Neuroscience & Biobehavioral Reviews, Vol. 2, pp. 271-276. Printed in the U.S.A.

The Insular Region: Part of the Prefrontal Cortex?

H A N S J. M A R K O W I T S C H A N D M O N I K A P R I T Z E L

Department of Psychology, University of Konstanz, P.O. Box 7733, D-7750 Konstanz, Federal Republic of Germany

(Rece ived 3 Oc tobe r 1978)

MARKOWlTSCH, H. J. AND M. PRITZEL. The insular region: Part of the prefrontal cortex? NEUROSCI. BIOBEHAV. REV. 2(4) 271-276, 1978.--Prefrontal and insular regions in different mammalian species are described on the basis of Brodmann's cytoarchitectonic findings. It is shown that the prefrontal cortex, defined cytoarchitectonically, and defined as the projection area of the mediodorsal thalamic nucleus, is often a considerably discordant area. An inverse relationship is assumed between the extent of insular cortex, which on the basis of mediodorsal thalamic afferents has to be termed prefrontal, and frontal cortex, which on the basis of the existence of a granular cell layer four has to be termed prefrontal. It is hypothesized that, because of a lower concordance of additional criteria, on which cortex may be termed prefrontal, and because of evidence, which makes the role of the mediodorsal nucleus for a definition of the prefrontal cortex questionable, nonprimates in comparison to primates in general will possess only "weaker copies" of the primate prefrontal cortex. Tentative support for this view is indicated.

Definition of prefrontal cortex Insular cortex Mediodorsal thalamic nucleus Cytoarchitecture

BRODMANN ([8], p. 127) divided the cerebral cortex grossly into main regions, and, more detailed, into areas. Among the eleven regions, which he classified as homolog- ous among mammals, this article will deal with his third and fourth regions, namely, with the 'regio frontalis' and the 're- gio insularis'.

Both of these regions share in common the fact that they seem to change considerably in topography, topology, and cytoarchitectonics between species. Therefore, we first of all will describe anatomical characteristics, separately for each of these two regions, and then, we will provide evidence for possible relationships between both with respect to a defini- tion of the prefrontal cortex.

THE REGIO FRONTALIS

For Brodmann [8] the regio frontalis consists of his areas 8-11 (sometimes 8-12) and A A A7" In man, these cortical fields are situated topologically in the frontal lobe, anterior to the precentral (areas 4 and 6) and cingular (areas 23-25 and 31-33) regions.

Topographically, man's regio frontalis---which Brodmann defined on the basis of presence of a distinct granular cell layer IV--overlaps largely with the prefrontal cortex as de- fined functionally [27, 28, 80, 82], or, as defined on the basis of its thalamic afferents from the mediodorsal nucleus [23,541.

For nonhuman primates, Brodmann [8,9] noted a corre- spondence between a decreasing number of (pre-)frontal fields and a decrease in phylogenetic development. So, apes only lack man's third frontal convolution, while monkeys in addition also lack the middle parts of the second frontal con- volution. Consequently, the number of prefrontal regions is reduced to five in monkeys, namely to areas 8-12. Area 12,

which may be homologous to area 11 in man, disappears again in prosimians.

In nonprimates, Brodmann [8,9] includes only one or two areas in his regio frontalis. In the honeybear (Cercoleptes caudivolvulus), the only carnivore investigated, he calls area 8 definitely "frontal granular cortex," while being un- sure whether area 12 belongs to the frontal or to the cingular region. In rodents, this area 12 remains solely as potential "granul~ire frontale Hauptregion" (Brodmann [8], p. 189).

From his investigations, Brodmann [9] (p. 174) concluded that the frontal granular cortex is one of the most variable regions of the cerebral cortex, not only with respect to ex- tent, number, and composition of its areas, but also with respect to its existence within the mammalian line.

Faced with these results from cytoarchitecture, anatomists developed different criteria to define the prefron- tal cortex. The currently most widely accepted definition was suggested by J. E. Rose and Woolsey [64], who stated that the extent of the prefrontal cortex ('orbitofrontal cortex' in their terminology) "be defined as the projection area of the mediodorsal nucleus" (p. 232) of the thalamus. This definition, though principally known since the last century [56], was adopted especially by students of the nonprimate prefrontal cortex [1, 4, 6, 19, 36, 39, 40, 50, 57, 77], though it was also used in primate research [23, 54, 61, 72, 76]

Based on this definition, a prefrontal cortex was detected also in rodents (e.g., [6,39]). Furthermore, it was found that in general larger regions of the cortex have to be named prefrontal than was apparent or expected from Brodmann's analysis. Especially in rodents and in marsupials--which ac- cording to Brodmann [9] also lack a prefrontal field---a con- siderable region of the anterior hemisphere is reached by mediodorsal afferents. In the rat, these zones are situated in the medial wall of the hemisphere (rostral and dorsal to the

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272 MARKOWITSCH AND PRITZEL

genu of the corpus callosum), as well as on the dorsal bank of the rhinal sulcus in the lateral wall of the hemisphere [39]; in the opossum, the "dorsolateral convexity of the hemisphere just rostral to the orbital sulcus" is reached by mediodorsal afferents, and in the rabbit the projection field occupies " the entire wall rostral to a midcorpus callosat level, wrap(s) around the frontal pole onto the lateral convexity and tail(s) off caudally on the dorsal bank of the rhinal sulcus" [6] (p. 251).

