The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness

Abstract

The thalamic midline and intralaminar nuclei, long thought to be a non-specific arousing system in the brain, have been shown to be involved in separate and specific brain functions, such as specific cognitive, sensory and motor functions. Fundamental to the participation of the midline and intralaminar nuclei in such diverse functions seems to be a role in awareness. It is unknown whether the midline and intralaminar nuclei, together often referred to as the ‘non-specific’ nuclei of the thalamus, act together or whether each nucleus is involved idiosyncratically in separate circuits underlying cortical processes. Detailed knowledge of the connectivity of each of these nuclei is needed to judge the nature of their contribution to cortical functioning. The present account provides an overview of the results of neuroanatomical tracing studies on the connections of the individual intralaminar and midline thalamic nuclei in the rat, that have been performed over the past decade in our laboratory. The results are discussed together with those reported by other laboratories, and with those obtained in other species. On the basis of the patterns of the afferent and efferent projections, we conclude that the midline and intralaminar thalamic nuclei can be clustered into four groups. Each of the groups can be shown to have its own set of target and input structures, both cortically and subcortically. These anatomical relationships, in combination with functional studies in animals and in humans, lead us to propose that the midline and intralaminar nuclei as a whole play a role in awareness, with each of the groups subserving a role in a different aspect of awareness. The following groups can be discerned: (1) a dorsal group, consisting of the paraventricular, parataenial and intermediodorsal nuclei, involved in viscero-limbic functions; (2) a lateral group, comprising the central lateral and paracentral nuclei and the anterior part of the central medial nucleus, involved in cognitive functions; (3) a ventral group, made up of the reuniens and rhomboid nucleus and the posterior part of the central medial nucleus, involved in multimodal sensory processing; (4) a posterior group, consisting of the centre médian and parafascicular nuclei, involved in limbic motor functions.

Introduction

The intralaminar and midline nuclei of the thalamus have long been considered to exert a global influence on cortical functioning. This thought has been challenged in recent years, however, on the basis of anatomical [11], [12], [13], clinical [87], [88], [152], [153], [154] and behavioral data [131]. The present paper attempts to extend the notion of the ‘specificity of the non-specific nuclei’ [11], [47] by proposing that these nuclei can be clustered in terms of their patterns of connectivity, suggesting functional homogeneity within these clusters and differences in function between them. First, the patterns of inputs and outputs of the intralaminar and midline nuclei of the rat are described, with special attention to evidence of topographical differences between efferent fibers emanating from individual nuclei. Subsequently, functional data and views with respect to particular parts of the midline and intralaminar complex will be considered.

The concept of the non-specificity of the intralaminar and midline thalamic nuclei originated from three sets of observations. First, this constellation of nuclei receives an extensive input from the mesencephalic, pontine and medullary reticular formation, which was thought to be rather non-discriminatory with respect to individual nuclei [27], [51], [94]. Second, the output of these nuclei to cortical target fields was described as diffuse and non-specific [67]. Third, electrophysiological stimulation of these regions in the thalamus causes the so-called cortical recruiting effect [62], [91]. Low-frequency stimulation causes slow-wave activity in the entire cortical mantle accompanied by somnolence, whereas high-frequency stimulation results in desynchronised cortical activity and arousal, leading into epileptiform activity when the stimulation is intense [58], [61].

Originally, adjacent nuclei such as the medial dorsal, pulvinar and ventral anterior nuclei were considered part of the non-specific group of nuclei on the basis of this recruiting effect, but later data have dissociated these nuclei from the intralaminar and midline nuclei based on laminar distribution patterns of their efferents and afferents [46], [48], [56].

Because of their strong brainstem inputs, the intralaminar and midline nuclei are considered as part of the ascending reticular activating system (ARAS), the rostral continuation of the reticular formation. For instance, it has been shown that intralaminar neurons receive monosynaptic input from the mesencephalic reticular formation and in turn connect monosynaptically with many cortical areas [143]. In line with this are functional imaging studies, showing that activation of thalamic nuclei is related to higher levels of wakefulness [41], [72], [77], [84], [109].

