Elsevier

Neuroscience

Volume 76, Issue 4, 15 January 1997, Pages 957-1006
Neuroscience

COMMENTARY
Substantia innominata: a notion which impedes clinical–anatomical correlations in neuropsychiatric disorders

https://doi.org/10.1016/S0306-4522(96)00405-8Get rights and content

Abstract

Comparative neuroanatomical investigations in primates and non-primates have helped disentangle the anatomy of the basal forebrain region known as the substantia innominata. The most striking aspect of this region is its subdivision into two major parts. This reflects the fundamental organizational scheme for this portion of the forebrain. According to this scheme, two major subcortical telencephalic structures, i.e. the striatopallidal complex and extended amygdala, form large diagonally oriented bands. The rostroventral extension of the pallidum accounts for a large part of the rostral subcommissural substantia innominata, while the sublenticular substantia innominata is primarily occupied by elements of the extended amygdala. Also dispersed across this region is the basal nucleus of Meynert, which is part of a more or less continuous collection of cholinergic and non-cholinergic corticopetal and thalamopetal cells, which stretches from the septum–diagonal band rostrally to the caudal globus pallidus. The basal nucleus of Meynert is especially prominent in the primate, where it is sometimes inappropriately applied as a synonym for the substantia innominata, thereby tacitly ignoring the remaining components.

In most mammals, the extended amygdala presents itself as a ring of neurons encircling the internal capsule and basal ganglia. The extended amygdala may be further subdivided, i.e. into the central extended amygdala (related to the central amygdaloid nucleus) and the medial extended amygdala (related to the medial amygdaloid nucleus), which generally form separate corridors both in the sublenticular region and along the supracapsular course of the stria terminalis. The extended amygdala is directly continuous with the caudomedial shell of the accumbens, and to some extent appears to merge with it. Together the accumbens shell and extended amygdala form an extensive forebrain continuum, which establishes specific neuronal circuits with the medial prefrontal–orbitofrontal cortex and medial temporal lobe. This continuum is particularly characterized by a prominent system of long intrinsic association fibers, and a variety of highly differentiated downstream projections to the hypothalamus and brainstem.

The various components of the extended amygdala, together with the shell of the accumbens, are ideally structured to generate endocrine, autonomic and somatomotor aspects of emotional and motivational states. Behavioral observations support this proposition and demonstrate the relevance of these structures to a variety of functions, ranging from the various elements of the reproductive cycle to drug-seeking behavior. The neurochemical and connectional features common to the accumbens shell and the extended amygdala are especially relevant to understanding the etiology and treatment of neuropsychiatric disorders. This is discussed in general terms, and also in specific relation to the neurodevelopmental theory of schizophrenia and to the neurosurgical treatment of neuropsychiatric disorders.

Introduction

Subcortical telencephalic structures are important agents in motivation and emotion, and are demonstrably involved in the most debilitating neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, schizophrenia, obsessive–compulsive disorders and in substance abuse, to mention the most prominent examples. Considering the immense human suffering and the staggering cost imposed on society by the neuropsychiatric disorders,[110]there is an urgent need to advance our understanding of these disorders in order to provide rational direction to the development of novel therapeutic approaches. Although many brain regions are thought to be involved in neuropsychiatric diseases, the substantia innominata and closely related structures of the mediobasal forebrain have often been the subject of special attention.18, 27, 31, 57, 90, 241, 336, 373, 390, 432, 475, 476, 501, 518, 519, 532

The term “substantia innominata” (or unnamed substance) is often linked to the name of Reichert, since in his atlas of the human brain, he[414]left part of the area underneath the posterior limb of the anterior commissure unnamed. As already indicated by Meynert,[342]however, it seems more appropriate to credit Reil,[415]who referred to the general area that extends laterally and caudally deep to the optic tract as “die ungenannte Marksubstanz” since he thought the naming of this area should be postponed until he was better able to appreciate its functional organization. It is not clear that he ever returned to this region in an attempt to devise an appropriate designation. For many of the decades that followed, experiments designed to illuminate this part of the brain have met with only limited success. Consequently, until modern times the substantia innominata has remained one of the least understood brain regions. However, since there is little doubt about the importance of this general region, it has become a popular topic of research in spite of its enigmatic name. In the process, the term has also come to mean different things to different people.

