Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain
Introduction
The basal forebrain comprises heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. The most prominent feature of the primate basal forebrain is the presence of continuous collection of aggregated and non-aggregated, large, hyperchromic neurons, often referred to as the “magnocellular basal forebrain system” (Hedreen et al., 1984). Compact cell clusters, especially those underneath the posterior limb of the anterior commissure and subpallidal (sublenticular) areas, are called the basal nucleus of Meynert. Large neurons in this area are continuous with similar cells in the medial septum and in the nuclei of the diagonal band and with scattered large cells in association with various fiber bundles, including the internal capsule and anterior commissure. A substantial proportion of the magnocellular neurons in primates represent cholinergic corticopetal projection neurons (Mesulam et al., 1983, Saper and Chelimsky, 1984, Mesulam and Geula, 1988) that have received particular attention due to their loss in Alzheimer's and related disorders (Perry et al., 1984, Price et al., 1986). Cholinergic neurons in rodents are intermingled with GABAergic, and glutamatergic corticopetal neurons and various peptidergic interneurons (reviewed in Zaborszky and Duque, 2003, Hur and Zaborszky, 2005).
The term basal nucleus of Meynert1 has been used in the past as a synonym with the substantia innominata (“Ungenante Mark-Substanze”, Reil, 1809), especially in the clinical literature. This latter term, however, lost its significance in the light of recent tracer and histochemical studies indicating that the main part of the basal forebrain that was previously called the substantia innominata belongs to nearby and better defined anatomical systems. The rostral, subcommissural part of the substantia innominata is mainly occupied by the ventral extensions of the striatum and globus pallidus, i.e. the ventral pallidum and the core/shell subdivisions of the nucleus accumbens (ventral striatum). More caudally, the sublenticular part of the substantia innominata is occupied by the “extended amygdala”, which refers to the subpallidal cell bridges extending from the centromedial amygdala to the bed nucleus of the stria terminalis (Heimer et al., 1985, Heimer et al., 1991; Zaborszky et al., 1985; Sakamoto et al., 1999, Heimer et al., 1999, Heimer, 2000, Riedel et al., 2002, de Olmos, 2004, Heimer and Van Hoesen, 2006).
Electrophysiological studies in rodents lend support to the notion that basal forebrain cholinergic and GABAergic neurons are important modulators of cortical activation (reviewed in Detari, 2000, Zaborszky and Duque, 2003, Lee et al., 2005). Furthermore, a substantial amount of experimental data in animals, including primates, suggest the involvement of the basal forebrain in attention, learning, memory, reward and cortical plasticity (Wilson and Rolls, 1990, Richardson and DeLong, 1991, Voytko et al., 1994, Chiba et al., 1995, Everitt and Robbins, 1997, Wang et al., 1997, Gaffan et al., 2002, Muir et al., 1994 Conner et al., 2005, Turchi et al., 2005, Sarter et al., 2006, McGaughy et al., 2002 Weinberger 2007). Similarly, imaging studies in humans – as detailed below – lend support for a role of the basal forebrain in a range of cognitive functions. Table 1 lists some of the imaging studies that reported coordinates with reference to the Talairach system (Talairach and Tournoux, 1988).
Paus et al. (1997) investigated the time course of changes in brain activity during a continuous performance auditory vigilance task. As the level of vigilance is shifted from high alert to drowsiness, regional cerebral blood flow (rCBF) decreased in the fronto-parietal network and in several subcortical structures, including the substantia innominata, medial thalamus, and ponto-mesencephalic tegmentum. These changes were interpreted by Paus et al. (1997) as coordinated functions of a separate cortical–subcortical arousal system and a cortical auditory attention network. In the study of Morris et al. (1998), conditioning-related, frequency-specific modulation of tonotopic responses in the auditory cortex of young male volunteers was studied. The modulated regions of the auditory cortex co-varied positively with activity in the basal forebrain, amygdala, and orbitofrontal cortex. Furthermore, in an aversive conditioning paradigm, Morris et al. (1997) manipulated the salience of visual stimuli and found that augmented activation of the right pulvinar co-varied with a region of the basal forebrain.
It has been long known that basal forebrain lesions in humans, including those from trauma, tumor, or rupture of the anterior cerebral or anterior communicating arteries result in impaired memory functions (Damasio et al., 1985, Morris et al., 1992, Diamond et al., 1997, Abe et al., 1998). Since multiple anatomic regions were often damaged in these cases, it has been difficult to determine the exact area of the lesion that caused the cognitive symptoms. A recent fMRI study in young male volunteers suggested that activity in the nucleus of the diagonal band of Broca and the subcallosal area is related to episodic memory recall (Fujii et al., 2002). In another study, using delayed match to sample paradigm sensitive for working memory, activations were found in the dorsolateral prefrontal cortex and basal forebrain regions (Swartz et al., 1995).
