Functions of the frontal cortex of the rat: a comparative review

Brain Research Reviews, 8 (1984) 65-98 Elsevier

BRR 90012

65

Functions of the Frontal Cortex of the Rat: A Comparative Review

BRYAN KOLB

University of Lethbridge, Lethbridge (Canada)

(Accepted June 12th, 1984)

Key worak: frontal cortex - cortex - neuropsychology - lesion studies - behavior - prefrontal cortex

CONTENTS

1. Introduction .............................................................................................................................................

2. Anatomy ................................................................................................................................................. 2.1 Cytoarchitectonics ................................................................................................................................ 2.2 Afferents ............................................................................................................................................ 2.3 Efferents ............................................................................................................................................ 2.4 Relationship with posterior cortex ............................................................................................................ 2.5 Anatomical issues .................................................................................................................................

3. Ablation of the Frontal Cortex ......................................................................................................................

4. Symptoms of Frontal-Lobe Lesions in Adults .................................................................................................... 4.1 Motor symptoms ................................................................................................................................. 4.2 Response inhibition ............................................................................................................................. 4.3 Serial ordering ................................................................................................................................... 4.4 Spatial orientation ............................................................................................................................... 4.5 Social and affective behavior .................................................................................................................. 4.6 Behavioral spontaneity ......................................................................................................................... 4.7 Olfaction .......................................................................................................................................... 4.8 Habituation ....................................................................................................................................... 4.9 Associative learning ............................................................................................................................ 4.10 Other symptoms in humans ................................................................................................................... 4.11 Other symptoms in rats and monkeys .......................................................................................................

5. Effects of Frontal Cortex Damage in Infancy .....................................................................................................

6. Discussion ................................................................................................................................................

Summary .....................................................................................................................................................

Acknowledgements ........................................................................................................................................

List of Abbreviations ......................................................................................................................................

References ...................................................................................................................................................

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1. INTRODUCTION

It was widely assumed in the 1930s and 40s that the

frontal lobes housed the highest human intellectual

capacities and that the frontal lobes of humans, and

perhaps certain other ‘higher’ non-human primates,

were unique. Behavioral research in the following

decades did little to dispel this belief as investigations

concentrated upon the study of the frontal lobes of

humans and old world monkeys such as rhensu rhesus macaques72.273. The heavy reliance upon studies of

non-human primates is likely to diminish in the com-

Correspondence: B. Kolb, Department of Psychology, University of Lethbridge, Lethbridge, Alb . . Canada TlK 3M4.

66

ing decades, however, so it becomes increasingly im-

portant to know whether other common laboratory

species such as the rat might provide a useful model

of mammalian, and particularly, human, frontal cor-

tex functioning. In addition, since the rat and other

closely related rodent species are becoming the sub-

jects of choice for most neurochemical studies of neo-

cortical function, utilization of the rat will become an

increasingly attractive choice for studies of neocorti-

cal function. This review therefore summarizes ana-

tomical and lesion studies of the rat frontal cortex

within the broader context of similar studies of hu-

mans and other primates. The overall conclusion is

that the frontal cortex of the rat may provide a good

model to study frontal cortical control of behavioral

processes in mammals, including humans.

2. ANATOMY

Unlike the posterior and temporal regions of the

neocortex, the cortex of the frontal pole of mammals

cannot be anatomically defined by a predominant in-

put from any sensory system. The absence of a mas-

sive homogeneous sensory input to the frontal pole

has thus led to a longstanding disagreement over

what constitutes equivalent frontal cortical areas in

different species. Historically, the frontal lobes of

primates have been divided into two regions: (I) a re-

gion roughly corresponding to the precentral gyrus of

hominoids and old world monkeys, which produces

movements when stimulated electrically and produc-

es gross motor deficits when removed; and (2) a more

rostra1 region, which does not produce movements

when stimulated electrically and does not produce

gross motor or sensory defects when removed. This

gross functional division can be related to an anatom-

ical distinction as Brodmann and later, othersi””

showed the rostra1 zone to have a granular cell layer

IV whereas the more posterior zone did not have this

cell layer. Thus, the ‘frontal granular cortex’ (also

known by the peculiar name of ‘prefrontal cortex’)

has been dissociated from the electrically excitable

motor and premotor cortex.

