Basal Forebrain Anatomical Systems in MRI Space

Basal Forebrain Anatomical Systems in MRI Space L Zaborszky, The State University of New Jersey, Newark, NJ, USA K Amunts, Institute of Neuroscience and Medicine (INM-1), Ju¨lich, Germany; JARA Ju¨lich-Aachen Research Alliance, Aachen, Germany; University of Du¨sseldorf, Du¨sseldorf, Germany N Palomero-Gallagher, Institute of Neuroscience and Medicine (INM-1), Ju¨lich, Germany; JARA Ju¨lich-Aachen Research Alliance, Aachen, Germany K Zilles, Institute of Neuroscience and Medicine (INM-1), Ju¨lich, Germany; JARA Ju¨lich-Aachen Research Alliance, Aachen, Germany; RWTH University Aachen, Aachen, Germany ã 2015 Elsevier Inc. All rights reserved.

Abbreviations ACh AChE AMPA BF BNM BST CaBP CCK CeM DARP-32

Acetylcholine Acetylcholinesterase Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid Basal forebrain Basal nucleus of Meynert Bed nucleus of the stria terminalis Calbindin Cholecystokinin Centromedial amygdala Adenosine 3’5’-monophosphate regulated phosphoprotein of Mr 32 kDa

Introduction The basal forebrain (BF) comprises heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. This region contains a number of well-recognized interdigitating anatomical structures, including the medial septal nucleus, the nucleus of the diagonal band of Broca, the basal nucleus of Meynert (BNM), the ventral striatopallidal system (ventral striatum (VS) or nucleus accumbens and ventral pallidum (VP)), and the cell groups underneath the globus pallidus in the substantia innominata (SI) that bridge the centromedial amygdala (CeM) to the bed nucleus of the stria terminalis (BST; extended amygdala (EA)). Among the different BF neuronal populations, the cholinergic corticopetal projection neurons (BNM or magnocellular corticopetal system) have received particular attention due to their loss in Alzheimer’s and related disorders (see Zaborszky et al., 2008). The SI, a term coined by Reil (1809), is the centerpiece of this heterogeneous collection of anatomical systems. SI is defined here as a forebrain region that is populated by magnocellular cells caudal to the nucleus accumbens. The SI can be divided into a rostral, subcommissural, and caudal, sublenticular components defined by its relation to the anterior commissure and the globus pallidus. The SI is delineated dorsally by the ventral edge of the globus pallidus and the anterior commissure and ventrally by the base of the brain. Laterally, the border is constructed by an artificial extension of the external capsule toward the ventral aspect of forebrain. Rostrally, this corresponds to the limen insulae; more caudally, the lateral border is an archiform line from the claustrum to the dorsolateral edge of the amygdaloid body. Parts of the ventral claustrum, the amygdalostriatal

Brain Mapping: An Encyclopedic Reference

GAP-43 GluR1 HDB IPAC MACM SI SP-IR TH VDB VIP VP VS

Growth-associated protein Subtype of AMPA receptor Horizontal limb of the diagonal band Interstitial nucleus of the posterior limb of the anterior commissure Meta-analytic connectivity modeling Substantia innominata Substance P immunoreactivity Tyrosine hydroxylase Vertical limb of the diagonal band Vasoactive intestinal peptide Ventral pallidum Ventral striatum

transition area, and the ventral putamen are not included in the SI. In addition to the magnocellular corticopetal cells, the SI also contains the cell islands and neuropil connecting the BST with the CeM, the so-called EA (Heimer et al., 1999). Although it was argued (Alheid, 2003; Heimer, 2003) that by dissecting the components of the SI, this term should be abandoned and replaced by the term EA, we kept the SI, since changing the terms would diminish the significance of the corticopetal system. In some publications, the SI is used to describe an area that also included the VP (Nieuwenhuys, Voogd, & van Huijzen, 2008) or used as a synonym for the BNM (see Martin, Powers, Dellovade, & Price, 1991). Although the term SI is well entrenched in the clinical literature, it is poorly defined and has little relevance from a functional-anatomical point of view. Aided by modern tracer and immunohistochemical methods, the main part of the SI can be viewed as belonging to nearby and better defined anatomical systems (Heimer, de Olmos, Alheid, & Za´borszky, 1991; Heimer & van Hoesen, 2006). This article does not discuss a group of structures that have sometimes been included in the BF: the preoptic anterior hypothalamus, the olfactory tubercle, the piriform cortex, and the amygdaloid body. The septal nuclei and diagonal band nuclei, which also contain cholinergic and GABAergic corticopetal and septohippocampal neurons, are only briefly mentioned. The vertical limb of the diagonal band is bordered laterally by the nucleus accumbens and contains the Ch2 cholinergic cell group. The horizontal limb of the diagonal band (HDB) contains the Ch3 cholinergic cell group and described in detail later. A substantial amount of experimental data in animals, including primates, suggests the involvement of the BF in

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cortical activation, attention, learning, memory, reward, and cortical plasticity (Conner, Chiba, & Tuszynski, 2005; Duque, Balatoni, Detari, & Zaborszky, 2000; Edeline, 2003; Everitt & Robbins, 1997; Richardson & DeLong, 1991; Rolls, Sanghera, & Roper-Hall, 1979; Sarter, Gehring, & Kozak, 2006; Weinberger, 2007; Wilson & Rolls, 1990; Zaborszky et al., 2013, 2014; Zaborszky, Van den Pol, & Gyengesi, 2012). The superimposition of postmortem anatomical and in vivo functional data in the same space of a reference brain allows correlations to be made between microstructural details and functional imaging data (Eickhoff et al., 2005; Roland & Zilles, 1994). While correlations of anatomical and functional data are extensively used in understanding the functional specialization of cortical regions, such studies were hampered in the BF due to the lack of delineations of the various anatomical systems in standardized stereotaxic space. In order to delineate the different BF anatomical systems, we initiated a series of studies in the BF in collaboration with the groups in Ju¨lich and Du¨sseldorf using postmortem brains that were imaged in the 3-D MRI space and subsequently cut into sections and stained with Merker’s silver technique (Merker, 1983). Figure 1, in six coronal silver-stained sections from a human brain, displays the regions of interest of this article.

