Changing Concepts of the Reticular Activating System Arousal Revisited

The concept of a reticular activating system has changed substantially since the original proposal by Moruzzi and Magoun. Although original concepts emphasized the brainstem and the notion of a primitive "nonspecific" architecture (a "reticulum" with diffuse projections), more recent concepts have emphasized a highly distributed multi-component system, containing many structures with exquisite specificity and yet broad connectivities. Consistent with this, the brainstem in general has very complex and highly specific connectivities, containing at least 50 different nuclei running from medulla to ventral diencephalons, with enormously disparate functions that belie the unitary designation of "brainstem." It is not a coincidence, as Parvizi and Damasio (2001) emphasize, that the systems that regulate homeostasis, those that arouse the forebrain, and others that form the ventral foundations for attentional mechanisms are all closely contiguous in the brainstem. One might add that the brainstem also includes basic somatotopic motor maps, integrating these components of attentional function, forebrain arousal, and homeostasis with mechanisms for mapping (and activating) the body in basic motor coordinates. Recent work conceptualizes an "extended" RAS as containing several groups of structures, which for didactic purposes we will group into three functionally related systems (see Fig. 3.2):

1. The classical reticular nuclei include the midline raphe (5-HT) systems running from medulla up to the midbrain, and the lateral reticular nuclei. These lateral reticular nuclei (including the cuneiform nucleus, deep mesencephalic nucleus, noncholinergic portion of pedunculopontine tegmental nucleus, pontis oralis, magnocellullaris, and parvocellularis) send presumably mostly gluta-matergic projections to basal ganglia (BG) and the more dorsal regions project to intralaminar nuclei (ILN). These lateral reticular nuclei located in the lower pons and medulla also project to ILN, but their brainstem afferents to ILN are most numerous in the upper brainstem, declining at lower levels of pons/medulla in a progressive gradient. Reticular nuclei in lower brainstem can modulate activity of upper brainstem nuclei, thus affecting the forebrain indirectly.

2. The "autonomic" nuclei include the parabrachial nucleus (PBN) and PAG in pons and midbrain. Clinicians are often surprised to discover that the PBN and PAG are thought to be reticular structures, though both systems have extensive reciprocal connections with many other reticular components. There are projections from PBN and PAG to the lateral reticular nuclei, to basal forebrain, and also to various hypothalamic and monoamine nuclei. PAG has extensive projections to all the monoamine systems (particularly DA), and reentrant communication with the hypothalamus, as well as with the nonspecific intralaminar systems in thalamus, and the central (output) nucleus of the amygdala. PBN and PAG have long been known for involvement in control of autonomic/visceral functions, but they also modulate global activity of cerebral cortex, paleocor-tex, and amygdala. PAG is probably essential for affective arousal being an active, motoric process; full lesions of this structure generate a severe form of AKM (see later case discussions), underlining its poorly understood but probably essential role in all motivated behavior. Thus, PBN and the PAG can modulate the activity of the entire cerebral cortex, through either ILN or basal forebrain projections, and can also influence the lateral reticular nuclei, and monoaminergic/cholinergic nuclei as well. From these multiple connectivities, PBN and PAG can presumably tune the thalamocortical complex consonant with emotional needs and affective states.

3. The monoamine and acetylcholine nuclei are the classical neuromodulatory systems upon which psychiatry has focused much of its clinical intervention and research. They include three monoamine systems with differential projection targets and differential global modulatory functions. There are direct noradren-ergic (NE) and serotonergic (5-HT) projections from the locus coeruleus/lateral tegmental area and rostral raphe systems, respectively, which spread to the cortical mantle. Dopaminergic (DA) projections are more targeted toward pre-frontal and paralimbic systems, with projections from the substantia nigra to putamen, caudate nucleus, nucleus accumbens, along with DA projections from the midbrain VTA to many cortical areas, with strong predominance toward prefrontal, cingulate, insular, and other paleocortical regions. There are also projections from brainstem DA, NE, and 5-HT nuclei to the basal forebrain, regulating key cholinergic systems in the basal forebrain. Cholinergic systems in the pons, including the laterodorsal tegmental nucleus and cholinergic portions of the pedunculopontine tegmental nucleus, project to several midline and nonspecific thalamic nuclei, including particularly the nucleus reticularis and ILN systems, thus regulating thalamocortical function, and to also cholinergic basal forebrain regions essential to cortical regulation/modulation. In turn, the nucleus reticularis thalami (nRt) receives collaterals from all thalamocortical axons, inhibiting their activity via GABA interneurons, functioning as a competitive "global gate" for cortex that presumably allows the thalamocortical complex to settle in and out of various states.

This is a complex set of processes with parallel and overlapping systems in the brain stem that regulate the forebrain, thalamus, and cortex directly, and by influencing the cholinergic basal forebrain, thereby modulating the cortex indirectly. The monoamines themselves have differential global modulatory roles, underlining further that forebrain arousal is not a unitary process. Noradrenergic systems (NE) appear crucial to sensory tuning, to signal to noise in sensory systems, and for attentional sharpening of posterior cortical processing. DA systems from VTA mediate a nonspecific seeking and motivational or affective arousal. ACh systems are central to thalamocortical and cognitive arousal, attention, and short-term memory. 5-HT, an indolamine, is relevant to behavioral inhibition, and may regulate "channelizing" of brain systems and some degree of inhibition of catecholamine systems. These differential roles are mirrored in their cortical projection targets (e.g., ACh tends to project to large pyramidal neurons critical to cortico-cortical communication, while 5-HT projections typically synapse onto inhibitory interneurons). As mentioned above, psychiatry has traditionally targeted the vast majority of its probes and therapies toward these systems. The basic topography of these aminergic regulatory systems for global state control can be summarized in terms of a few basic projection systems (see Fig. 3.1):

1. Largely glutamatergic projections from the dorsal portions of the lateral reticular nuclei into ILN, and continuing glutamatergic projections from ILN to cortex, as thalamic extensions of the RAS.

