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Trajectories of Cholinergic Pathways Within the Cerebral Hemispheres of the Human Brain

Trajectories of Cholinergic Pathways Within the Cerebral Hemispheres of the Human Brain

(1998), 121, 2249–2257 Trajectories of pathways within the cerebral hemispheres of the

Nathan R. Selden,1,2 Darren R. Gitelman,1 Noriko Salamon-Murayama,1 Todd B. Parrish1 and M.-Marsel Mesulam1

1Cognitive Neurology and Alzheimer Disease Center, Correspondence to: M.-Marsel Mesulam, Cognitive Northwestern University Medical School, Chicago, Illinois Neurology and Alzheimer Disease Center, Northwestern and 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] Michigan, USA

Summary All sectors of the human receive dense curved around the rostrum of the to cholinergic input. The origin of this projection is located enter the and merged with fibres of the lateral in the Ch4 cell group of the of Meynert. pathway within the occipital lobe. It supplied the However, very little is known about the location of the parolfactory, cingulate, pericingulate and retrosplenial pathways which link the cholinergic of the nucleus cortices. The lateral pathway was subdivided into a basalis to the human cerebral cortex. This question was capsular division travelling in the of the addressed in whole-hemisphere sections processed for the and and a perisylvian visualization of multiple cholinergic markers. Two highly division travelling within the . Branches of the organized and discrete bundles of cholinergic fibres perisylvian division supplied the frontoparietal extended from the nucleus basalis to the cerebral cortex , insula and superior temporal gyrus. Branches and and were designated as the medial and of the capsular division innervated the remaining parts lateral cholinergic pathways. These bundles contained of the frontal, parietal and temporal . acetylcholinesterase, choline acetyltransferase and Representation of these cholinergic pathways within a 3D growth factor receptors, confirming their cholinergic MRI volume helped to identify white matter lesion sites nature and origin within the basal . The medial that could interfere with the corticopetal flow of pathway joined the white matter of the gyrus rectus, cholinergic pathways.

Keywords: nucleus basalis; cerebral hemispheres; choline acetyltransferase; receptor; acetylcholinesterase

Abbreviations: ACh ϭ ; AChE ϭ acetylcholinesterase; ChAT ϭ choline acetyltransferase; nbM ϭ nucleus basalis of Meynert; NGFr ϭ nerve growth factor receptor

Introduction Magnocellular neurons of the primate provide basalis of Meynert (nbM–Ch4) provide the principal a massive and widespread cholinergic input to the cholinergic input of the remaining cerebral cortex and telencephalon and influence nearly all aspects of cortical amygdala (Mesulam et al., 1983; Everitt et al., 1988; Alonso function, especially in the domains of attention, memory and et al., 1996). (Mesulam, 1996; Everitt and Robbins, 1997). These Basal forebrain cholinergic neurons are the only CNS projections originate from the four overlapping Ch1–Ch4 cell neurons that continue to express high levels of the p75 nerve groups of the basal forebrain. Cholinergic neurons of the growth factor receptor (NGFr) during adulthood (Hefti et al., (also known as the Ch1 cell group) 1986; Mesulam et al., 1992b). The presence of NGFr therefore and the vertical limb nucleus of the diagonal band (Ch2) leads to the inference that a cholinergic axon originates provide the major cholinergic input of the ; within the Ch1–Ch4 complex of the basal forebrain (Heckers cholinergic neurons of the horizontal limb nucleus of the et al., 1994). The , cytochemistry, connectional diagonal band (Ch3) provide the major cholinergic input of topography and cortical distribution of cholinergic pathways the ; and cholinergic neurons of the nucleus originating in the basal forebrain have been investigated in © Oxford University Press 1998 2250 N. R. Selden et al.