The designation of frontal granular cortex has

been a problem, however, as non-primate species

have a rather modest. or even absent, frontal granu-

lar area. One solution to this dilemma is to propose

that the frontal cortex should be defined not by its cy-

toarchitectonic characteristics but by its thalamic af-

ferents. Rose and Woolsey1Z7 suggested that, since

all mammals appear to have some cortical area near

the frontal pole that receives projections from the nu-

cleus medialis dorsalis (MD), this projection field

could be considered equivalent across mammals. Al-

though this definition has proven useful for the last 30

years, it too has recently been criticized since the cor-

tical regions included in this definition can also be

designated cingulate or insular cortex on the basis of

other anatomical criteria. In spite of this problem,

however, the definition of the prefrontal cortex as

the projection area of MD has the advantage that it

can be used as a provisional starting point for defi-

ning equivalent regions in different speciesi:g~i”). De-

tailed studies of the cytoarchitectonics, afferents and

efferents of the provisionally equivalent areas will be

necessary to establish probable homologies32. I shall

thus use Leonard’sihg identification of the MD-pro-

jection cortex in rats as our starting point and con-

sider the cytoarchitectonics, afferents and efferents

of the frontal cortex, including both the motor and

premotor cortex, as well as the ‘prefrontal cortex’. I

shall use the term prefrontal cortex rather than ‘frontal

granular cortex’ since the rat is one of those species

without a frontal granular area and the common des-

ignation of ‘frontal cortex’ can include motor cortex.

2.1. Cytoarchitectonics

The earliest detailed description of the cytoarchi-

tecture of the frontal cortical regions in the rat was

provided by Brodmann. Although other cytoarchi-

tectonic maps of the rats’ cortex were subsequently

producedIs’, the precise topography and structure

was not studied in detail until a recent study by Kret-

tek and Priceis”. On the basis of examination of nor-

mal Nissl-stained material, Krettek and Price identi-

fied 4 major divisions of the frontal cortex of the rat:

(1) a precentral area; (2) a prelimbic rostra1 area; (3)

an orbital area; and (4) an agranular insular area (see

Fig. 1).

Precentral area

The precentral area encompasses the areas desig-

nated as 4 and 6 by Brodmann. Krettek and Price di-

vide this zone into a ~ediaiprecentra~ area and a l&-

era1 precentral area, The medial area probably corre-

67

Fig. 1. Schematic drawings illustrating the approximate bound- aries of the cytoarchitectonic regions of the frontal cortex of the rat. A, a lateral (left) and saggittal (right) view of the cytoarchi- tectonic divisions; B, coronal sections showing cytoarchitec- tonic regions. See list of abbreviations for explanation of the symbols.

sponds to the frontal eye fields described by the stim-

ulation experiments of Hall and Lindholml~. The

lateral precentral area appears to correspond to

Brodmann’s areas 4 and 6 which has been defined

electrophysiologically as the rats’ primary motor cor-

texim.

Prelimbic rostra1 area

Three regions can be recognized on the rostra1 me-

dial cortical surface medial to the precentral area: the

infralimbic area, the prelimbic area and the anterior

cingulate area, corresponding to Brodmann’s areas

25,32 and 24, respectively.

Orbital area

The term orbital is very confusing when used with

respect to the frontal cortex as it has been used to de-

scribe a gyrus in primates and carnivores and to the

entire projection field of MD in the rabbit and mon-

key**‘. Krettek and Price use this term to describe

the cortex forming the ventral aspect of the frontal

lobe of the rat (see Fig. 1B) and I shall adopt their

terminology. This zone can be subdivided into 4 sub-

areas on the basis of thalamic connections, although

Krettek and Price do not rule out the possibility that

there are architectonic differences. The subareas are

labeled with respect to their relative positions and in-

clude: (1) a medial orbital zone located on the most

ventral aspect of the medial wall of the frontal pole;

and (2) ventral orbital, ventral lateral orbital and lat-

eral orbital zones on the ventral aspect of the pole.

All of the orbital subareas are small and are seen on

only the most anterior coronal sections through the

frontal pole (see Fig. 1B).

Agranular insular area

The agranular insular cortex of the rat includes 3

subareas, although only two of them are likely to be

equivalent to frontal cortical areas in primates. The

tissue forming the dorsal bank of the rhinal fissure

caudal to the lateral orbital area forms the ventral ag-

ranular insular area (see Fig. 1B). Together, the

ventral agranular and lateral orbital areas form

Leonard’+ sulcal cortex. The cortex lying just dor-

sal to the rhinal sulcus on the lateral surface of the

hemisphere forms the dorsal agranular insular area.

Just caudal to this region is the third agranular insular

area, the posterior agranular insular area. This latter

area is probably not equivalent to any prefrontal area

in carnivores or primates, although its equivalent

zone is uncertainiso. In addition to these 3 agranular

insular areas, there is a granular insular area immedi-

ately dorsal to the caudal portion of the dorsal agra-

nular insular area and the entire posterior agranular

insular area (see Fig. 1A). This cortex forms the gus-

tatory cortex and corresponds to the zone described

by Benjamin and Akertlo.

