ofthe pathways. There is currently no information about thewhite matter trajectory of the pathways that connect thecholinergic Ch4 neurons of the nbM with the cerebral cortexin the human brain. The purpose of the present report is toinvestigate the organization of these pathways with the helpof selective cholinergic markers.

Material and methodsSubjectsMore than 50 human brains processed for the visualizationof cholinergic markers in whole-hemisphere sections wereexamined. Five representative specimens were chosen forthis study. They were among the optimally stained specimensbut did not differ in anatomical detail from the others. Thespecimens used in this study came from subjects with noneurological or psychiatric disease as determined by clinicalrecords. Their ages ranged from 27 to 101 years and three were


female. Although cortical cholinergic innervation displays aminor age-related decline in density (Geula and Mesulam,1989), the trajectories of the pathways do not change withage. The post-mortem autolysis interval was between 4 and12 h. Cause of death included myocardial infarction (two),congestive heart failure, cardiorespiratory arrest and gunshotwound. No specific neuropathological alterations were foundin sections stained with haematoxylin–eosin and cresyl violet.Thioflavin S histofluorescence showed some neuritic plaques

and neurofibrillary tangles in brains from the oldest subjects,but in a density and distribution that were below the diagnosticthresholds for Alzheimer’s disease (Mirraet al., 1991).

Histological proceduresSlabs of whole cerebral hemispheres were fixed, cryo-protected and sectioned coronally at a thickness of 40µm,as described previously (Mesulamet al., 1991). A set of


matching sections through each brain was stained with cresylviolet for cytoarchitectonic identification and acetylcholin-esterase histochemistry using a modification of the directcolouring Karnovsky–Roots method (Tagoet al., 1986;Mesulam et al., 1987). Adjacent sections were processedimmunohistochemically using a monospecific, polyclonalantibody raised against human placental choline acetyl-transferase (ChAT, generously donated by Lewis B. Hersh)and a monoclonal antibody raised against human NGFr(generously donated by Mark Bothwell) (Germanet al.,1985; Maranoet al., 1987).

The immunohistochemical procedure was based onformation of the avidin–biotin complex and useddiaminobenzidine as the chromogen (Mesulamet al., 1991).In selected sections, additional intensification of the reactionproduct was obtained using silver nitrate (Kittet al., 1988).For control sections, an irrelevant IgG was substituted forthe primary antibody.

Data analysisThis study is confined to the cholinergic projections thatemanate from the nbM. The more fully investigatedhippocampal, olfactory and amygdaloid cholinergic pathways(which travel in the fornix, olfactory tract, stria terminalisand ventral amygdalofugal pathway) will not be addressed.Acetylcholinesterase (AChE) histochemistry provided themost intense staining and was used as the principal methodfor illustrating the trajectory of cholinergic pathways. Thepattern of this staining was compared with that obtained withChAT and NGFr immunohistochemistry to ascertain thatAChE could be used as a specific marker of cholinergicpathways. The location, course and density of AChE-richfibres in six representative sections spanning the rostrocaudalextent of the cerebral hemispheres were then charted usinga plotter electronically coupled to the stage of a compoundmicroscope. These chartings were imported into thePhotoshop graphics program (Adobe Systems Incorporated,San Jose, Calif., USA) for differential coloration of pathways.

Fig. 3 Electronic plotter charts of AChE-rich (cholinergic) fibre bundles in the hemispheric white matter of six coronal sections.A ismost rostral andF is most caudal. The medial cholinergic pathway is represented in green, and the two divisions of the lateral pathwayin red (capsular division) and orange (perisylvian division). The cholinergic Ch4 neurons of the nucleus basalis of Meynert (nbM) arerepresented in blue. (A) The medial pathway remains medial to the rostrum of the corpus callosum (R) and gives off fibres to thecingulate gyrus (CG) and medial frontal cortex, whereas the lateral pathway courses within the white matter of the frontal lobe and givesoff fibres to the dorsal and lateral prefrontal cortex. The orbitofrontal cortex receives fibres from both the medial and lateral cholinergicbundles. (B) The medial pathway courses anteriorly under the corpus callosum in the white matter of the parolfactory gyrus (PG) and,having curved up around the rostrum at more anterior levels, courses posteriorly in the cingulum (Ci), dorsal to the corpus callosum. Thetwo lateral components course within the external capsule (red) and the claustrum (orange). (C andD) The lateral and medial pathwaysemanate from the nbM–Ch4. The components of the lateral pathway extend dorsally into frontoparietal cortex and ventrally into thetemporal lobe. (E andF) The medial pathway continues its caudad course in the cingulum and curves around the splenium (Sp) tosupply the cingulate and pericingulate cortices. The lateral pathway courses in the form of discrete bundles within the deep white matterof the parietal, temporal and occipital lobes and gives off AChE-rich fibres to adjacent cortical areas. Magnification,31.5. ac5 anteriorcommissure; Am5 amygdala; C5 caudate; CaS5 calcarine sulcus; CC5 corpus callosum; CeS5 central sulcus; CiS5 cingulatesulcus; CoS5 collateral sulcus; dg5 dentate gyrus; En, entorhinal cortex; GP5 globus pallidus; H5 hippocampus; IN5 insula;mb 5 mammillary body; P5 putamen; SF5 Sylvian fissure; Th5 thalamus; TP5 temporal pole; V5 ventricle.