The Ventral Striatopallidal System The Ventral Striatum, Fundus, and Interstitial Nucleus of the Posterior Limb of the Anterior Commissure The terms VS and VP were introduced in the late 1970s, realizing that in the rat brain, the allocortex (olfactory or piriform cortex and the hippocampus) and the cortical-like basolateral amygdala, like the neocortex, are linked to the basal ganglia via cortical–striatal–pallidal–thalamic circuits (Heimer, 1978). This contradicted the then-held view that the rostral part of the substantia innominata (SI) is an important gateway from the primary olfactory cortex to the hypothalamus. Instead, Heimer and his colleagues demonstrated that projections from the piriform and periamygdaloid cortices terminate in a BF region that includes the nucleus accumbens, the ventral part of the main body of the striatum (called fundus striati or ventral striatal pocket at the time), the medium-sized cells of the olfactory tubercle, and the cell bridges that connect the dorsal striatum with the olfactory tubercle. These structures were collectively termed as the ‘VS’. Axon terminals from the olfactory tubercle and nucleus accumbens were then traced to a subcommissural SI area, termed as ‘VP.’

Figure 1 Low-magnification series of coronal sections from rostral (a) to caudal (f) from a male subject stained with the Merker (1983) silver method to show the location of major basal forebrain cell groups in relation to other brain structures. The various Ch cell groups as delineated on the images of the sections are color-coded: Ch1–2, red; Ch3, green; Ch4, blue; Ch4p, yellow-brown. ACb, nucleus accumbens; ac, anterior commissure; Cd, caudate nucleus; Cl, claustrum; EGP, external globus pallidus; IGP, internal globus pallidus; ic, internal capsule; MD, mediodorsal thalamic nucleus; ox, optic chiasm; Pu, putamen, slSI, sublenticular substantia innominata. Bar scale: 5 mm. Modified from Figure 1 in Zaborszky, L., Hoemke, L., Mohlberg, H., Schleicher, A., Amunts, K., & Zilles, K. (2008). Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. NeuroImage, 42, 1127–1141.

INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Basal Forebrain Anatomical Systems in MRI Space

In primates, including humans, the nucleus accumbens and the rostroventralmost aspects of the caudate and putamen form the VS. The VS reaches the ventral surface of the brain in the region of the anterior perforated space, occupying a region underneath and in front of the lateral extension of the anterior commissure, that is, in the subcommissural SI. Between the ventral extensions of the caudate/putamen, underneath the rostroventral aspect of the internal capsule, and dorsal to the nucleus accumbens, a transitory region is distinguished and referred as the fundus (fundus caudati, fundus putaminis, and fundus striati; see Heimer, 2000; Lauer and Heinsen, 1996; Prensa, Richard, and Parent, 2003). The VS receives input from the olfactory, orbitofrontal, cingulate, and temporopolar cortices; the hippocampus; the entorhinal area; the amygdala; and the dopaminergic neurons of the midbrain (Haber, Adler, & Bergman, 2012; Heimer et al., 1999). Since projections from the cortical areas to the VS overlap to a considerable extent with neocortical projections targeting the dorsal striatum (putamen/caudate nucleus), it is not possible to draw a precise border between the VS and dorsal striatum, although a number of cytoarchitectural and histochemical features do distinguish the VS from the main dorsal part of the caudate nucleus and putamen (see Haber and Knutson, 2010; Heimer, 2000; Heimer et al., 1999). For example, the nucleus accumbens is characterized by higher cell density than the dorsal striatum and packed with slightly smaller cells of round/oval shape (12–14 mm in ventral and 15–18 mm in dorsal). Also, the cells are stronger stained in Nissl in the ventral than in the dorsal striatum. Additionally, the subcommissural and sublenticular part of the nucleus accumbens shows a heterogeneous cell distribution due to intermingling with various cell clusters, called interface islands, terminal islands, or islands of Calleja (Alheid, de Olmos, & Beltramino, 1995; Heimer et al., 1999; Meyer, GonzalezHernandez, Carillo-Padilia, & Ferres-Torres, 1989; Sanides, 1957). In the fundus, the cells are more homogeneously distributed, less dense than that of the nucleus accumbens, but slightly denser then dorsal striatum and are of more fusiform or spiny shape. Another characteristic of the fundus is that the caudal part of the nucleus accumbens is invaginated by ventral pallidal islands, which is not the case in the fundus (Lauer & Heinsen, 1996). The striosome–matrix organization that can be revealed with a number of histochemical methods in the dorsal striatum (Graybiel & Ragsdale, 1983) is less clear in the VS, which has a more complex, multicompartmental organization (Holt, Graybiel, & Saper, 1997). The realization of and subsequent support for the concept of the VP and VS served to simplify the structural analysis of the ventral forebrain. Thus, a large portion of the rostral forebrain that includes the rostral subcommissural SI can now be viewed as more or less continuous extension of the better known dorsal striatopallidal complex.

Shell and Core of the VS While studying the afferent input to the VS in rats, a serendipitous observation led to a new anatomical parcellation within the nucleus accumbens that was quickly incorporated into the second edition of the Paxinos–Watson rat atlas (Zaborszky et al., 1985). It was easy to recognize using various cyto- and