Cocaine infusion into cocaine-dependent volunteers leads to significant fMRI signal changes in a basal forebrain region that is populated by cholinergic cells (Breiter and Rosen, 1999). However, the same region has been claimed as part of the “sublenticular extended amygdala”, a continuum between the centromedial amygdala and the bed nucleus of the stria terminalis (Heimer and Van Hoesen, 2006). It remains an open question whether or not activations related to the basal forebrain corticopetal system can be segregated from those cell groups that belong to the extended amygdala system.
Finally, consistent with the state-dependent changes of unit recordings in rodents across sleep stages (e.g., Lee et al., 2005), basal forebrain areas in humans were among those that showed significant changes in glucose metabolism (rCMRglu) or rCBF throughout the sleep–wake cycle (Braun et al., 1997, Maquet et al., 1997, Nofzinger et al., 2002).
Due to the complex anatomy of the basal forebrain, the contribution of a specific anatomical system to a particular cognitive function has not been well understood. The superimposition of postmortem anatomical and in vivo functional data into the same reference space allows correlations between cerebral microstructure and functional imaging data (Rolland and Zilles, 1994, Amunts et al., 2002, Zilles et al., 2002, Amunts et al., 2004). A microstructural map of the basal forebrain region, however, is not available. Therefore, the goal of the present study was to provide cytoarchitectonic probabilistic 3D maps of basal forebrain structures that contain cholinergic projection neurons. Since cholinergic neurons are often aggregated in clusters and constitute most of the large neurons (> 20 μm long axis) in this brain area (Mesulam et al., 1983), the areas containing such magnocellular cell groups within the septum, the horizontal and vertical limbs of the diagonal band, and in the sublenticular basal forebrain can be easily delineated in histological sections stained with a modified Gallyas's silver method for cell bodies (Merker, 1983). This method has been proven as an excellent marker for cytoarchitectonic studies (Uylings et al., 1999, Zilles et al., 2002). The cytoarchitectonic maps of ten human brains were warped to the reference space of the Montreal Neurological Institute (MNI) single subject brain (Collins et al., 1994, Holmes et al., 1998). The resulting probabilistic maps can now be correlated with functional neuroimaging data for a better understanding of the role of various basal forebrain systems in cognitive functions.
Section snippets
Fixation, MRI and histological processing
Brains from five males and five females with no record of neurological or psychiatric diseases were obtained at autopsy (Table 2). All subjects were included in the body donor program of the Institute of Anatomy at the University of Duesseldorf (Germany). The mean age of the subjects was: 64.9 years (range 37–75 years, Table 2). Seven brains were fixed in 4% formaldehyde for several months; three brains were fixed in Bodian-fixative. The brains were suspended at the basilar artery to avoid
Diagonal band of Broca and basal nucleus of Meynert in histological sections
Fig. 1 shows the position of all magnocellular compartments as delineated in this study from a male brain #1696 at six coronal levels. Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7 illustrate the cytoarchitecture of the delineated areas as traced from high resolution images of the same sections shown in Fig. 1.
Discussion
In the present study, we manually delineated the magnocellular cell aggregates of the human basal forebrain in silver-stained sections in order to generate cytoarchitechtonic probabilistic maps in stereotaxic space. Most of the neurons of the extended amygdala are small or medium-sized and occupy a different position than the cholinergic neurons in the subcommissural/subpallidal territory in primates (Ghashghaei and Barbas, 2001). Since most of the cholinergic neurons are larger than cells in
Concluding remarks
Probabilistic maps of the magnocellular cell groups in standardized stereotaxic space can provide the fine-grained parcellation necessary to localize neuropathological changes in a heterogeneous region such as the basal forebrain. The ability to delineate precisely microstructural details together with the improved sensitivity of advanced MRI, and with neuropsychological battery for memory disorders should allow the identification of patients with mild cognitive impairment, a patient population
Acknowledgments
This project was supported by PHS/NINDS grant NS023945 to L.Z. The Human Brain Project/Neuroinformatics research was funded jointly by the National Institute of Mental Health, NINDS, the National Institute of Drug Abuse, the National Cancer Center (KZ and KA), the Helmholtz Gemeinschaft (KZ and KA), and by the Bundesministerium fur Bildung and Forschung, Brain Imaging Center West (KZ). The authors thank Dr. Susan Feldman for providing with constructive criticisms of a previous version of this
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