2.2. Afferents

Little was known of the projections to the frontal

cortex of the rat until Leonard’s168 classic demonstra-

tion using Fink-Heimer degeneration techniques

that MD projected to a medial zone roughly corre-

sponding to Brodmann’s areas 24 and 32, and a sulcal

zone within the cortex forming the dorsal bank of the

rhinal fissure. Since Leonard’s study, a variety of his-

tological methods (silver degeneration, retrograde

horseradish peroxidase, anterograde autoradio-

graphic, fluorescence histochemical) have been used

to demonstrate major specific afferents from the

thalamus, basal forebrain. and brainstem in addition

to a variety of non-specific afferents from the thala- mus and ~~~~~~~~~7.l2~lJ.~2,5~,S7,6l~.6~.6X.7~.77.7X.lO~,lOY,

11X-150.167.171~.171.?13, A composite map of the major

projections described in these papers is presented in

Fig. 2. In order to facilitate discussion of the affer-

ents and efferents of the cytoarchitectonically de-

fined subareas as well as our discussion of different

areas of the frontal cortex. I have grouped the ar-

chitectonic areas described by Krettek and Pricers”

into 3 zones that I have labeled ‘medial frontal’, ‘ven-

tral frontal’ and ‘motor and premotor’.

Thalamocortical afferents

It is apparent from Fig. 2 that both the medialis

dorsalis and ventralis medialis nuclei of the thalamus

project extensively over the frontal cortex of the rat.

These projections are complex, however, as both nu-

clei can be divided into several subregions, each of

which has a specific projection to a region or regions

of the frontal cortex (see Table I). In addition, the

anterior medialis nucleus projects to the anterior cin-

gulate, prelimbic and medial precentral regions and

the ventralis lateralis nucleus projects to the medial

precentral and lateral precentral regions.

Specific non-thalamic afferents

Until Krettek and Price148 definitively demon-

strated a specific cortical projection from a non-tha-

lamic subcortical structure in rats and cats, it was

generally accepted that only the thalamus sent specif-

ic projections to the cortex. It is now clear, however,

that the amygdala and adjacent pyriform cortex send

specific projections to the prefrontal cortex, as do

cell groups A9 and A10 in the brainstem (see Fig.2).

The projections of the amygdala are remarkably spe-

cific as discrete regions of the basolateral or cortical

amygdaloid nuclei project to restricted medial or ag-

ranular insular cortex. Similarly, discrete projections

to the prefrontal cortex originate in the dopaminergic

cells in A9 of substantia nigra and A10 in the ventral

tegmentum. The A9 projection appears to go exclu-

sively to the anterior cingulate area whereas the me-

dial part of A10 projects to the prelimbic area. the

most lateral part of A10 projects to the dorsal and

ventral agranular insular areas and the intermediate

region of A10 projects to the anterior cingulate area.

Non-specific afferents

In addition to the afferents that project to restrict-

ed regions of the frontal cortex. there are a large

number of afferents that project non-specifically to

all of the neocortex. These include serotonergic pro-

jections from the dorsal and central raphe. noradren-

ergic projections from the locus coeruleus, choliner-

gic projections from the basal forebrain, as well as

projections from the axial nucleus of the thalamus,

claustrum, lateral hypothalamus, zona incerta and

intralaminar and midline nuclei of the thalamus.

2.3. Efferents

Our knowledge of the efferent connections of the

rat’s frontal cortex is largely limited to two silver de-

generation studies.iY.171 an audiographic tracing

study7, a few studies of specific projectionstl8J6”. and

several lesion studies that examined glutamate up- take33.56.6Y.182.267.268 The principle efferents de-

scribed in these studies are summarized in Figs. 3 and

4. As with the afferents, 1 have grouped cytoarchitec-

tonic areas to facilitate discussion.

Cortical efferents

The anterior cingulate, prelimbic and agranular in-

sular cortex all project to the posterior cingulate, ret-

rosplenial, entorhinal and presubicular cortical

areas, and the orbital and insular areas both project

to the pyriform cortex. The projections to the presu-

bicular and entorhinal regions are particularly note-

worthy as they provide a connection with the hippo-

campus, a structure whose functions have some strik-

ing similarities with the frontal cortex.

Striatal and basal forebrain efferents

Rosvold*-‘t emphasized the importance of topogra-

phic frontal cortico-striatal connections in his de-

scription of the ‘prefrontal systems’ of the monkey.

69

Fig 2. Highly schematic drawing illustrating the afferents to the different frontal regions. Shading within the boxes demarcating the frontal areas correspond to the shading in the boxes marking the different afferents.

Similar connection appear in the rat as the medial frontal systems in the rat as wells4. Several laborato-

frontal areas project to the medial zone of the cau- ries have shown that fronto-striatal afferents are like-

date-putamen and the ventral frontal areas project to ly to be glutamatergic and apparently influence both

the ventral lateral zone of the caudate-putamen (see the mesolimbic and nigro-striatal dopamine net-

Fig. 3), suggesting that there may be analogous pre- work33,69,182,267.