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immunocytochemical markers that the nucleus accumbens consists of two compartments, the centrally located core and the peripheral, ventrally and medially located shell. These two compartments of the nucleus accumbens differ in their efferent projections: The core projects primarily to the ‘classical’ striatal targets, for example, the VP, the entopeduncular nucleus, and the substantia nigra, while the shell projects diffusely throughout the rostrocaudal extent of the lateral hypothalamus and caudal mesencephalic areas associated with locomotor function (Heimer et al., 1991). Axons from the shell also terminate in the BST. These ‘nonclassical’ striatal projections originate primarily in the medial shell; the ventral and lateral shell forming a transitional area that, in a lateral direction, exhibits more of striatal output characteristics (Voorn, Vanderschuren, Groenewegen, Robbins, & Pennartz, 2004). As it turned out, these anatomical differences reflect functional differences that are important in the expression of maternal, feeding, and defensive behaviors and as targets of antipsychotic drugs (Voorn et al., 2004). Functional differences are especially clear between the medial shell and the core (Ikemoto, Qin, & Liu, 2005). Shell lesions disrupt maternal behavior (Li & Fleming, 2003), and infusion of GABAA receptor agonists or amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists into the rostral shell evokes feeding and conditioned place preferences but, in the caudal shell, instead elicits unconditioned fearful, defensive behavior (Kelley, 2004; Reynolds & Berridge, 2002). Acquisition of lever pressing for food is a function of the core but not the shell (Kelley, 2004), whereas the opposite holds true for the acquisition of conditioned taste aversion (Fenu & Chiara, 2003). The enhancement by psychostimulant drugs of behaviors influenced by active or passive presentations of conditioned stimuli is a function of the shell (Ikemoto et al., 2005; Kelley, 2004). On the other hand, cocaine-conditioned locomotion (Hotsenpiller, Giorgetti, & Wolf, 2001) and expression of context-specific psychomotor sensitization depend on the core (Bell, Duffy, & Kalivas, 2000). The shell mediates spatial contextual control over conditioned approach behavior (Pennartz et al., 2009). Hedonic hot spots in the accumbens shell and the VP are part of larger opioid circuits that control ‘liking’ or ‘wanting’ for food reward (Smith & Berridge, 2007). A recent study of the nucleus accumbens in transgenic mice using dopamine D1–D3 and adenosine A2A receptors supports the idea of multiple accumbal shell subterritories (Gangarossa et al., 2013) proposed earlier by Zahm and Brog (1992). The subdivisions of shell and core established for the nucleus accumbens of rodents are also applicable in primates, including humans. In general, compared to the core, the shell is rich in the subtype of AMPA receptor, growth-associated protein (GAP-43), acetylcholinesterase (AChE), m opiate receptors, serotonin, substance P, and calretinin; on the other hand, the core is rich in calbindin (CaBP), while the medial shell is poor. However, these markers show mediolateral and rostrocaudal gradients often in a complex pattern, and borders between compartments may not be in close register with one another using different markers (Brauer, Ha¨ußer, Ha¨rtig, & Arendt, 2000; Haber et al., 2012; Haber & Knutson, 2010; Holt et al., 1997; Ikemoto, Satoh, Maeda, & Fibiger, 1995; Meredith, Pattiselanno, Groenewegen, & Haber, 1996; Morel, Loup, Magnin, & Jeanmonod, 2002; Prensa et al., 2003; Voorn,

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Brady, Berendse, & Richfield, 1996). Taken together, neurotransmitters and receptors help distinguish the ventral and medial borders of the VS and the shell/core subterritories within it. However, the dorsal and lateral boundaries are more problematic; here, the VS merges imperceptibly with the dorsal striatum. Figure 2 shows the distribution of M2 receptors labeled with the antagonist [3H]AF-DX 384 (panel C) and of a1 adrenoceptors labeled with [3H]prazosin (panel D); both receptor binding sites are much denser expressed in the dorsomedial shell than in the ventral shell/core. In human imaging studies, putative core/shell subdivisions show differential responses to thermal pain and gambling tasks: the shell signals thermal pain onset and value predictions for monetary reward and the core signals cessation of pain (negative reinforcement value of analgesia), but the core activation is independent of perceived gains or losses in the gambling task. Moreover, the core/shell subdivision poses differential functional connectivity during different cognitive states and at rest (Baliki et al., 2013), which in part corresponds to differential structural connectivity (Haber & Knutson, 2010). Resting-state analysis and meta-analytic connectivity modeling (MACM) of the nucleus accumbens predict

coactivation in regions implicated in reward circuitries, including the orbitofrontal and ventromedial prefrontal cortices, insula, globus pallidus, mediodorsal nucleus of the thalamus, amygdala, and midbrain that are known to be connected to the nucleus accumbens (Camara, Rodriguez-Fornells, Ye, & Mu¨nte, 2009; Cauda et al., 2011). Interestingly, coactivation of the nucleus accumbens shows laterality, supporting imaging studies that revealed a predominant involvement of the left medial orbital, subgenual anterior cingulate, ventrolateral prefrontal, and related striatal–pallidal–thalamic structures in regulating emotional expression in cases with depressive relapses (Drevets, Price, & Furey, 2008). In caudal striatal regions, including the lateral amygdalostriatal area, caudoventral putamen, and medial tail of the caudate nucleus, a caudal VS can be defined based upon its moderate AChE staining, strong tyrosine hydroxylase (TH) immunoreactivity, and the presence of amygdaloid input, characteristics of the classical, rostral VS (Fudge, Breitbart, Danish, & Pannoni, 2005; Fudge, Breitbart, & McClain, 2004). The lateral amygdalostriatal area is further distinguished by low CaBP-IR, reminiscent of the shell subterritory of the rostral VS (Fudge & Haber, 2002). The caudoventral part of the striatum

Figure 2 (a) Low-magnification image from panel (a) in Figure 1 to show the septal region. Outlined area corresponds to the vertical limb of the diagonal band. (b) High magnification from panel (a) to demonstrate the cytoarchitecture of the Ch1–2 groups (black lines). (c) Muscarinic M2 receptor binding sites from comparable level as (a) and (b). The medial shell of the nucleus accumbens (white line) shows strong binding to muscarinic M2 receptors. (d) Binding to a1 adrenoceptors. Note rich binding in the medial shell (white line). ACb, nucleus accumbens; ASc, shell of the nucleus accumbens; DBv, vertical limb of the diagonal band; EGP, external globus pallidus; LV, lateral ventricle; LS, lateral septal nucleus; MS, medial septal nucleus. Modified from Figure 2 in Zaborszky, L., Hoemke, L., Mohlberg, H., Schleicher, A., Amunts, K., & Zilles, K. (2008). Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. NeuroImage, 42, 1127–1141.

INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Basal Forebrain Anatomical Systems in MRI Space

also includes the interstitial nucleus of the posterior limb of the anterior commissure (IPAC or fundus striati in rodents; Fudge et al., 2005), a transition zone between the EA and the VS, located around the posterior component of the anterior commissure. According to functional studies, this caudal ventral striatal region and the ‘classical’ rostral VS respond similarly to amphetamine-induced dopamine release suggesting a continuum of the ‘limbic’ related striatum along the entire rostrocaudal aspect of the striatum (Drevets et al., 2001; Fudge et al., 2004; Martinez et al., 2003). In summary, tracing studies in primates and imaging studies in humans support the notion that the accumbens shell; rostroventral and caudoventral striatum, with inputs from the insula; various amygdaloid nuclei (basal, accessory basal, and centromedial); hippocampus; orbitofrontal–ventromedial prefrontal and anterior cingulate cortices; and midbrain dopamine cell groups process various primary and secondary rewards and contextual information to mediate emotionally charged goal-directed behaviors (Camara et al., 2009; Cho, Ernst, & Fudge, 2013; Cho et al., 2013; Ernst & Fudge, 2009, Haber & Knutson, 2010). Differential dysfunction within these circuits by causing abnormally valenced motivational salience could contribute to human obesity, drug addiction, anxiety, depression, and paranoid psychosis (Reynolds & Berridge, 2002; Smith & Berridge, 2007). The role of the human nucleus accumbens in reward learning was recently demonstrated in patients undergoing deep brain stimulation for treatment of major depression (Cohen et al., 2009).

The Ventral Pallidum VP in 3-D histological volume: Underneath the anterior commissure in a silver-stained specimen of the human brain, a darker area can be differentiated from the nucleus accumbens that belongs to the ventral extension of the globus pallidus (Figure 1(b)). As described earlier, fingerlike processes of the VP invade the VS, especially caudally, where a clear distinction for imaging studies is impossible. Due to the difficulty in separating the VP from its dorsal counterpart, we did not include in our analysis (see Figure 7) the ventral part of the globus pallidus at coronal levels just behind the crossing of the anterior commissure. In rodents, the boundaries of the VP are defined by woolly fiber-like elements showing substance P immunoreactivity (SPIR) and enkephalin-IR (Groenewegen & Russchen, 1984; Haber & Nauta, 1983; Heimer et al., 1991; Hill & Switzer, 1984; Zahm, Zaborszky, Alheid, & Heimer, 1987). The primate VP is a crescent-shaped structure ventral to the anterior commissure expressing both enkephalin-IR and SP-IR woolly fibers. The VP in primates shares features of both the external and internal segments of the globus pallidus. The external, enkephalin-rich component of the VP lies ventral and adjacent to the anterior commissure. The internal, SP component of the VP lies as a ventral and rostral extension of the internal segment of the globus pallidus, often interdigitating with fingerlike processes of the VS (accumbens). The primate VP projects to the mediodorsal thalamus, lateral habenular, and subthalamic and pedunculopontine nuclei and receives accumbal, subthalamic, and dopaminergic projections from the midbrain (Haber & Knutson, 2010). Due to the fact that human imaging studies lack sufficient resolution to distinguish the VP from the

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VS, often, activations in the VP are described as located in the VS (e.g., Alexander & Brown, 2010; Ballard & Knutson, 2009; Camara et al., 2009; Cowdrey, Park, Harmer, & McCabe, 2011) as MACM analysis using VP and accumbens coordinates defined by maximum probability maps suggest (Yuan, Biswal, Zaborszky, in preparation).

Bed Nucleus of the Stria Terminalis: Extended Amygdala Anatomy Rostrally, the BST merges with the posterior aspect of the nucleus accumbens ventrally and the caudate nucleus dorsally. Medially, the BST is bounded by the ventral division of the lateral septal nucleus. Caudally, the BST is bounded medially by the lateral ventricle and the column of the fornix, dorsally by the internal capsule, and ventrally with preoptic and anterior hypothalamic areas. For subdivisions of the BST in primates, including humans see de Olmos (1990), Heimer et al. (1999), Martin et al. (1991), and Walter, Mai, Lanta, and Go¨rcs (1991). Johnston (1923) called attention to a close relationship between the BST and the CeM as continuous structures in the human embryos interconnected via cell bridges within the stria terminalis as it makes a semicircular detour in the ventrolateral edge of the lateral ventricle. Another cellular continuum between the BST and CeM is located underneath the basal ganglia in the sublenticular SI. A ventral connection between the BST and amygdala in the area of the nucleus ansae peduncularis was already demonstrated in 1962 by Nauta in monkey (Nauta, 1962) and later by de Olmos using silverstained preparations of the adult rat brain (de Olmos & Ingram, 1969, 1972). This continuous neuropil between the BST and CeM through the sublenticular gray was termed as ‘EA’ (see historical discussion in de Olmos and Heimer, 1999). In rat, angiotensin II is prominently expressed in the EA, but not in basal ganglia, while epidermal growth factor labels dorsal and VP, but not the striatum or EA. Noradrenergic terminals are found in the central division of the rat EA and the shell of the nucleus accumbens, but not in the medial division of the EA (Alheid, 2003; Berridge, Stratford, Foote, & Kelley, 1997; Freedman & Cassell, 1994; Swanson & Hartman, 1975). Martin et al. (1991), Heimer et al. (1999), and Alheid (2003) described two cell/neuropil corridors in the sublenticular SI of primates, including humans. The dorsolateral one, connecting the lateral division of the BST with the central nucleus of amygdala (central division of the sublenticular EA), is rich in SP, enkephalin, AChE, cholecystokinin (CCK), neurotensin (NT), vasoactive intestinal peptide (VIP), and somatostatin. The ventromedial corridor of cells and neuropil connects the medial amygdala with the medial part of the BST (medial division of the sublenticular EA) and is rich in CCK, NT, and secretoneurin. The majority of the neurons in the SI that connect the BST–CeM in primates are medium-sized, fusiform perikarya with long dendrites. These neurons form narrow, tightly packed bands that have little overlap with the neurons of the BNM. Thus, it is possible that neurons that form the BST–amygdala continuum and cholinergic neurons that reside within the SI are unrelated two systems that maintain