Three-dimensional imagingA contiguous, 1 mm, T1-weighted MRI volume (TR5 15ms, TE5 6 ms, flip angle5 20°, FOV 5 165 3 220 mmwith a 1923 256 matrix) was obtained in the coronal planefrom a neurologically normal 62-year-old right-handed femaleusing a 1.5 Tesla scanner (Siemens Vision, Erlangen,Germany). The exact plane of image acquisition wasdetermined to match the plane of section in the anatomicalreference cases. The MRI slices were then exported intoPhotoshop and the principal cholinergic pathways were tracedbased on their location in matching anatomical sections. Onlydense cholinergic fibre bundles coursing within the whitematter were represented. The entire volume was thenreconstructed within AVS (Applied Visual Systems, Waltham,Mass., USA) in order to enable the visualization of thesepathways in additional planes of section.

ResultsAll regions of the cerebral cortex displayed a dense net ofAChE-rich fibres (Fig. 1A). The white matter containedAChE-rich fibre bundles (Fig. 1B). Adjacent sections showedthese fibres to be both ChAT- and NGFr-immunoreactive,providing definitive confirmation that they are cholinergic(because of the ChAT) and that they originate in the basalforebrain (because of the NGFr) (Fig. 1C and D). IndividualAChE-rich axons emanated from these cholinergic bundlesand fanned towards the cerebral cortex (Fig. 2). Cholinergicfibre bundles originated from the nbM–Ch4 region andformed a medial and a lateral pathway (Fig. 3). The lateralpathway was further subdivided into a capsular componenttravelling within the external capsule and a perisylviancomponent travelling within the claustrum.

The medial cholinergic pathway emanated anteriorly fromthe nbM–Ch4 and joined the white matter of the gyrusrectus (parolfactory gyrus) and medial orbital gyrus, passedanteriorly to the rostrum of the corpus callosum, entered thecingulum, travelled posteriorly to the splenium and curvedventrally to enter the retrosplenial white matter. Individual


Fig. 4 The medial and lateral cholinergic pathways are represented within a volume-rendered MRI format, enabling their visualization inplanes other than that of the anatomical sections. As in Fig. 3, the medial pathway is shown in green and the lateral pathway in red(capsular division) and orange (perisylvian division). The nbM–Ch4 is shown in blue (arrowheads). Only the dense bundles within whitematter are included. The fine fibres which take off from these bundles to innervate adjacent areas of cortex are not shown in the interestof clarity. The trajectories shown in this figure also help to identify white matter sites where lesions (for example vascular) couldinterrupt the more distal flow of cortical cholinergic pathways. (A) and (B) Horizontal sections at the level of the frontal horns of thelateral ventricles and the upper level of the corpus callosum, respectively. (C) Parasagittal view obtained 4 mm lateral to theinterhemispheric fissure. The medial pathway originates in the anterior nbM–Ch4 (arrowhead) and courses around the corpus callosum,predominantly within in the cingulum. (D) Intersection of a coronal section at the level of the posterior border of the thalamus and ahorizontal section at the level of the anterior commissure. The arrowhead points to the nbM–Ch4 neurons which give rise to thecorticopetal cholinergic pathways. ac5 anterior commissure; C5 caudate; CC5 corpus callosum; CeS5 central sulcus; CiS5cingulate sulcus; IPS5 intraparietal sulcus; OF5 orbitofrontal gyri; P5 putamen; R5 rostrum of corpus callosum; SF5 Sylvianfissure; Sp5 splenium of corpus callosum; Th5 thalamus.


axons radiated from this pathway to supply medialorbitofrontal, subcallosal, cingulate, pericingulate andretrosplenial cortices (Figs 2 and 3).

The capsular division of the lateral cholinergic pathwaycoursed in a densely packed and highly organized bundle offibres immediately adjacent to the putamen in the medialaspect of the external capsule (Figs 1B and 3). Additionalfibres travelled ventrally in the white matter of the uncinatefasciculus, adjacent to the fundus of the putamen and theamygdala (Fig. 3). Some of these fibres appeared to penetratethe substance of the amygdala while others continued in adense bundle into the white matter of the temporal lobe.Individual fibres radiated from the capsular division to supplythe dorsal frontoparietal neocortex, the middle and inferiortemporal gyri, the inferotemporal cortex and theparahippocampal gyrus (Fig. 3).

The perisylvian division of the lateral cholinergic pathwaycoursed within the claustrum, curving laterally into the whitematter of the inferior frontal and superior temporal gyri.Individual fibres radiated from the perisylvian division tosupply the frontoparietal opercular cortices, superior temporalgyrus and the insula (Fig. 3).