TABLE I

Cytoarchitectonic areas of the rat frontal cortex and the respective specific thalamic afferents

Major area Subareas Thalamic afferent

1. Medial frontal

2. Motor and premotor

3. Ventral: orbital

4. Ventral: agranular insular

(a) Infralimbic (area 25) (b) Prelimbic (area 32) (c) Anterior cingulate (area 24) (a) Medial zone (b) Lateral zone (a) Medial orbital (b) Ventral orbital (c) Ventrolateral orbital (d) Lateral orbital (a) Dorsal agranular (b) Ventral agranular insular (c) Posterior agranular insular

V”P AM, VM,, MD,,, AM, VM,, MD, AM, VM,, VL WM,, VL VM,, P’I WM,, MD, VM,,, Parat MV,, MD, VM,, MD,, Pf VM,, MD, VM,,

70

MEDIAL

FRONTAL

VENTRAL

FRONTAL

CORTEX STRIATUM and

BASAL FOREBRAIN

-

Presubiculum

c

I-

Fig. 3. Schematic drawing showing the cortical, striatal and basal forebrain targets of frontal efferents

I noted earlier that the amygdalo-cortical afferents

in the rat were particularly discrete. In contrast, cor-

tico-amygdaloid efferents are rather more diffuse as

both the agranular insular area as well as the prelim-

bit area project to both the basolateral nucleus and

lateral nuclei of the amygdala.

Thalamic efferents

In general, corticothalamic projections are aimed

mainly at midline nuclei that project to the frontal

cortex. It is noteworthy, however, that the precise

nature of the thalamocortical projections, especially

of medialis dorsalis and ventralis medialis, are not

faithfully reciprocated by the corresponding cortico-

thalamic projections7, an observation made pre-

viously by Domesick5Y in the corticothalamic projec-

tions to the anterior nuclei from the retrosplenial

areas. In addition to reciprocal connections with the

midline thalamic nuclei, there are substantial projec-

tions to nuclei that do not themselves project to the

frontal cortex (see Fig. 4).

Brainstem efferents

A variety of brainstem structures receive frontal

projections. Two points are particularly noteworthy

with regard to these projections. First, there is a

striking parallel between the projections of the pre-

limbic and agranular insular areas: both regions pro-

ject to the lateral, and lateral preoptic hypothalamic

nuclei, the ventral tegmentum and substantia nigra.

Second, both the anterior cingulate and prelimbic

areas project to the pretectum and the intermediate

and deep layers of the superior colliculus. These lat-

ter projections are no doubt related to the control of

eye movements as Hall and Lindholmi@) provided

functional evidence that these cortical regions corre-

71

spond to the frontal cortical eye fields. Finally, Van

Der Kooy et al.‘W demonstation of direction in pre-

frontal insular solitary nucleus provides evidence of a

role of this cortex in visceral function.

2.4. Relationships with posterior cortex

It is evident from Fig. 5 that the frontal cortex rep-

resents only about one-quarter to one-third of the to-

tal neocortex in the rat. An examination of the more

posterior cortical areas is relevant to the study of the

functions of the frontal cortex because these more

posterior zones provide the sensory information nec-

essary for the brain, and presumably the frontal cor-

tex, to control behavior. It would thus seem reasona-

ble to expect to find direct cortico-cortical connec-

tions between the frontal cortex, especially the pre-

frontal cortex, and the sensory zones of the posterior

cortex. A variety of such connections have been

identified in the monkey including afferents and ef-

FROHTAL

ferents from the parietal, temporal, occipital and en- torhinal cortex9,92,195.206.207.263.

It is dif~cult to identify with certainty the zones in

the rat equivalent to parietal and ‘temporal associa-

tion cortex in the monkey, but the result of recent be-

havioral and anatomical studies in the rat suggest

that equivalent zones may exist.

Par~etal cortex The parietal cortex of the primate includes the pri-

mary and secondary somatosensory cortex in addi-

tion to a polysensory zone roughly equivalent to

Brodmann’s areas 5, 7a and 7b. The ventrobasal

complex of the thalamus projects to the primary and

secondary somatosensory cortex whereas the re-

maining zones receive projections from the nucleus

lateralis dorsalis, lateralis posterior and the pulvinar.

In the rat, a similar arrangement appears to exist as

SI receives projections from the ventrobasal com-

plexQ.117. Kreig’s area 7 receives projections from

THALAM”S HvPOTHALAmJS mAINSTEM

Fig. 4. Schematic drawing illustrating the thalamic, hypothalamic and brainstem targets of frontal efferents.

Fig. 5. Photomicrograph of adjacent Nissl-stained transverse sections through the cortex of the right hemisphere of a rat. Different cy-

toarchitectonic regions can be visualized, presumably owing to differences in cortical laminae.

73

lateralis dorsalis and lateralis posteriorio7Ji3, and

area 39 receives projections from as yet unspecified

areas of the posterior complex@.