Fig. 1 (A) AChE histochemistry in the insula demonstrates a dense network of AChE-rich cholinergic axons. (B) Photomacrograph of the region of the external capsule and claustrum revealing dense AChE reaction product over the (P) and a thick network of AChE-rich fibres in the (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 the capsular 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 is definitively cholinergic and that it originates in the Ch1–4 cells of the NbM. ec ϭ external capsule; LII, LIII ϭ cortical layers II and III; P ϭ putamen. Medial is towards the left and dorsal towards the top. Magnifications: A, ϫ186; B, ϫ11.3; C and D, ϫ371. Cholinergic fibre pathways 2251

Fig. 2 (A) AChE histochemistry in the 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 section demonstrating individual AChE-rich fibres streaming from the lateral pathway to the cortex of the (arrows). The arrowheads in (A) and (B) serve as a reference marker for the identical anatomical area. L ϭ lateral pathway; OF ϭ . Magnifications: A, ϫ1.56; B, ϫ6.86. considerable detail in the macaque monkey with the help of Using injections of tritiated amino acids into the midportion axonally transported tracers, enzyme assays and of the nbM and surrounding structures in rhesus monkeys, immunohistochemistry (Mesulam et al., 1983, 1986; Satoh Kitt et al. (1987) described a medial projection to the and Fibiger, 1985; Everitt et al., 1988; Kordower et al., 1989; that travelled within the cingulum, a lateral Geula et al., 1993). projection to the frontoparietal and insular cortices that The human brain displays an analogous topographic and travelled within the external and extreme capsules and a cytochemical organization of cholinergic cells in the basal ventral projection to the temporal cortex and the amygdala forebrain, with perhaps an even greater degree of anatomical that travelled within the uncinate fasciculus. However, these differentiation, especially within the nbM (Mesulam and studies did not include specific histochemical or immuno- Geula, 1988). Furthermore, the density of cholinergic axons in histochemical markers to ascertain the cholinergic nature of the human cerebral cortex displays orderly regional variations the pathways. There is currently no information about the which obey the systems-level organization of information white matter trajectory of the pathways that connect the processing streams (Mesulam et al., 1992a). Although direct cholinergic Ch4 neurons of the nbM with the cerebral cortex axonal tracing experiments are not possible in the human in the human brain. The purpose of the present report is to brain, the study of patients with Alzheimer’s disease suggests investigate the organization of these pathways with the help that the topography of the projections connecting the Ch1– of selective cholinergic markers. Ch4 cell groups to the cerebral cortex is similar to that identified in the monkey (Mesulam and Geula, 1988). Some of the cholinergic pathways emanating from the basal forebrain travel within easily identifiable fibre tracks. Material and methods For example, cholinergic pathways extending from Ch1–2 to Subjects the hippocampus travel predominantly within the More than 50 human processed for the visualization (Green and Mesulam, 1988; Alonso et al., 1996), those that of cholinergic markers in whole-hemisphere sections were reach the olfactory bulb within the (Kitt et al., examined. Five representative specimens were chosen for 1987; Luiten et al., 1987) and those to the amygdala within this study. They were among the optimally stained specimens the ventral amygdalofugal pathway and the but did not differ in anatomical detail from the others. The (Carlsen et al., 1985; Heckers and Mesulam, 1994). The specimens used in this study came from subjects with no trajectories of connections between the nbM and the cerebral neurological or psychiatric disease as determined by clinical cortex are less well understood. records. Their ages ranged from 27 to 101 years and three were 2252 N. R. Selden et al. female. Although cortical cholinergic innervation displays a and neurofibrillary tangles in brains from the oldest subjects, minor age-related decline in density (Geula and Mesulam, but in a density and distribution that were below the diagnostic 1989), the trajectories of the pathways do not change with thresholds for Alzheimer’s disease (Mirra et al., 1991). age. The post-mortem autolysis interval was between 4 and 12 h. Cause of death included