Studies, employing behavioral techniques to explore the prefrontal cortex of nonprimates, tended to support the view that the prefrontal cortex of nonprimates may be comparable also functionally with the respective areas of primate brains (reviews in [44,45]).

THE REGIO INSULARIS

While the extent of the regio frontalis seems to expand from rodents through carnivores to primates, the reverse seems to be true for the regio insularis. This region consists principally of four areas (areas 13-16) in man, nonhuman primates, carnivores, and rodents. In rodents, areas 50 and 8 may be termed insular region as well. On the other hand, the morphological divisibility enlarges in carnivores and pri- mates, where the insular region can be subdivided further into a dorso-caudal granular (area 13) and a ventro-rostral agranular part (areas 14-16) [8,9].

Interestingly, in spite of its consistent presence between species [8, 26, 67, 75], the insular region cannot be affixed topologically to a specific cortical landmark: In primates, the main parts of the insular region are hidden within the sylvian fissure, in carnivores they are located around the (pseudo-) sylvian fissure ("tr igonum sylvii" [30]), and in rodents and marsupials, the insular cortex lies bare on the lateral wall of the hemisphere, extending anteriorly to the frontal pole (and sometimes even further until reaching the medial wall), and ventrally to the basal cortex [8, 9, 67].

Contrary to the wealth of behavioral studies of the pre- frontal cortex (for review: [35, 45, 62, 81]), only a few behav- ioral investigations have been done on the insular cortex (for review: [17, 31,751).

INTERRELATIONS OF FRONTAL AND INSULAR REGIONS WITH RESPECT TO A DEFINITION OF THE PREFRONTAL CORTEX

Neuroanatomical research of the last decade revealed that aside from Brodmann's regio frontalis, several other of his cortical regions receive projections from the mediodorsat nucleus as well [34, 36, 39, 40, 41, 49, 50, 53, 73, 74, 78, 79]. Most consistently between species, projections were found to those regions which have to be termed insular cortex. In the rat, the most detailed investigation of this kind [36] (see esp. their Fig. 2) based the description of its results on ar- chitectonic maps of Brodmann [8], of J. E. Rose and Woolsey [65], and of M. Rose [66,67]. Following the ter- minology of M. Rose, Krettek and Price described a projec- tion from the posterior part of the medial segment of the mediodorsal nucleus to the dorsal agranular insular area (Fig. 1A). Furthermore, they referred to unpublished obser- vations of Krettek, Price and Jones in the cat, which had revealed an analogous projection in the cat. This projection in the cat has been confirmed in studies of Markowitsch et al. [49,50]. Using the horseradish peroxidase technique, these authors obtained projections from the postero-lateral

part of the mediodorsal nucleus to the cat 's agranular insular cortex (Fig. 1B), as defined by Krettek and Price [37] (see esp. their Fig. IA). Efferent projections from the insular cor- tex of cat and rat to the mediodorsal nucleus have been observed by Cranford et al. [17], Paula-Barbosa et al. [60], and by Siegel et al. [70,71]. In addition, that part of the cat 's prefrontal cortex, which is situated around the frontal pole, receives afferents from the insular cortex 12, 17, 32, 51, 60].

In the monkey, analogous results have not been stated explicitly in connection with a definition of the prefrontal cortex. They seem, however, to be included in several recent studies. Locke [41] observed afferents from the ventral paralamellar division of the mediodorsal nucleus to the basal anterior insula. Trojanowski [78] noted labeled neurons in the mediodorsal nucleus after injections into the superior temporal gyrus, and Mesulam et al. [53] and Stanton et , I . [73,74] occasionally found labeled mediodorsal cells after horseradish peroxidase injections, which could have entered the dorsal parietal bank of the sylvian fissure (Fig. 1C).

Aside from these three species, which are predominantly used in neuroanatomical research, we wish to refer to obser- vations in the tree shrew [72], rabbit [6], and opossum [77]. As stated earlier, all of the cortical projections of the mediodorsal nucleus in the opossum enter--according to Brodmann's definition---insular cortex. In the rabbit, the majority of the mediodorsal projections are situated within zones, which Brodmann [8,9] and M. Rose 167] term insular regions; and much of the prefrontal cortex of the tree shrew, which on the basis of mediodorsal afferents is situated either "on the lateral convexity of the frontal pole," or "l ies along the anterior extent of the rhinal fissure" [72], probably would have been assigned insular cortex by Brodmann or by M. Rose, if they had investigated this species.