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segregated afferent and efferent connections (Martin et al., 1991). The neurons of the EA in the rhesus monkey contain adenosine 3’5’-monophosphate-regulated phosphoprotein of Mr 32 kDa (DARP-32), unlike the magnocellular cholinergic neurons, although they seem to share input from the orbitofrontal cortex and particularly from the medial area 32 (Ghashghaei & Barbas, 2001). Bcl-2, an intracellular protein, also labels scattered cells through the primate central EA (Fudge, 2004). Although the transmitter specificities of neurons bridging the BST and amygdala in the SI are not known, some of these neurons may be GABAergic and are the recipients of extensive somatostatin, enkephalin, NT, or CCK innervations in primates (Martin et al., 1991). In the macaque, the dorsomedial shell, similarly to the central division of the BST, receives input from the corticoamygdaloid transition area and CeM, while the ventral shell/ core and the juxtacapsular division of the BST receive input from the basal and accessory basal nucleus of the amygdala (deCampo & Fudge, 2013). These data support the idea that the shell and certain subdivisions of the BST are transitional areas with the EA (deCampo & Fudge, 2013). Panels (a)–(c) in Figures 3 and 4(a) show the distribution of a1 adrenoceptor binding sites. Consulting with adjacent silverstained sections, it seems that the a1 adrenoceptor strip close to the ventral brain surface underneath and caudal to the nucleus

accumbens in the sublenticular gray is likely to represent an extension of the amygdala. As it can be appreciated, this ventral a1 adrenoceptor strip seems to be continuous rostromedially with similar intense receptor binding in the BST (Figure 3(a)), with the shell of the nucleus accumbens (Figure 2(d)) and caudolaterally with the medial amygdala (Figure 3(c)). An additional column of neurons in rat, belonging to the central EA, is the IPAC, which follows the posterior limb of the anterior commissure along the caudal surface of the nucleus accumbens to join the lateral BST (Alheid, 2003). An area congruent with IPAC that was termed earlier as the ventral striatal pocket (Nauta, Smith, Faull, & Domesick, 1978) or fundus striati (Paxinos & Watson, 1986) in rodents has also been identified in primates (Cho, Fromm, et al., 2013b). According to Shammah-Lagnado, Alheid, and Heimer (2001) in rodents, only the medial component of the IPAC is related to the EA, while its lateral part represents striatal territory. The positions of the dorsomedial and ventrolateral divisions of the EA around the magnocellular cholinergic cell groups in the human SI are reminiscent of the twisted banded pattern of the 3 calcium-binding protein containing neurons (calbindin, calretinin, and parvalbumin) around the cholinergic projection neurons in the entire extent of the BF in rats (Zaborszky, 2002; Zaborszky, Buhl, Pobalashingham, Bjaalie, & Nadasdy, 2005; Zaborszky et al., 2014).

Figure 3 (a–c) Series of coronal sections to show the distribution of a1 adrenoceptor binding sites in the subcommissural and sublenticular substantia innominata (SI). There is a strong binding in the bed n. of the stria terminalis (white star in panel (a)) and along a stripe close to the ventral edge of the brain in the SI (white line in (c) and EA in (b)). (d) Low-magnification view of muscarinic M3 receptor binding sites (labeled with [3H]4-DAMP). Note the similar strong binding in the putamen (Pu) and in the nucleus accumbens (patchy receptor staining), underneath of the anterior commissure. (e) Enlarged view of the ventral part of the image (d). The receptor image was overlaid on the adjacent silver-stained section, and the opacity of the receptor image was adjusted to view the magnocellular cell groups of Ch3 (delineated by white hyphenated lines) medial to the accumbens. Another cluster of large neurons, just underneath of the anterior commissure (acp) that belongs to the Ch4 group, is delineated by white lines in the black box. A third magnocellular cell cluster is ventrolateral to acp, underneath heavy receptor expression in the ventral part of the putamen. The ventral stripe of neuropil is nearly free of receptor binding. Compare this image to panel (b) in which the a1 adrenoceptor binding sites are rich in the similar region of the SI (labeled by EA in (b)). The narrow longitudinal black box from the underlying silver-stained section is shown with higher magnification in (f). ic, internal capsule; VP, ventral pallidum. (f) High-magnification view of the boxed area from E to show the diversity of cytoarchitecture of the SI. Arrows point to a cluster of magnocellular cell group belonging to the Ch4 group that is delineated by white lines in the black box of panel (e). Black interrupted line in (f) demarcates the approximate border between the ventral part of the nucleus accumbens (ACb) and the extended amygdala (EA). White star labels a parvicellular island.

INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Basal Forebrain Anatomical Systems in MRI Space

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Bienkowski & Rinaman, 2013; Bourgeais, Gauriau, & Bernard, 2001; Freedman & Shi, 2001). A unifying anatomical term also contradicts the fact that the BST and CeM appear to play related but not identical roles in fear, anxiety, social interaction, reproductive behavior, ethanol self-administration, and hypoalgesia in response to noxious stimuli (see Bienkowski and Rinaman, 2013). In humans, activation of the putative BST is correlated with continuous threat monitoring and sustained fear, while signals in the dorsal amygdala, consistent with the location of the central amygdaloid nucleus, are correlated with transient activity to aversive stimuli (Alvarez, Chen, Bodurka, Kaplan, & Grillon, 2011; Sommerville et al., 2010). These data support the rodent model, according to which the BST is critically involved in unlearned fear and contextual conditioned fear responses, whereas the amygdala is involved in the acquisition and expression of conditioned fear to both contextual and auditory conditioned stimuli (Fendt, Endres, & Apfelbach, 2003; Sullivan et al., 2004; Walker & Davis, 1997; Zimmerman & Maren, 2011). These functional differences may relate to broad differences in connectional and receptor distributions in the respective brain areas: for example, gonadal receptors tend to aggregate in the medial amygdaloid nucleus and its afferents, and glucocorticoids/CRF receptors are densely distributed in the central nucleus and its afferents. Thus, the medial EA has been considered a mediator of reproductive and social defensive behaviors, while the central EA has been considered a mediator of fear responses.

Figure 4 (a) High-magnification view of a1 adrenoceptor binding sites from panel (c) of Figure 3, close to the ventral surface of the brain in the substantia innominata (SI). The receptor image was overlaid on the adjacent silver-stained section, shown in (b). The transparency of the receptor image was adjusted to view the location of the magnocellular cell group that has a low receptor binding as compared to the strong expression in the neuropil ventral to this magnocellular group (Ch4). The strong receptor binding in the ventral part of the SI may correspond to the extended amygdala (EA). (b) Silver-stained section adjacent to the section showing the a1 adrenoceptor binding sites. Thin arrows surround a magnocellular cell cluster belonging to the Ch4 group. Black stars label the area that shows dense receptor binding in panel (a). ac, anterior commissure; CeM, centromedial amygdala.