Often, the substantia innominata is defined vaguely as that part of the mediobasal forebrain which is located between the olfactory tubercle (or the anterior perforated space) and the nucleus of the horizontal limb of the diagonal band ventrally, and the posterior limb of the anterior commissure and globus pallidus dorsally, and which borders on the septum and preoptic area medially and amygdaloid body laterally.84, 89, 103, 182, 248, 304, 366, 375, 434, 472, 481, 486The rostral and caudal borders of the substantia innominata are even more ambiguous. In the rat, its rostral border usually coincides with the caudal aspect of the accumbens,[284]whereas in Riley's[420]classic atlas of the human brain, the substantia innominata also includes the septum and the diagonal band. Sometimes, the subcaudate white matter of the orbital cortex is also included in the term.221, 272Others consider the substantia innominata to be synonymous with the basal nucleus of Meynert, or alternatively the area is described as the substantia innominata–nucleus basalis complex.5, 76, 206, 340, 359, 374, 397

When it was discovered that a large part of the rostral, subcommissural territory of the substantia innominata (i.e. the area underneath the posterior limb of the anterior commissure) belongs to the pallidal complex,[213]it was suggested that the term substantia innominata should be restricted to the caudal, subpallidal part,[212]which Miodonski[345]referred to as the sublenticular substantia innominata (i.e. the area underneath the globus pallidus and putamen, together referred to as the lenticular nucleus).

In the two decades since the concept of the ventral pallidum was introduced, a large body of evidence has favored this segmentation of the basal forebrain into a rostral portion related to basal ganglia and a distinctive caudal zone, but it is not always the case that this distinction is acknowledged in descriptions of basal forebrain experiments. In some instances, the term substantia innominata is used as a synonym for the ventral pallidum.84, 284, 486There are several variations on this practice, including lumping the substantia innominata or the subpallidal region together with the ventral pallidum into a “ventral pallidum–substantia innominata complex” or a “ventral pallidum–subpallidal complex”.105, 426, 510, 545

This lack of anatomical precision by those reporting otherwise useful experimental data is unfortunate, since it is likely to lead to misinformation and contradictions when the results are incorporated in material intended for instruction of new scientists and clinicians. For example, in the latest edition of the authoritative Comprehensive Textbook of Psychiatry,[256]the introductory neuroanatomy chapter depicts the substantia innominata as the ventral subcommissural part of the globus pallidus (Fig. 1,2-5 in Ref. 296[296]), whereas in a subsequent chapter, the substantia innominata is considered to be an independent structure sending “limbic striatal efferents” to the frontal lobe (Fig. 14.1-1 in Ref. 90).

With so many different opinions of what the substantia innominata is supposed to mean (also see Ref. 25[25]), the term has become counterproductive.[14]Fortunately, an increasing number of neuroanatomical experiments fortified with sensitive tract-tracing techniques and sophisticated immunohistochemical methods have examined the relations of the mediobasal telencephalon, and during the course of the last 20 years, the mystery surrounding this part of the brain has in large part dissipated and a new systematic anatomy is emerging. As a result, the term substantia innominata has become an anachronism, and should be deleted from the anatomical nomenclature.

Historically, classic developmental and comparative anatomical studies by Johnston[247]identified a close relationship between the bed nucleus of the stria terminalis and the centromedial amygdaloid complex. Many years later, de Olmos119, 120discovered a histochemically distinct sublenticular continuum (labeled SLEAc in Fig. 1) between the central amygdaloid nucleus and the bed nucleus of the stria terminalis, thereby setting the stage for a more detailed segmentation of this part of the brain. Subsequently, on connectional grounds it was appreciated[213]that a large part of the rostral subcommissural substantia innominata is a pallidal structure (VP in Fig. 2),1 which can easily be distinguished in Nissl preparations from the caudally adjacent, more cell-dense sublenticular region described a few years earlier by de Olmos. While the functional relevance of the ventral extension of the pallidum can be found in analogy with the large dorsal component of the pallidum (or globus pallidus), the role of de Olmos' sublenticular territory is likely to reflect the fact that it is an integral part of a continuum reaching from the central amygdaloid nucleus to the bed nucleus of the stria terminalis.[68]The sublenticular region was clearly appreciated as part of a larger functional entity, distinctly different from the adjacent ventral pallidum.[207]

At about the same time, Divac[130]and Kievit and Kuypers,[265]aided by the newly developed retrograde tracer methods, described the extensive collection of large and medium-sized corticopetal cells in the basal forebrain. Many of these cells were shown to be cholinergic,340, 341and such cells are located both in the rostral, subcommissural part (ventral pallidum) and in the caudal, sublenticular (subpallidal) part of the substantia innominata. It should be emphasized, however, that cholinergic and non-cholinergic corticopetal cells are located in many other parts of the forebrain, including the septum, diagonal band, globus pallidus and lateral hypothalamus, and it is therefore inappropriate to identify them as belonging exclusively to the substantia innominata, or to use the term substantia innominata to refer to this extensive array of neurons. Nor is the term “corticopetal” particularly appropriate for this system as a whole, since cells in this widely dispersed system project to several other parts of the brain, including the thalamus (especially the mediodorsal and reticular thalamic nuclei), basal ganglia and amygdaloid complex,202, 274, 339, 384, 451, 474in addition to the cerebral cortex. The magnocellular basal forebrain complex, which is often used as a synonym for the corticopetal basal forebrain system, is generally considered to be an integral part of the ascending activating system, which is significant for cortical arousal and related mechanisms of learning and memory.