myocardial infarction (two), congestive heart failure, cardiorespiratory arrest and gunshot Histological procedures wound. No specific neuropathological alterations were found Slabs of whole cerebral hemispheres were fixed, cryo- in sections stained with haematoxylin–eosin and cresyl violet. protected and sectioned coronally at a thickness of 40 µm, Thioflavin S histofluorescence showed some neuritic plaques as described previously (Mesulam et al., 1991). A set of Cholinergic fibre pathways 2253 matching sections through each brain was stained with cresyl Three-dimensional imaging violet for cytoarchitectonic identification and acetylcholin- A contiguous, 1 mm, T1-weighted MRI volume (TR ϭ 15 esterase histochemistry using a modification of the direct ms, TE ϭ 6 ms, flip angle ϭ 20°, FOV ϭ 165 ϫ 220 mm colouring Karnovsky–Roots method (Tago et al., 1986; with a 192 ϫ 256 matrix) was obtained in the coronal plane Mesulam et al., 1987). Adjacent sections were processed from a neurologically normal 62-year-old right-handed female immunohistochemically using a monospecific, polyclonal using a 1.5 Tesla scanner (Siemens Vision, Erlangen, antibody raised against human placental choline acetyl- Germany). The exact plane of image acquisition was transferase (ChAT, generously donated by Lewis B. Hersh) determined to match the plane of section in the anatomical and a monoclonal antibody raised against human NGFr reference cases. The MRI slices were then exported into (generously donated by Mark Bothwell) (German et al., Photoshop and the principal cholinergic pathways were traced 1985; Marano et al., 1987). based on their location in matching anatomical sections. Only The immunohistochemical procedure was based on dense cholinergic fibre bundles coursing within the white formation of the avidin–biotin complex and used matter were represented. The entire volume was then diaminobenzidine as the chromogen (Mesulam et al., 1991). reconstructed within AVS (Applied Visual Systems, Waltham, In selected sections, additional intensification of the reaction Mass., USA) in order to enable the visualization of these product was obtained using silver nitrate (Kitt et al., 1988). pathways in additional planes of section. For control sections, an irrelevant IgG was substituted for the primary antibody. Results All regions of the cerebral cortex displayed a dense net of Data analysis AChE-rich fibres (Fig. 1A). The white matter contained This study is confined to the cholinergic projections that AChE-rich fibre bundles (Fig. 1B). Adjacent sections showed emanate from the nbM. The more fully investigated these fibres to be both ChAT- and NGFr-immunoreactive, hippocampal, olfactory and amygdaloid cholinergic pathways providing definitive confirmation that they are cholinergic (which travel in the fornix, olfactory tract, stria terminalis (because of the ChAT) and that they originate in the basal and ventral amygdalofugal pathway) will not be addressed. forebrain (because of the NGFr) (Fig. 1C and D). Individual Acetylcholinesterase (AChE) histochemistry provided the AChE-rich axons emanated from these cholinergic bundles most intense staining and was used as the principal method and fanned towards the cerebral cortex (Fig. 2). Cholinergic for illustrating the trajectory of cholinergic pathways. The fibre bundles originated from the nbM–Ch4 region and pattern of this staining was compared with that obtained with formed a medial and a lateral pathway (Fig. 3). The lateral ChAT and NGFr immunohistochemistry to ascertain that pathway was further subdivided into a capsular component AChE could be used as a specific marker of cholinergic travelling within the external capsule and a perisylvian pathways. The location, course and density of AChE-rich component travelling within the claustrum. fibres in six representative sections spanning the rostrocaudal The medial cholinergic pathway emanated anteriorly from extent of the cerebral hemispheres were then charted using the nbM–Ch4 and joined the white matter of the gyrus a plotter electronically coupled to the stage of a compound rectus (parolfactory gyrus) and medial orbital gyrus, passed microscope. These chartings were imported into the anteriorly to the rostrum of the corpus callosum, entered the Photoshop graphics program (Adobe Systems Incorporated, cingulum, travelled posteriorly to the splenium and curved San Jose, Calif., USA) for differential coloration of pathways. ventrally to enter the retrosplenial white matter. Individual