The medial and lateral cholinergic pathways mergedanteriorly in the white matter of the orbitofrontal gyri andposteriorly in the occipital lobe beneath the optic radiations(Fig. 3).

The manual reconstruction of anatomically identifiedcholinergic pathways within corresponding MRI sectionsallowed a 3D reconstruction of their distribution within thehuman cerebral hemispheres (Fig. 4). The entire curvedtrajectory of the medial cholinergic pathway was visualizedin a single parasagittal plane of section (Fig. 4C).Representation of cholinergic pathways within axial sections,which are commonly used in clinical studies, showed thatthese pathways course through regions of white matter thatare frequently involved in many different disease processes,including cerebrovascular and demyelinating diseases andneoplasm (Fig. 4A and B).

DiscussionThe neurons of nbM–Ch4 are selectively responsive to noveland motivationally relevant sensory events (Wilson and Rolls,1990; Morris et al., 1997). Novel and emotionally salientevents are therefore particularly effective in eliciting therelease of acetylcholine (ACh) in the cerebral cortex. Themajor effect of ACh upon neurons of the cerebral cortex ismediated through the m1 subtype of muscarinic receptorsand causes a prolonged reduction of potassium conductanceso as to make cortical neurons more receptive to otherexcitatory inputs (Satoet al., 1987; McCormick, 1990).Cortical cholinergic pathways also promote long-termpotentiation and experience-induced synaptic remodelling(Huerta and Lisman, 1993; Cruikshank and Weinberger, 1996;Baskervilleet al., 1997). The cholinergic pathway from thebasal forebrain to the cerebral cortex is therefore in a position

to promote the impact and memorability of novel andmotivationally relevant events. The degeneration of nbM–Ch4 neurons observed in various neurological diseases,including Alzheimer’s disease and Parkinson’s disease, resultsin a depletion of cortical cholinergic innervation andundoubtedly contributes to the altered mental state that isobserved in these conditions (Geula and Mesulam, 1994).

Although cholinergic projections reach all areas of thecerebral cortex and are generally described as diffuse, ourstudies demonstrate that they travel in discrete, organizedbundles. The medial cholinergic pathway travels withinthe cingulum and supplies the orbitofrontal, subcallosal,cingulate, pericingulate and retrosplenial cortices. The lateralcholinergic pathway includes a perisylvian division, whichcourses within the claustrum to supply opercular and insularcortices, and a capsular division, which courses within theexternal capsule and uncinate fasciculus to supply remainingareas of the cerebral cortex. Our findings in the human brainare generally in concordance with those in the rhesus monkey(Kitt et al., 1987) and provide additional histochemical andimmunohistochemical validation concerning the cholinergicnature of these pathways. Such specific validation is importantsince the nbM also contains non–cholinergic neurons whichproject to the cerebral cortex (Grittiet al., 1993).

The discrete topography of cholinergic pathways within thecerebral hemispheres suggests that corticopetal cholinergicneurotransmission may be vulnerable to focal pathologicalinsults of the white matter even when the nbM itself remainsintact. The representation of cholinergic pathways within 3DMRI volumes allows the identification of the lesion sites thatare most likely to interrupt these pathways. Cingulotomly isoccasionally performed to treat intractable depression orobsessive–compulsive disorders (Cosgrove and Ballantine,1998). One unexpected consequence of this procedure maybe to cause a cholinergic denervation of cingulate andpericingulate cortices caudal to the lesion site.

The centrum semiovale, the external capsule and claustrumare commonly involved in cerebrovascular disease. Suchlesions could cause a widespread disconnection of remotecortical areas from their source of cholinergic innervation inthe basal forebrain. The resulting cholinergic denervationcould contribute to the emergence of mental stateimpairments. Multi-infarct dementia and Alzheimer’s diseasemay therefore share a common neurochemical pattern ofcortical cholinergic depletion through completely differentmechanisms. The ascending cholinergic axons of the nucleusbasalis are mostly unmyelinated (Wainer and Mesulam,1990). It therefore remains to be seen if demyelinatingdiseases such as multiple sclerosis can also damage thewhite matter pathways which carry cholinergic fibres to thecerebral cortex.

Investigation of the human brain is progressing rapidly,especially as a consequence of remarkably powerful methodsrelated to functional imaging. However, delineating theanatomy of neural connections in humans continues to poseserious challenges. Our results demonstrate that transmitter-


specific anatomical markers in post-mortem specimens maymake useful contributions to this area of inquiry.

AcknowledgementsN.R.S. wishes to thank Dr Julian Hoff for advice andencouragement. This study was supported in part by anAlzheimer’s Disease Center Grant (1-P30 AG13854) andNS20285.

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Received 5 June, 1998. Revised July 27, 1998.Accepted July 28, 1998

trajectories of cholinergic pathways within the cerebral - brain

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