Temporal cortex The temporal cortex of the primate includes the

primary and secondary auditory areas (Brodmann’s

areas 41, 42, 22) as well as a number of visual ‘asso-

ciation’ areas (Brodmann’s areas 20,21,37). The au-

ditory areas receive thalamic projections from the

medial geniculate nucleus whereas the visual associa-

tion areas receive thalamic projections from the pul-

vinar and posterior complex. The temporal areas are

not as thoroughly studied in the rat (see Fig. 5), but it

appears that the anatomical arrangement, although

much simpler, parallels that of the primate. The tem-

poral auditory zones receive thalamic projections

from the medial geniculate nucleusli6 and the visual

zones (Krieg’s areas 18, 18A and 20) receive thalam-

ic projections from the lateralis posteriorr”‘.

In summary, there are tentative anatomical

grounds for believing that the rat has parietal and

temporal cortical areas that may be considered

equivalent areas to those found in primates. Given

this, it is likely that a pattern of cortico-cortical con-

nections similar to that of the monkey exists between

these areas and the frontal cortex of the rat. Such a

conclusion awaits proper anatomical verification,

however.

2.5. Anatomical issues

Both primates and rodents clearly possess cortex

anterior to the motor cortex that can be subdivided

into at least two separate zones on the basis of cytoar-

chitecture, afferents and efferents. The issue re-

mains, however, as to whether the medial frontal and

ventral frontal cortex of rats are homologous to the

dorsolateral and orbital frontal cortex of primates.

Simpson originally put forward several criteria for es-

tablishing homologies and these have been nicely

adapted for the nervous system by Campbell and Ho-

dosQ: (1) experimentally determined fiber connec-

tions, (2) topography, (3) position of reliably occur-

ring sulci, (4) embryology, (5) morphology of indi-

vidual neurons, (6) histochemistry, (7) electrophys-

iology, and (8) behavioral changes resuiting from

stimulation and lesions. The more similarity there is

between the neural structures of two species with re-

spect to these criteria, the greater the justification for

drawing the inference that the neural structures may

have been derived from corresponding structures in a

common ancestor (that is, homoiogous). Although

there is an obvious similarity between the frontal re-

gions of the rodent and primate on several of these

criteria, there remain several significant differences

that prevent a conclusion of homology in the prefron-

tal cortex of these species. First, although the origi-

nal suggestions of homology in the rodent and pri-

mate prefrontal cortex were based upon afferents

from MD, MD has since been shown to project both

to the cingulate and premotor cortex of primates.

Second, the rat has only a macrocellular region in

MD whereas primates have an additional microcellu-

lar component, a difference in prefrontal afferent in-

put that may be of major functional significance.

Third, the cytoarchitectonics of the medial frontal

cortex of the rat are rather different from those of the

dorsolateral cortex of monkeys (especially areas 8, 9

and 10) and are actually more similar to those of the

premotor cortex cingulate areas 24 and 32. Hence, it

could be argued that the medial frontal cortex of rats

might be homologous to the cingulate and premotor

regions of primates, rather than the dorsolateral

frontal cortex. This issue cannot be resolved at pres-

ent, so it is important that caution is exercised in our

conclusions regarding functional similarities. In par-

ticular, I shall presume for the remainder of the pa-

per that the medial frontal cortex of the rodent and

the dorsolateral (and possibly anterior cingulate and

premotor) regions of the primate are analogous and I

shall demonstrate that there is a remarkable similari-

ty in the functions of these zones in rodents and pri-

mates.

3. ABLATION OF THE FRONTAL CORTEX

The oldest and still most widely used approach to

the problem of human brain function is to analyze the

behavioral effects of a lesion of circumscribed re-

gions of the cortex. Lesions may be produced surgi-

cally by the direct removal of brain tissue, or by the

destruction of brain tissue either electrically or by the

injection of relatively specific chemical neurotoxins

directly into brain regions (e.g. 6-hydroxydopamine,

kainic acid, ibotinic acid). In humans. brain lesions

may also result from cerebral vascular accidents, tu-

74

mors, or head injuries, although the extent of the

‘naturally occurring lesions’ is more difficult to docu-

ment accurately. Reversible lesions may be pro-

duced by cryogenic depression of localized regions of

neocortex or by systemic injections of relatively spe-

cific short acting drugs (e.g. atropine sulfate, am-

phetamine). In each case, the behavior of subjects

with lesions is compared to the behavior of normal

control subjects on a variety of standardized tests and

the functions of a particular brain area are then infer-

red from the behavioral changes.

A number of factors restrict the inferences one can

make about brain function from the study of subjects

with brain lesionsi43. In particular, brain damage or

dysfunction can affect behavior not only directly but

also indirectly. It is naive to assume that brain lesions

affect only the region actually damaged, because any

lesion initiates changes in those regions that are con-

nected to the damaged area. For example, if lesions

occur in the neocortex, cells die in the thalamus, be-

cause the axons of thalamic cells, which project to the

neocortex, are damaged by the cortical lesion. Fur-

thermore, lesions of one area of the brain may de-

prive other areas of afferents necessary to accurately

control certain types of movements, or may func-

tionally disconnect widespread areas of the brain.