CONCLUSIONS

Two intermingled trends seem apparent: First, the extent of Brodmann's regio frontalis expands both within and be- tween orders (rodents, carnivores, primates), while the ex- tent of the insular regions seems to diminish reciprocally. Second, the extent of those areas, which have to be named prefrontal cortex on the basis of thalamic afferents, but not on the basis of cytoarchitecture, diminishes from rodents through carnivores to primates.

Though interspecies comparisons between orders do not reflect evolutionary trends [10,29], they nevertheless show that the insular "prefrontal" structures of the brain tend to become replaced by granular prefrontal structures in animals with a higher degree of encephalization [3,38]. This tendency was confirmed within orders by Brodmann [8,91, Hailer [26], M. Rose [67], and Stephan [751.

As now, on the one hand, the frontal pole seems to be- come increasingly occupied by the regio frontalis, and as, on the other hand, afferents between thalamic nuclei and corti- cal areas generally follow an anterior-posterior gradient [34, 57, 69], the significance of the mediodorsal afferents for a definition of the prefrontal cortex becomes questionable [48]. The doubtfulness of using the mediodorsal nucleus for a definition of the prefrontal cortex is reinforced further, since in primates most of the cortical areas, invaded by mediodor- sal fibers, meet additional criteria which are characteristic of the prefrontal cortex, like granularization, electrical inex- citability, and an anterior locus [8, 9, 21, 22, 28, 80], while in nonprimates these criteria are met much less.

I N S U L A R R E G I O N 273

A

B

C

\

FIG. 1. Lateral view of the cortex o f rat (A), cat (B), and rhesus monkey (C). The approximate location o f the anterior insular region is shown by arrows (according to Brodmann [8,9]); for the rhesus monkey , the main parts of

the insular region are, however , buried within the sylvian fissure, sr: sulcus rhinalis, sl: sulcus lateralis.

274 MARKOWlTSCH AND PRITZEL

Consequently, we postulate that in marsupials, rodents, and carnivores only "weaker copies" of the primate frontal cortex exist, which should become apparent in behavioral and electrophysiological research.

Tentative support for such a view has been given in a comparative analysis of certain learning tasks between rats, cats, and rhesus monkeys [45]. These authors conclude that " there appears to be a tendency for learning and retention impairment to increase from rats through cats to monkeys in the spatial-task groups" (p. 826), after prefrontal lesions. Interspecies comparisons of behavioral effects of lesions of the insular cortex are not so readily obtainable, as, on the one hand, research seems to have concentrated on the cat [11-15, 25, 33], and as, on the other hand, areas situated outside the insular region have often been included in the ablations [16, 18, 58]. Nevertheless, results of the available investigations suggest that the insular cortex "in the cat is a multimodal brain region of special importance for certain higher order perceptual abilities" [14] (p. 9). This view is confirmed also by electrophysiological studies. Loe and Ben- evento [42], e.g., concluded that units in the insular cortex of the cat--which would have to be termed prefrontal on the basis of its mediodorsal afferents--"appear to behave much like those described in other association areas" (p. 398). This correspondence between units of the insular and of other association areas does not hold for units of the cat 's granular prefrontal cortex (i.e., the gyrus proreus), as was shown by Markowitsch and Pritzel [46], who found that " the sluggish reactivity and long latency, . . . , distinguish the prefrontal units from those of the other cortical association regions" (p. 70). Likewise, electrophysiological recordings in different

areas of the monkey's frontal lobe revealed different re- sponse modes to polysensory stimulation in different subre- gions of the dorsolaterai, orbitofrontal, opercular, and insu- lar subregions [7].

Taken together, these findings in cat and monkey suggest that the insular region may predominantly play a role in in- tegrating multimodal sensory--and possibly also sensory- visceral [17J---information, while the traditional prefrontal cortex (i.e., the regio frontalis of Brodmann [8,91) may select, evaluate, and transmit information, which ultimately may lead to motor acts [20, 24, 43, 47, 52, 55, 59, 63]. In terms of Mesulam and Geschwind [52], the regio frontalis may be " a nodal point for the convergence of neuronal inputs from 'high-order' association areas for sensory infor- mation" (p. 251), whereas the regio insularis may be viewed as a high-order association area. Seen in this connection, it might especially be worthwhile to investigate the role of the insular cortex of different species in processing olfactory and gustatory information [5,68].

Based on the foregoing analysis of prefrontal and insular interrelations, and based on the above-mentioned tentative support for differences between so-called prefrontal areas between and within species, we would like to encourage combined investigations of both the regio insularis and the regio frontalis with the aim, to either support specific insular and specific prefrontal functions, independent of a possibly underlying mediodorsal invasion, or--al ternat ively--with the aim to establish a functional concordance between mediodorsally invaded regions, independent of variables like locus and granularization.

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