Fig. 3 Electronic plotter charts of AChE-rich (cholinergic) fibre bundles in the hemispheric white matter of six coronal sections. A is most rostral and F is most caudal. The medial cholinergic pathway is represented in green, and the two divisions of the lateral pathway in red (capsular division) and orange (perisylvian division). The cholinergic Ch4 neurons of the nucleus basalis of Meynert (nbM) are represented in blue. (A) The medial pathway remains medial to the rostrum of the corpus callosum (R) and gives off fibres to the cingulate gyrus (CG) and medial frontal cortex, whereas the lateral pathway courses within the white matter of the frontal lobe and gives off fibres to the dorsal and lateral . The orbitofrontal cortex receives fibres from both the medial and lateral cholinergic bundles. (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. The two lateral components course within the external capsule (red) and the claustrum (orange). (C and D) The lateral and medial pathways emanate from the nbM–Ch4. The components of the lateral pathway extend dorsally into frontoparietal cortex and ventrally into the . (E and F) The medial pathway continues its caudad course in the cingulum and curves around the splenium (Sp) to supply the cingulate and pericingulate cortices. The lateral pathway courses in the form of discrete bundles within the deep white matter of the parietal, temporal and occipital lobes and gives off AChE-rich fibres to adjacent cortical areas. Magnification, ϫ1.5. ac ϭ ; Am ϭ amygdala; C ϭ caudate; CaS ϭ calcarine sulcus; CC ϭ corpus callosum; CeS ϭ central sulcus; CiS ϭ cingulate sulcus; CoS ϭ collateral sulcus; dg ϭ ; En, entorhinal cortex; GP ϭ ; H ϭ hippocampus; IN ϭ insula; mb ϭ ; P ϭ putamen; SF ϭ Sylvian fissure; Th ϭ ; TP ϭ temporal pole; V ϭ ventricle. 2254 N. R. Selden et al.