Nevertheless, in spite of these problems, the lesion

technique remains one of the most powerful tech-

niques available for psychologists to evaluate brain-

behavior relationships, especially if they wish to

make comparisons between studies of humans and

non-humansids. Before comparing the effects of fron-

tal cortex lesions in primates and rodents, it will be

necessary to examine briefly 6 factors that compli-

cate the analysis of behavioral symptoms following

damage to the frontal cortex including: (1) the nature

of the disease, (2) bilateral versus unilateral damage,

(3) cerebral asymmetry, (4) age at injury, (5) prob-

lems with neuropsychological learning tests, and (6)

the study of species-specific behavior. I shall consider

each of these factors separately before examining the

literature in general.

First, the nature of the disease producing the lesion

is a significant factor in the subsequent behavioral

syndrome. For example, large tumors of the frontal

lobe release hand and foot grasp reflexes48 and may

produce certain forms of apraxiasi74. but such symp-

toms are not normally observed after more restricted

damage to the frontal lobes such as occurs with surgi-

cal excisions of atrophied tissue or small benign tu-

mors. In order to facilitate the comparison of the be-

havioral effects of frontal cortex damage in different

species, I therefore have chosen to draw most of my

conclusions from studies using patients with surgical

excisions for the relief of epilepsy or the excision of

benign tumors, as well as patients with missile

wounds .of the brain. This choice of patients presents

a bias in my interpretation of the literature, but it

provides a rational position from which to attempt to

generalize from non-human species in which lesions

are almost always surgically induced.

A second factor to be considered is that nearly all

studies of frontal-lobe function in humans consider

patients with unilateral damage whereas most studies

of frontal cortex function in non-humans prepare

subjects with bilateral excisions. Although there are

few systematic comparisons of the effects of unilater-

al and bilateral lesions in human subjects, there is

reason to believe that some effects of bifrontal le-

sions cannot be duplicated by lesions of either hemi-

sphere alone”. For example, patients with bifrontal

lesions are severely impaired at reporting the time of

day and in decoding proverbs. effects seldom seen

following unilateral frontal lesions. Nevertheless, in

my own experience with a limited number of bifron-

tal cases, it has been clear that they show all of the

symptoms normally observed following unilateral

damage, in addition to variable additional symptoms.

Since there are very few systematic studies of pa-

tients with bilateral frontal lesions I shall restrict my

discussion to patients with unilateral damage. One

should not be overly impressed with the relatively

more severe effects of frontal cortex lesions in non-

humans, however, since the ‘animal studies’ almost

always report the effects of bilateral removals.

Third, the effects of left and right frontal-lobe exci-

sions in humans can be doubly dissociatedlab. but

there is little reason to believe that this is the case in

non-human species 1?~13h The only evidence of func-

tional asymmetry in the cerebral cortex of the rat

comes from studies of movement or turning, studies

that are not easily generalized to primate species.

This species difference does not impugn the useful-

ness of non-human species as models of human fron-

tal-lobe functioning but it is a detail that is best not

overlooked.

75

Fourth, there is good reason to believe that the age

of injury is a relevant consideration in understanding

the effects of frontal-lobe damage in humans. Ras-

mussen and Milne9 have reported, for example,

that Broca’s area may ‘move’ if damaged in early in-

fancy whereas other functional regions of the frontal

lobe may show little sparing at all from early injury.

The understanding of cortical organization following

early injury of the frontal cortex has been a particular

focus of work in both primates and rodents so I shall

consider the literature on this topic separately.

Fifth, neuropsychologists have traditionally stud-

ied the ability of rats to learn, or to relearn, after var-

ious neurological manipulations. This interest in

learning stems from neuropsychology’s close histori-

cal association with comparative psychology, which

has a long standing interest in the comparison of the

performance of different species on standard learn-

ing tests, and from a belief that the most interesting

and important aspects of human behavior involve

learning. Neuropsychological studies of learning

have been strongly influenced by three, frequently

tacit, assumptions: (1) the learning of new habits by

rats represents activity of the ‘highest’ levels of psy-

chological ability and indicates the activity of infer-

red processes such as cognition, memory, mapping,

attention, etc. (2) The capacity for learning can be

used as a method for neuropsychologists to gain clues

about the animal’s neurological representation of the

world, and how this representation may have been al-

tered by some neurological treatment. (3) It is possi-

ble to generalize about the functions common to oth-

er mammals, especially humans, by studying the per-

formance on various tasks by rats.

There is nothing inherently wrong with any of

these assumptions, provided that one is aware that

they are merely assumptions and may be in error.

The major difficulty in using learning tasks is that

psychologists are often tempted to view the tasks as a

way of discovering the neural structure(s) of sys-

tem(s) whose functioning corresponds to one of the

cognitive psychologists inferred mental processes

such as memory, attention, perception, etc. I shall

endeavour to avoid this pitfall and try to interpret the

results of learning studies in terms of the behavioral

changes that are actually observed, rather than

merely inferred, although many inferences are truly

seductive!