Anatomical–Functional Correlations of the EA Few authors dispute similarities in the neurochemical, developmental, and cellular composition between the BST and the CeM as well as the presence of interconnections and scattered cell groups through the SI between subdivisions of the BST and their counterparts in the CeM, in both primates and rodents. However, the validity of the EA (Alheid, 2003; Bupesh, Abella´n, & Medina, 2011; de Olmos & Heimer, 1999; Swanson, 2003) as an anatomical–functional macrosystem vis-a`-vis the ventral striatopallidal system as separate BF information processing channels is debated (Martin et al., 1991; McDonald, 2003; Swanson, 2003). Also, a unifying term implicitly suggests that corresponding parts of the BST, CeM, and SI have the same input–output and intrinsic connections, which is certainly not true and the ‘mirroring,’ or ‘symmetrical,’ aspects of the BST and CeM are less exact (Alheid, 2003;

Basal Nucleus of Meynert Basic Anatomy in Histological Sections and Probabilistic Maps in MRI The widely dispersed, more or less continuous collection of aggregated and nonaggregated large neurons that extend obliquely from the septum rostrally to the level of the lateral geniculate body caudally is often called the ‘magnocellular basal nucleus’ (Saper & Chelimsky, 1984), or ‘magnocellular BF system’ (Hedreen, Struble, Whitehouse, & Price, 1984). The rostral portion of these neurons is associated with the medial septum and the nucleus of the diagonal band of Broca and primarily projects to the hippocampus. On the other hand, neurons located more caudally in the subcommissural and sublenticular SI, often referred to as the BNM, project topographically to various cortical areas (Jones, Burton, Saper, & Swanson, 1976; Mesulam, Mufson, Levey, & Wainer, 1983; Pearson, Gatter, Brodal, & Powell, 1983). The topographical organization of corticopetal cholinergic projection in humans has been confirmed in cases of Alzheimer’s disease that had relatively selective cell loss in various sectors of the BF. From these cases, one can conclude that the medial frontal and cingulate cortices are innervated from more medial cell groups, whereas the lateral neocortex, including the dorsal and lateral prefrontal, temporal, parietal, and occipital areas, receives its projections from more lateral and caudal subdivisions of the BNM (Arendt, Bigl, Tennstedt, & Arendt, 1985; Mesulam & Geula, 1988). The inhomogeneous, dense clusters of neurons in the magnocellular basal complex are interrupted by regions of low cellular density in humans (Halliday, Cullen, & Cairns, 1993) as well as in rodents and monkeys (Zaborszky, Pang, Somogyi, Nadasdy, & Kallo, 1999). Computational analysis of

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several thousand of cholinergic and noncholinergic projection neurons from multiple experimental cases in rats suggests that the clusters may be nodal points of this system projecting to functionally connected cortical areas (Gombkoto et al., in preparation; Zaborszky et al., 2013). Since cholinergic neurons are often aggregated in clusters and constitute the majority of large neurons in the BNM (Mesulam et al., 1983), the areas containing such magnocellular cell groups within the septum, the HDB, and the SI can be easily delineated in histological sections stained with a modified Gallyas’s silver method for cell bodies (Merker, 1983). This method has been used to generate outlines of the magnocellular cell groups in ten postmortem brains to generate 3-D spatially normalized maps of this system in the MRI space. For delineation of the magnocellular compartments, we used a modified version of the Ch1–Ch4 nomenclature of Mesulam (Mesulam et al., 1983). Mesulam et al. (1983) proposed a Ch nomenclature to differentiate cholinergic neurons according to their cortical target areas. According to this scheme, the entire Ch4 space is subdivided into six compartments termed anteromedial (Ch4am), anterolateral (Ch4al), anterointermediate (Ch4ai), intermediodorsal (Ch4id), intermedioventral (Ch4ai), and posterior (Ch4p). However, this original subdivision for delineations in standardized MRI space was impractical due to the fact that in many instances, it is not possible to consistently define boundaries between individual compartments. For example, the boundaries between Ch1 and Ch2 seem to be arbitrary, and these two regions were taken together in our study, similar to the delineations used by Vogels et al. (1990). The Ch3 group, according to the original description of Mesulam et al. (1983), refers to a band of fusiform neurons close to the ventral surface of the brain, at the ventral border of the SI (Mesulam & Geula, 1988; Mufson, Bothwell, Hersh, & Kordower, 1989). The cell group designated as Ch3 in our delineation represents a transitory area between the septumdiagonal band complex and the SI and may correspond to be part of the anteromedial Ch4 group of Mesulam. We, as well as others, noted that a separation of the anterior Ch4 group into medial and lateral sectors by a vascular structure, as proposed by Mesulam and his coworkers, is ambiguous due to the variation of the vessels (Halliday et al., 1993; Iraizoz, Lacalle, & Gonzalo, 1991; Swaab, 2003). Similarly, delineations of other Ch4 subdivisions are hard to reproduce due to lack of specific landmarks, except for a well-defined posterior subgroup behind the supraoptic nucleus where the optic tract attaches to the internal capsule/cerebral peduncle. Our Ch4p corresponds to the posterior subdivision of the BNM by Iraizoz et al. (1991) and probably corresponds to the nucleus subputaminalis of Ayala (Ayala, 1915; Simic´ et al., 1999). Hyperchromic, large neurons can often be found underneath the nucleus accumbens and around the medial, lateral, and dorsal borders of the posterior limb of the anterior commissure along the putaminal border or more caudally within the ventral putamen itself. We incorporated these cell groups into the Ch4 group, since these cells seem to be connected to the bulk of Ch4 cell aggregates in 3-D renderings. For a detailed description of the delineation of the subcompartments, their visualization, and analysis in the Montreal Neurological Institute (MNI) space, please consult the original communication (Zaborszky et al., 2008). This postmortem probabilistic map

was recently validated against manual and automated methods of in vivo MRI (Butler et al., 2014). Panels in Figures 1–5 display various compartments of the magnocellular cell groups in humans, and Figure 6 shows all Ch cell groups in the MNI single-subject reference space.