Fig. 4 The medial and lateral cholinergic pathways are represented within a volume-rendered MRI format, enabling their visualization in planes 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 white matter are included. The fine fibres which take off from these bundles to innervate adjacent areas of cortex are not shown in the interest of clarity. The trajectories shown in this figure also help to identify white matter sites where lesions (for example vascular) could interrupt the more distal flow of cortical cholinergic pathways. (A) and (B) Horizontal sections at the level of the frontal horns of the lateral ventricles and the upper level of the corpus callosum, respectively. (C) Parasagittal view obtained 4 mm lateral to the interhemispheric 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 a horizontal section at the level of the anterior commissure. The arrowhead points to the nbM–Ch4 neurons which give rise to the corticopetal cholinergic pathways. ac ϭ anterior commissure; C ϭ caudate; CC ϭ corpus callosum; CeS ϭ central sulcus; CiS ϭ cingulate sulcus; IPS ϭ intraparietal sulcus; OF ϭ orbitofrontal gyri; P ϭ putamen; R ϭ rostrum of corpus callosum; SF ϭ Sylvian fissure; Sp ϭ splenium of corpus callosum; Th ϭ thalamus. Cholinergic fibre pathways 2255 axons radiated from this pathway to supply medial to promote the impact and memorability of novel and orbitofrontal, subcallosal, cingulate, pericingulate and motivationally relevant events. The degeneration of nbM– retrosplenial cortices (Figs 2 and 3). Ch4 neurons observed in various neurological diseases, The capsular division of the lateral cholinergic pathway including Alzheimer’s disease and Parkinson’s disease, results coursed in a densely packed and highly organized bundle of in a depletion of cortical cholinergic innervation and fibres immediately adjacent to the putamen in the medial undoubtedly contributes to the altered mental state that is aspect of the external capsule (Figs 1B and 3). Additional observed in these conditions (Geula and Mesulam, 1994). fibres travelled ventrally in the white matter of the uncinate Although cholinergic projections reach all areas of the fasciculus, adjacent to the fundus of the putamen and the cerebral cortex and are generally described as diffuse, our amygdala (Fig. 3). Some of these fibres appeared to penetrate studies demonstrate that they travel in discrete, organized the substance of the amygdala while others continued in a bundles. The medial cholinergic pathway travels within dense bundle into the white matter of the temporal lobe. the cingulum and supplies the orbitofrontal, subcallosal, Individual fibres radiated from the capsular division to supply cingulate, pericingulate and retrosplenial cortices. The lateral the dorsal frontoparietal neocortex, the middle and inferior cholinergic pathway includes a perisylvian division, which temporal gyri, the inferotemporal cortex and the courses within the claustrum to supply opercular and insular (Fig. 3). cortices, and a capsular division, which courses within the The perisylvian division of the lateral cholinergic pathway external capsule and uncinate fasciculus to supply remaining coursed within the claustrum, curving laterally into the white areas of the cerebral cortex. Our findings in the human brain matter of the inferior frontal and superior temporal gyri. are generally in concordance with those in the rhesus monkey Individual fibres radiated from the perisylvian division to (Kitt et al., 1987) and provide additional histochemical and supply the frontoparietal opercular cortices, superior temporal immunohistochemical validation concerning the cholinergic gyrus and the insula (Fig. 3). nature of these pathways. Such specific validation is important The medial and lateral cholinergic pathways merged since the nbM also contains non–cholinergic neurons which anteriorly in the white matter of the orbitofrontal gyri and project to the cerebral cortex (Gritti et al., 1993). posteriorly in the occipital lobe beneath the optic radiations The discrete topography of cholinergic pathways within the (Fig. 3). cerebral hemispheres suggests that corticopetal cholinergic The manual reconstruction of anatomically identified neurotransmission may be vulnerable to focal pathological cholinergic pathways within corresponding MRI sections insults of the white matter even when the nbM itself remains allowed a 3D reconstruction of their distribution within the intact. The representation of cholinergic pathways within 3D human cerebral hemispheres (Fig. 4). The entire curved MRI volumes allows the identification of the lesion sites that trajectory of the medial cholinergic pathway was visualized are most likely to interrupt these pathways. Cingulotomly is in a single parasagittal plane of section (Fig. 4C). occasionally performed to treat intractable depression or Representation of cholinergic pathways within axial sections, obsessive–compulsive disorders (Cosgrove and Ballantine, which are commonly used in clinical studies, showed that 1998). One unexpected consequence of this procedure may these pathways course through regions of white matter that be to cause a cholinergic denervation of cingulate and are frequently involved in many different disease processes, pericingulate cortices caudal to the lesion site. including cerebrovascular and demyelinating diseases and The , the external capsule and claustrum neoplasm (Fig. 4A and B). are commonly involved in cerebrovascular disease. Such lesions could cause a widespread disconnection of remote cortical areas from their source of cholinergic innervation in Discussion the basal forebrain. The resulting cholinergic denervation The neurons of nbM–Ch4 are selectively responsive to novel could contribute to the emergence of mental state and motivationally relevant sensory events (Wilson and Rolls, impairments. Multi-infarct and Alzheimer’s disease 1990; Morris et al., 1997). Novel and emotionally salient may therefore share a common neurochemical pattern of events are therefore particularly effective in eliciting the cortical cholinergic depletion through completely different release of acetylcholine (ACh) in the cerebral cortex. The mechanisms. The ascending cholinergic axons of the nucleus major effect of ACh upon neurons of the cerebral cortex is basalis are mostly unmyelinated (Wainer and Mesulam, mediated through the m1 subtype of muscarinic receptors 1990). It therefore remains to be seen if demyelinating and causes a prolonged reduction of potassium conductance diseases such as multiple sclerosis can also damage the so as to make cortical neurons more receptive to other white matter pathways which carry cholinergic fibres to the excitatory inputs (Sato et al., 1987; McCormick, 1990). cerebral cortex. Cortical cholinergic pathways also promote long-term Investigation of the human brain is progressing rapidly, potentiation and experience-induced synaptic remodelling especially as a consequence of remarkably powerful methods (Huerta and Lisman, 1993; Cruikshank and Weinberger, 1996; related to functional imaging. However, delineating the Baskerville et al., 1997). The cholinergic pathway from the of neural connections in humans continues to pose basal forebrain to the cerebral cortex is therefore in a position serious challenges. Our results demonstrate that transmitter- 2256 N. R. 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