Finally, although neuropsychologists have paid

little attention to the study of species-specific behav-

iors, tending to focus upon behaviors that require the

learning of some new habit, there is now little doubt

that many species-specific behaviors require the neo-

cortex for their normal executionl41,144,*71.278. Spe-

cies-specific behaviors are here defined as the reper-

toire of ‘fixed’ or ‘modal’ action patterns that are

characteristically observed in all individuals of a par-

ticular species in their natural environments. The de-

tails of the behaviors in each species’ repertoire may

be rather different as they have been shaped by fac-

tors involved in survival in a unique niche and partic-

ular way of life but all species engage in species-spe-

cific behaviors and the functions of these behaviors

are common to a particular class (e.g. mammaha).

(For a further discussion of the characteristics of

class-common behavior see Kolb and Whishawi45

and Warren and Kolb*7*. Thus, for example, if hu-

mans with frontal-lobe lesions exhibit marked abnor-

malities in social behavior we might expect to ob-

serve abnormalities following frontal cortex lesions

in other mammals, even though the details of the ab-

normalities might be very different indeed. After all,

other species do not use verbal language to interact

with one another, and olfactory cues are far less sa-

lient for social behavior in humans than most other

mammals. I will use examples of species-specific be-

haviors to reinforce arguments derived largely from

other types of behavioral observations. It must be

recognized, however, that I am not attempting to

draw inferences about the details of species-specific

behaviors in humans and rats, but rather I am making

more general comments regarding the role of the

frontal cortex in the regulation of behavioral process-

es common to the class Mammalia.

4. SYMPTOMS OF FRONTAL-LOBE LESIONS IN

ADULTS

Although different writers might disagree upon

the grouping of particular behavioral deficits, 1 be-

lieve there is likely to be general agreement that rela-

tively restricted damage to the frontal lobes of hu-

mans produces a constellation of behavioral symp-

toms similar to those summarized in Table II. This

classification of behavioral symptoms is not intended

to be a complete summary of all symptoms of frontal

76

TABLE II

Summary of behavioral symptoms of frontal cortex lesions in humans _______

Inferred function

1. Motor

2. Response inhibition

3. Temporal ordering 4. Spatial orientation

5. Social and affective

6. Behavioral spontaneity

7. Olfaction 8. Habituation 9. Associative learning

10. Language

_~___. ~~ _ ..__... Behavioral symptoms

-_ _.._-__ -__ (a) loss of distal movements and loss of speed and power (b) poor voluntary eye gaze (c) poor copying of complex arm and facial movements (a) impaired performance on tasks requiring changes

in behavior (a) impaired recall of order of events (a) impaired body part focalization (b) poor maze learning (a) impaired social behavior (b) impaired perception of facial expression (c) altered sexual behavior (a) reduced verbal fluency (b) reduced design fluency (c) reduced facial expression (d) altered levels of spontaneous talking [a) poor olfactory discrimination (a) impaired habituation of orienting reactions (a) impaired learning of conditioned associate

learning tasks (a) aphasia (b) poor spelling

-I.-_ _ -_. (c) poor phenotic discrimination

.~__ ____.

lobe dysfunction, but rather to provide a framework

from which to evaluate the effects of frontal cortex

damage in other species. It might be expected that if

the frontal cortex of monkeys and rats is organized in

a manner similar to that of humans, at least superfi-

cially similar symptoms might be observed following

ablation of frontal cortex, and that does appear to be

the case, as summarized in Tables III and IV. I shall

consider each class of behavioral symptoms sepa-

rately, with particular emphasis upon data from stud-

ies of rats.

4.1 Motor symp tams

Damage to the primary motor cortex of primates is,

normally associated with a chronic loss of the ability

to make fine independent finger movements. pre-

sumably due to a loss of direct cortico-spinal projec-

tions onto motoneurons 152. In addition, there is a loss

of speed and power in both hand and limb move-

ments. Although damage anterior to the primary mo-

tor cortex does not produce such severe motor dis-

ruptions, there are more subtle disruptions of ‘volun-

tary’ movements associated with ‘prefrontal’ lesions.

For example, although frontal-lobe patients are ca-

Area damaged

area 4 area 8,9

prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal prefrontal

prefrontal area 44 on left area 4 (face) area 4 (face)

Basic reference _.-- __ ~~ 152 2.53 ~ 262 127

188 186, 187 238

40,189 15

139 267 188 114 126 139 217 175

214 27

251 251

pable of copying individual movements of the fin-

gers, hands, limbs or face, they have difficulty in

copying a series of these movementsl27. Similarly, al-

though frontal-lobe patients appear able to move

their eyes about normally upon cursory examination,

they appear to have difficulty moving their eyes effi-

ciently in various types of visual search tasks~74.253.262

or in making certain types of saccadesyy. Localization

of these motor impairments is still uncertain although

on the basis of studies of direct cortical stimulationa

and blood flow226 the critical focus may be expected

to be in the supplementary motor cortex and frontal

eye fields, respectively. Up until about 1970, observations of motor func-

tion following motor cortex ablation in rats led to the

general conclusions that the motor cortex of the rat

does not play a significant role in rnovernent2&.7’.‘~~.