Functions Associated with the BNM Experimental work in rodents and primates, including humans, indicates complex cognitive-behavioral involvement of the BF cholinergic system. In rodents, increasing cholinergic activity in gustatory cortex enhances the salience of a familiar, conditioned stimulus in taste aversion learning (Clark & Bernstein, 2009). Cholinergic deafferentation lowers the signal-to-noise ratio of target-evoked responses in posterior parietal neurons (Broussard, Karelina, Sarter, & Givens, 2009). Infusion of a cholinergic immunotoxin in the BF compromises cued target detection (Bushnell, Chiba, & Oshiro, 1998), and acetylcholine (ACh) release in the frontal cortex is

Figure 5 (a) Coronal section through the posterior portion of the Ch4 complex (Ch4p) at the level of the ventromedial hypothalamic nucleus (M). The same section as panel (f) in Figure 1. The two cell aggregates are marked with arrows. The medial cell cluster labeled with double arrow is enlarged in (b). Asterisk marks the same vessel in (a) and (b) for orientation. (b) Enlarged view of the triangular-shaped cell group from (a). ac, anterior commissure; EGP, external globus pallidus; f, fornix; I, intercalated cell group in the amygdala; ic, internal capsule; IGP, internal globus pallidus; mt, mammillothalamic tract; ot, optic tract; Pu, putamen. Modified from Figure 7 in Zaborszky, L., Hoemke, L., Mohlberg, H., Schleicher, A., Amunts, K., & Zilles, K. (2008). Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. NeuroImage, 42, 1127–1141.

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Figure 6 Maximum probability maps (MPMs) of all Ch groups in the anatomical MNI space ((a) rostral; (f) caudal). In the MPM, each voxel is assigned to the cytoarchitectonic compartment that showed the greatest overlap among the ten examined brains. Note the colors represent individual Ch compartments, similarly as in Figure 1, red, Ch1–2 cell groups; green, Ch3; blue, Ch4; yellow, Ch4p. In this figure, the left hemisphere is right. Similar as Figure 13 in Zaborszky, L., Hoemke, L., Mohlberg, H., Schleicher, A., Amunts, K., & Zilles, K. (2008). Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. NeuroImage, 42, 1127–1141.

linked to stimulus detection (Parikh, Kozak, Martinez, & Sarter, 2007). Other work suggests that BF neurons encode saliency irrespective of valence of the stimuli (Lin & Nicolelis, 2008; Wilson & Ma, 2004). These results are concordant with improved sensory perception, enhanced behavioral performance (Froemke et al., 2013), and learning-related or memory-promoting role for the cholinergic BNM that places it ‘downstream’ of motivational systems (Miasnikov, Chen, Gross, Poytress, & Weinberger, 2008), consistent with the anatomical finding that the cholinergic neurons in the BF receive input from the nucleus accumbens (Zaborszky & Cullinan, 1992). The role of BF cholinergic system in working memory and episodic memory encoding and retrieval in primates, including humans, has been amply supported (Croxson, Browning, Gaffan, & Baxter, 2012; Croxson, Kyriazis, & Baxter, 2011; Fujii et al., 2002; Leube et al., 2008, Rombouts et al., 2000). Psychopharmacological imaging in humans shows that cholinergic drugs enhance task-relevant stimulus processing

within sensory cortical areas, but irrelevant stimuli are suppressed. However, the same cholinergic drug can have differential modulation in early versus higher visual processing (see Bentley, Driver, & Dolan, 2011). Donepezil, a cholinesterase inhibitor, facilitates reaction time to targets following a cue that instructs voluntary shift of attention (Rokem, Landau, Garg, Prinzmetal, & Silver, 2010). Attentional modulation in frontoparietal regions includes reductions in cholinergic activity in the default network and increases in activity in the dorsolateral frontoparietal network, reflecting shift from internal to external stimulus processing and increased recruitment of attentional–executive processes (Bentley et al., 2011). Medial temporal regions show enhanced activation with procholinergic drugs (e.g., physostigmine) during encoding but suppression during retrieval and vice versa with anticholinergic agents (e.g., scopolamine). Prefrontal regions show a pattern of responses that is similar to medial temporal regions. However, in one study, physostigmine-induced reductions in dorsal prefrontal cortex activity during encoding and

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maintenance phases of working memory task have been interpreted as enhanced processing efficiency (Furey, Pietrini, Alexander, Schapiro, & Horwitz, 2000). The interpretation of these human psychopharmacological imaging studies requires caution for several reasons: (1) Pharmacological challenges in humans are always systemic and will affect every brain region containing the respective receptors; (2) the neural response may depend on the density of receptors and/or density of cholinergic terminals; (3) changes in brain activity may occur downstream from the initial site of pharmacological action; (4) in addition to the BF cholinergic cell groups, in rodents, the mesopontine cholinergic neurons send projections to the forebrain, including the BF, thalamus, and prefrontal cortex; thus, the effects seen may not relate solely to affecting the BF cholinergic corticopetal system; and (5) GABAergic and cholinergic systems interact at different levels, for example, cholinergic neurons in the rodent BF receive a massive GABAergic input at least in the VP (Zaborszky, Heimer, Eckenstein, & Leranth, 1986) and cortical ACh release has been prominently modulated by GABAmimetics acting at the level of the BF (Wu, Shanabrough, Leranth, & Alreja, 2000). Thus, it is unclear whether the systemically acting drugs that enhance or inhibit cholinergic transmission act through (i) BF cholinergic or GABAergic corticopetal neurons, (ii) postsynaptic receptors on their cortical targets, (iii) presynaptic thalamocortical axons, or (iv) intracortical connections. The participation of the BF cholinergic system in global functions and the fact that BF neurons innervate all cortical areas have contributed to lumping the cholinergic BF system as part of the ‘diffuse cortical projection system’ (Saper, 1987). In contrast to the role of ACh as a diffuse modulator, anatomical (see Zaborszky et al., 2013, 2014), functional, and computational studies in rodents (Gu & Yakel, 2011; Mun˜oz & Rudy, 2014; Roopun et al., 2010) suggest spatiotemporal specificity in cholinergic control of neocortical function. Using postmortem probabilistic mask, the volume of the Ch1–2 space is a good predictor of source memory accuracy (Butler et al., 2012), and the Ch4 compartment showed positive connectivity with the medial prefrontal cortex, including the rostral/perigenual/subgenual anterior cingulate cortex, supplementary motor area (SMA) as well as pre-SMA, medial orbitofrontal cortex, inferior temporal pole, hippocampus, amygdala, insula, thalamus, midbrain, and basal ganglia (Li et al., 2014). These data support a role of the BNM in processing salient and novel stimuli for learning and cognitive motor control, as suggested in animal experiments (Howe et al., 2013; Paolone, Angelakos, Meyer, Robinson, & Sarter, 2013). Studies in progress suggest that the various Ch compartments (e.g., Ch1–2 vs. Ch4 and Ch4p) are linked to different functional cortical networks (Rui, Biswal, Zaborszky, in preparation).