Figure 3.1. Graphic for the Extended Reticular Activating System. Glutamatergic projections from classical lateral reticular nuclei to thalamus, and from thalamic ILN systems to cortex. Dopaminergic, serotonergic and noradrenergic projections in midbrain and pons that bypass thalamus and project directly to cortex. DA, NE, 5-HT and lateral reticular glutamatergic projections regulating basal forebrain. Pontine and basal forebrain cholinergic systems projecting to thalamus and cortex respectively (from Parvizi and Damasio 2000, with permission from Elsevier Science). See ftp site for color image.

Figure 3.1. Graphic for the Extended Reticular Activating System. Glutamatergic projections from classical lateral reticular nuclei to thalamus, and from thalamic ILN systems to cortex. Dopaminergic, serotonergic and noradrenergic projections in midbrain and pons that bypass thalamus and project directly to cortex. DA, NE, 5-HT and lateral reticular glutamatergic projections regulating basal forebrain. Pontine and basal forebrain cholinergic systems projecting to thalamus and cortex respectively (from Parvizi and Damasio 2000, with permission from Elsevier Science). See ftp site for color image.

2. Projections from the cholinergic pontine nuclei into the thalamus, especially targeting nonspecific thalamic system; additional cholinergic projections from basal forebrain to cortex from four basal forebrain nuclei: nucleus basalis (sub-stantia innominata in earlier terminology), medial septal nucleus, diagonal band of Broca, and magnocellular preoptic field.

3. Projections from the monoaminergic nuclei (serotonin, norepinephrine, and dopamine) bypassing the thalamus directly into forebrain and cortex, with differential projections to more anterior (dopaminergic) vs. somewhat more posterior (noradrenergic) cortical systems, consistent with the more executive or motivational as opposed to the sensory signal-to-noise function of those amine systems, respectively.

4. Projections from the lateral reticular nuclei, pontine cholinergic nuclei, and the NE, DA, and 5-HT aminergic nuclei (from locus ceruleus, VTA, serotoner-gic raphe, respectively) to basal forebrain regulating the cholinergic systems there.

5. There have been recent suggestions that hypothalamic histamine and orexin systems should be added to the RAS, given evidence that they are centrally involved in wakefulness.

Traditionally, the RAS has been seen as functionally synonymous with the concept of a nonspecific arousal system. There are large and generally unappreciated gaps in what this notion really explains. First of all, the notion of arousal as nonspecific is clearly mistaken from the standpoint of widely differential contributions from these many reticular structures. Additionally, the notion of "arousal" has been used in very different ways. Arousal has referred to: (1) any process that increases the likelihood of neuronal depolarization or that increases firing rates of distributed forebrain neurons, (2) affective arousal (as in states of anger), and (3) processes that mediate global state shifts, such as into wakefulness, dreaming, and the various stages of sleep. The first meaning of arousal (increased firing rates in forebrain) is not an adequate explanation at a neurodynamic level for either the achievement of arousal in behavioral/affective terms or for arousal to wakefulness, as consciousness cannot be meaningfully explained by the simple notion of increased firing of forebrain neurons under brainstem influence. The second and third meanings of the term are intrinsically related, as arousal to consciousness is fundamentally a "hot" (motivational) rather than "cool" process, gaining only the appearance of affective neutrality and cognitive calm in humans as we have a great deal of inhibitory neocortex. Lastly, arousal, as in simple arousal to wakefulness, is not an adequate functional correlate for the extended RAS systems, as wakefulness is preserved in PVS, where no consciousness is presumed present, often in the context of extensive RAS-mesodiencephalic lesions. Thus arousal to a conscious state cannot be conflated with simple wakefulness and requires other integrative functional "envelopes" (core elements) that we have emphasized: attention, intention, and emotion. Further, if arousal means that stimuli generate coherent behavioral responses, this notion simply begs many crucial questions about how these structures (and their modulators and connectivities) underpin consciousness.

These aminergic neuromodulatory systems sit in close communication with several more dorsal and equally critical mesodiencephalic structures: the thalamic intralaminar nuclei (ILN), the thalamic reticular nucleus (nRt), and the midbrain reticular formation [primarily the superior colliculus (SC) and cuneiform nucleus (CUN)]. ILN and nRt functional specialization are reviewed below in some detail. The functional roles of SC and CUN are incompletely mapped, particularly CUN. They may function as "gating" or "priming" systems, offering a kind of attentional "biasing" to higher resolution cortical systems. For example, SC projects to nRt, and also to various thalamic and cortical systems central to spatial mapping, and lesions of SC can cause hemispatial neglect (Mesulam, 2000). SC may offer a kind of low-resolution multimodal mapping of the total sensory envelope for the organism, with this basic biasing available to and essential for the higher resolution mappings the cortex is capable of making (Newman and Baars, 1993).

Evidence suggests that these distributed RAS and other closely situated mesodiencephalic systems underpin the brain's ability to instantiate global neurodynamics, providing for the functional integration of highly distributed systems running from top to bottom of the brain. In this sense, the notion of arousal cannot be neatly separated from the formidable process of widespread functional integration, and differential, task-variant, recruitment/inhibition. Modeling this neurodynamically, and thus illuminating the brain's functional integration in conscious states, is still the most difficult challenge facing the neuroscience of consciousness.

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