In the words of Llinas and Paré, the intralaminar and midline nuclei serve to generate intrinsic functional modes, leading to wakefulness that is independent of the absence or presence of sensory stimulation [81]. This wakeful functional mode of the brain would allow for faster execution or greater efficiency of cortical processing [140], or lower thresholds for cortical activation by incoming stimuli [61], [68]. In other words, intralaminar/midline-induced cortical activation would lead to greater vigilance, necessary for awareness of incoming information. It is important to stress that the midline and intralaminar nuclei do not ‘produce’ awareness, but rather provide the necessary arousal of cortical and subcortical regions supporting information processing that is correlated with awareness [142]. The intralaminar and midline nuclei can be thought to facilitate the entry into a functional mode, involved, as Jasper states, in “the control of states of consciousness and perceptual awareness” rather than dealing with the contents of awareness per se [63].

A role for the intralaminar and midline structures in awareness of stimuli of various sensory modalities has been proposed [139]. Evidence pertaining to the involvement of the intralaminar and midline nuclei in auditory vigilance, comes from a positron emission tomography study investigating sustained attention [105]. In this test, vigilance was measured by asking the subjects to attend for a duration of 60 min to a possibly occurring sudden intensity drop. It appeared that the level of activation of the midline and intralaminar nuclei, together with that of the anterior cingulate cortex, correlated with the level of vigilance. Similarly, it was postulated that the intralaminar nuclei play a role in visual awareness [110], in line with thalamic activation found in functional imaging paradigms of visual attention [138], [144]. Animal experiments indicating a role in visual awareness show ocular and cephalic movements towards visual stimuli in both cats and monkeys, coinciding with electrophysiological activity recorded from the intralaminar region; alternatively, electrical stimulation of the intralaminar nuclei causes head movements and increased electrophysiological response to visual stimuli [57], [134], [135]. In accord with a role for the intralaminar and midline nuclei in visual awareness and the response to visual stimuli, Schiff et al. [133] describe oculogyric crises as a pathological state of this complex. They state that aberrant monoaminergic and cholinergic input causes ‘dystonia’ of the intralaminar-midline complex. This leads to a syndrome characterized by fixed eye deviation, thought disorder, and postural and autonomic disturbances, together called the Von Economo crisis. The combination of such seemingly disparate symptoms fit with the widespread anatomical connectivity of these nuclei as a group.

A role in the awareness of tactile and nociceptive information has been described as well for the midline and intralaminar nuclei. This derives from the anatomical evidence that the above nuclei receive nociceptive input from the spinothalamic and spinoreticulothalamic projections [144], [44], [107], from electrophysiological experiments showing that these nuclei respond to noxious stimuli [37] and from functional imaging studies showing thalamic activation in vibrotactile perception [65] and pain modulation [53]. In turn, the intralaminar and midline nuclei project to the cingulate area, which has been taken to mean that their role is related to the affective processing of the incoming tactile or nociceptive information [111], [161].

Rather than ascribing to the intralaminar and midline nuclei of the thalamus a uniform function, Bentivoglio et al. [11] and Groenewegen and Berendse [47] have argued that, although the inputs to the diverse thalamic structures may be partly overlapping, the output is organized in segregated and parallel pathways. In this way, the general effects on cortical functioning of the intralaminar and midline nuclei can be thought to arise from a concerted influence of the individual nuclei on the various cortical areas. On the other hand, the selective pattern of cortical inputs and outputs of these nuclei warrant the assumption that they might also exert more specific influences on selective cortical areas, as evidenced for instance by the fact that single intralaminar cells receiving midbrain afferents each have particular cortical targets instead of projecting to multiple areas [143]. Recently, we have added that in addition to differences in the patterns of projection arising from the various midline and intralaminar nuclei, the pattern of projections from a single nucleus may also differ for subregions in that nucleus [35], [153]. This offers the possibility of even more fine-grained influences on cortical functioning. Knowledge of the anatomical specificity of connections of the midline and intralaminar nuclei will allow the prediction of the roles that these nuclei may play in normal brain functioning and diseases of the brain.

This review therefore offers an overview of afferent and efferent connections of the individual midline and intralaminar nuclei in the rat, founded on the large database of injections of anterograde tracers made in these nuclei of the thalamus over the last decade in our laboratory. Some cases have been used for studies published previously [12], [13], [35], [47], [165], [166], [167]. For nuclei where information was lacking, we made additional injections. In the analysis of the results, special attention was paid to topographical differences in the patterns of projection from different parts of the nuclei. This could only be done in reasonably large nuclei, with rostro-caudal, medio-lateral or dorso-ventral dimensions that allow differential placement of the tracer injections; this was the case for the paraventricular, the reuniens, the intermediodorsal, and the central medial nuclei.