to no neuronal loss at all (Chui, Bondareff, Zarow, & Slager, 1984; De Lacalle, Iraizoz, & Ma Gonzalo, 1991; Whitehouse et al., 1983). In addition to Alzheimer’s disease, structural and biochemical changes in the BF are occasionally found in Parkinson’s disease, Rett syndrome, progressive supranuclear palsy, parkinsonism–dementia complex of Guam, dementia pugilistica, Pick’s disease, Korsakoff’s syndrome, Down syndrome, Wernicke’s encephalopathy, and Creutzfeldt–Jakob disease (reviewed in Swaab, 2003). However, much controversy remains whether or not the neuropathologic changes are primary or secondary, what the time course of changes is, and whether or not the neuropathologic changes occur in the entire extent of the cholinergic space or are restricted to its specific regions. Some of the unresolved issues are at least partly due to the fact that neuropathologic examinations are restricted to postmortem cases from a single time point of advanced stages of the disease. Although age-related gray matter loss in the BF was reported in voxel-based MRI studies (George et al., 2011; Hanyu et al., 2002; Ishii et al., 2005; Muth et al., 2010; Sasaki et al., 1995), due to the fact that on MRI scans the different compartments of the cholinergic space lack clear anatomical borders, it is difficult to define to what extent the described changes relate to pathology in the specific cholinergic space or reflect general gray matter atrophy. Studies, using microstructure correlation with singlesubject (Teipel et al., 2005) or that of the 10-subject probabilistic mask (Zaborszky et al., 2008), indeed reported age-correlated volume loss of the cholinergic space in normal postmortem brains. However, it could not be determined in these studies whether the volumetric changes reflect neuronal loss, shrinkage, or glial changes. Using the ten-brain probabilistic 3-D mask in a Spanish MCI population, reduction of subcompartments of the Ch space correlated well with impaired delayed recall. Moreover, volumes of different magnocellular compartments varied significantly with regional gray matter atrophy in regions known to be affected by AD and were found to correlate with cognitive decline in this group of MCI patients (Grothe et al., 2010). In an AD group, the diagnostic accuracy of the BF volume reduction reached the same diagnostic accuracy as hippocampus gray matter volume loss – to date, the best-established structural maker for AD – and the combined BF and hippocampus volumes significantly increased the diagnostic accuracy for discrimination between AD and healthy control subjects (Grothe, Heinsen, & Teipel, 2012). Interestingly, the Ch1–2 compartment is enlarged in human temporal lobe epilepsy (TLE) without mesial temporal sclerosis, suggesting that septal stimulations may be a relevant strategy in refractory TLE (Butler et al., 2013).

Concluding Remarks Age and Disease-Related Changes in the Volume of BNM Severe involvement of the magnocellular basal complex has been found in Alzheimer’s disease, where various studies reported cell loss up to 90% (Cullen & Halliday, 1998; Iraizoz et al., 1991; Lehe´ricy et al., 1993; Vogels et al., 1990; Whitehouse et al., 1983). Estimations of the neuronal loss of BNM during normal aging also vary greatly from 23% to 50%

As reviewed in this article, various anatomical system interdigitate in the BF, which is especially true for the SI, where in the rostral, subcommissural part, the magnocellular corticopetal system shares the same space with the ventral extension of the caudate and putamen, namely, the nucleus accumbens, while in the more caudal, subcommissural SI, the magnocellular cholinergic system is in close proximity to the cell groups that interconnect the CeM with the BST, that is, the EA. Using

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Figure 7 Maximum probability maps of all Ch groups (red) together with the surrounding structures, including the nucleus accumbens (green), fundus (light blue), ventral pallidum (yellow), and bed n. of the stria terminalis (dark blue). All structures delineated in high-resolution histological sections were transferred after spatial normalization into the 3-D MNI space, and structure labels were assigned to each voxel that exceeded a threshold of 40% from the individual 10 brains. Rostral is upper left and caudal lower right. Left hemisphere is at right.

probabilistically based correlation with microstructural details, recent resting-state and task-related fMRI studies have begun to shed light on the extent of overlap and functional segregation between the nucleus accumbens and the BNM (Li et al., 2014). Figure 7 displays the cholinergic space with the surrounding structures, including the VP, nucleus accumbens, and the BST using maximum probability maps. Having a means to identify the putative BF subdivisions that are correlated with microstructural details will allow us to define the extent to which the various BF anatomical systems and subcompartments of the BNM might interface with different functional networks in different behavioral contexts and how functional connectivity is shifted or breaks down in various disease states.

Acknowledgment This article was supported by PHS/NINDS grant 23945 to L.Z. The processing of the human tissue was funded by the National Institute of Mental Health, the NINDS, the NIDA, the National Cancer Centre, the Portfolio Theme ‘Supercomputing and Modeling for the Human Brain’ of the Helmholtz Association (KZ and KA), and the Bundesministerium fu¨r Bildung und Forschung, Brain Imaging Center West (KZ).

See also: INTRODUCTION TO ANATOMY AND PHYSIOLOGY: Amygdala; Basal Ganglia; Cytoarchitectonics, Receptorarchitectonics, and Network Topology of Language; Cytoarchitecture and Maps of the Human Cerebral Cortex; Insular Cortex; The Olfactory Cortex; Transmitter Receptor Distribution in the Human Brain.

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