An important part of the magnocellular basal forebrain complex is the basal nucleus of Meynert (sometimes referred to as the nucleus basalis of the substantia innominata), which is located in the general region under discussion. This dense collection of mostly cholinergic neurons2 is especially prominent and easy to recognize even in conventional Nissl sections and especially in primates.248, 338, 440Since the basal nucleus of Meynert is so prominent, especially in the human brain, it has tended to overshadow the other components of the substantia innominata, which are the main focus of our attention. The basal nucleus of Meynert has attracted special attention because of its frequent involvement in Alzheimer's disease,27, 57, 138, 163, 241, 532, 542and it has accordingly been discussed extensively in the literature80, 337, 438, 450, 451, 473, 514, 550and will be mentioned only in passing in this article. The septum–diagonal band complex, which also contains a large number of corticopetal cells, some of which are cholinergic, is occasionally included in the substantia innominata, but it will not be discussed in this commentary. Its relevance to the general organization of the basal forebrain has been discussed in other papers.14, 15, 173, 242, 488

Most of the neuroanatomical experiments designed to partition the substantia innominata into more rational compartments have been carried out in the rat, and the importance of this region can be best appreciated by reviewing some of the critical experiments in that species. It should be emphasized, however, that the basic organizational plan of the basal forebrain of the human appears to be essentially similar to that of the rat, and we will present relevant information to that effect.

Section snippets

Definition of the ventral striatopallidal system

The original description of the ventral pallidum as a rostroventral continuation of the dorsal pallidal complex into the substantia innominata was based on light and electron microscopic analyses of normal and experimental material, including silver impregnation of degenerating fibers and terminals following lesions in the accumbens and the olfactory tubercle in the rat.[213]This discovery has been amply verified (see Ref. 214[214]for further references), and our present understanding is that

Definition of the extended amygdala

The term extended amygdala[14]encapsulates the argument that portions of the amygdaloid body, i.e. the centromedial part, extend through the sublenticular substantia innominata as well as along the stria terminalis to include the bed nucleus of the stria terminalis. The identification of the extended amygdala originally evolved from developmental and comparative anatomical considerations,[247]but was subsequently expanded and reinforced by histological, histochemical13, 21, 119, 120, 122, 175,

The “two-part division” of the substantia innominata reflects a fundamental organizational scheme of the basal forebrain

One of the themes developed in this commentary, i.e. that of a “two-part division” of the substantia innominata, is based primarily on studies in rats, and to some extent in primates. Investigations of human brains, although limited in number,14, 16, 121, 317, 320, 321also show a similar situation. It must be emphasized, however, that the “two-part division” of the substantia innominata is important only insofar as it reflects a fundamental organizational scheme of this part of the forebrain.

The anatomy of the basal forebrain in the context of neuropsychiatric disorders

There is a vast literature dealing with the pharmacology and physiology of the various basal forebrain structures included in the ventral striatopallidal system and extended amygdala. To the extent that such studies have focussed on issues important to neuropsychiatry, they leave little doubt that both systems are particularly relevant to understanding neuropsychiatric disorders, especially those accompanied by emotional derangements and associated viscero-endocrine and behavioral symptoms.

Closing remarks

The message from the many functional–anatomical and clinical correlations mentioned above can hardly be more compelling. When confronted with neuropsychiatric disorders characterized by significant disruptions of emotional behavior with concomitant visceral and neuroendocrine disturbances, it would seem especially rewarding to pay close attention not only to the cortico-subcortical re-entrant circuits of the ventral striatopallidal system, but also to the extended amygdala. The shell of the

Acknowledgements

This work was supported by USPHS Grant NS-17743 (L.H and G.F.A.), USPHS Grant DA-06194 (R.E.H.), a grant from the Deafness Research Foundation (M.M.G.) and by Consejo Nacional de Investigaciones Cientificas y Tecnicas of Argentina (J.deO.). We would like to thank Drs Juan Burzaco, Michael Forbes, John Jane, Ladislau Steiner, Gary van Hoesen and Scott Zahm for valuable suggestions. We would also like to thank Ms Debra Swanson and Ms Vickie Loeser for technical and secretarial assistance, and we

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