The elegant behavioral and anatomical studies on

monkeys by Lawrence and Kuypers and their collea-

guesls*J63J~ led to a re-examination of the effects of

motor cortex lesions in rodents with emphasis upon

the study of the distal effecters. It is now established

that ablation of the motor cortex in rodents produces

severe disruptions in discrete digit movements36, forelimb movements7h.lOh.124.142.213.222.2~8, tongue ex_

77

TABLE III

Summary of behavioral symptom of frontal cortex lesions in monkeys - Inferred function Behavioral symptoms Area damaged Basic reference

..-. 1. Motor (a) paralysis area 4 163

(b) poor voluntary eye gaze area 8 162 (c) impaired opening of puzzles dorsolateral 49

2. Response inhibition (a) difficulty in shifting responses orbital 191 3. Temporal ordering (a) apparent difficulty in separating the order of discrete trials dorsolateral 221

(b) poor ‘motor record dorsolateral 208 4. Spatial orientation (a) poor performance on spatial learning tasks dorsolateral 191 5. Social and affective (a) reduced social aggression and interaction orbital 31

(b) increased aggression with reduced emotional expression dorsolateral 184,194 6. Behavioral spontaneity (a) reduced spontaneous facial expressions and vocalizations prefrontal 194 7. Olfaction (a) defective odor discrimination orbital 250 8. Habituation (a) impaired response habituation prefrontal 64 9. Associative learning (a) impaired learning of conditioned association dorsolateral 215

10. Mobility (a) increased activity orbital 234 (b) hyperreactivity dorsolateral 98

11. Feeding (a) reduced food intake orbital 31 12. Contralateral neglect (a) no response to sensory stimuli area 8 46

tension and manipulation37,3s.*” and claw ~uttingz?s. Although there are fewer studies of fine motor be-

havior in rats with lesions restricted to the medial or ventral frontal regions, removal of these regions does appear to produce ‘motor’ deficits. Ablation of the medial frontal cortex produces a chronic disturbance in coordinated use of the forelimbs as can be seen in the manipulation of food or other objects whereas, in contrast, removal of the ventral frontal cortex pro-

duces a severe impairment in tongue extension. We have consistently seen these effects in rats with re- stricted lesionst4*J~J73 but, owing to the difficulty in making the lesions, it is entirely possible that the ap- parent severity of these effects results, in part, from incursions into the neighbouring secondary forepaw area196 or motor representation of the tongue area of the motor cortex, respectively. Animals with motor cortex lesions show a remarkable capacity for recov-

TABLE IV

Summary of the effects ofprefrontaf lesions in rats -._

Inferred function Behavioral symptoms Area damaged Basic reference

I. Motor (a) loss of distal movements MF; motor 36,142 (b) poor execution of chains of complex movements MF 142 (c) restricted tongue mobility VF; motor 278

2. Response inhibition (a) impaired performance on tasks requiring changes in behavior VF; MF 133

3. Temporal ordering (a) difficulty in ordering movements MF 140 4. Spatial orientation (a) poor learning of spatial tasks MF 137 5. Social and affective (a) abnormal social interaction VF; MF 122,30

(b) abnormal male sexual behavior MF 154,1X5,183 6. Behavioral spontaneity (a) inability to initiate new response strategies VF 137 7. Olfaction (a) defective odor disc~mination VF 64 8. Habituation (a) impaired habituation of many behaviors MF 123 9. Activity (a) hyperactivity VF 119,30

(b) exaggerated response to starvation VF 177 (c) abnormal circadian rhythms VF 119

10. Homeostasis (a) hyperresponsive to starvation VF 177 (b) reduced chronic body weight VF 146,30 (c) transient anorexia VF 130

11. Contralateral neglect (a) no response to sensory stimuli MF 46

78

ery after subtotal lesions*r, but we have not been able

to identify any retrograde degeneration in the motor

thalamus of many animals with clear impairments, so

it is likely that prefrontal lesions in the rat may indeed

produce some motor impairments. This question de-

serves further study, however, with very small le-

sions.

A final deficit in the control of movement in rats

can be seen in studies of swimming. Rats swim with a

characteristic pattern; their back is nearly horizontal

in the water, their forepaws are tucked up beneath

the chin, and they propel themselves with vigorous

thrusts of the back limbs235. Complete decortication

spares swimming behavior but abolishes the inhibi-

tion of the forepaw movements when rats are allowed

to swim down a long alleywayr4rJ@. Similarly, remo-

val of the medial frontal, motor cortex or ventral cor-

tex also abolishes forepaw inhibition in this

testi4*.*42.14”. This behavioral deficit has been inter-

preted as an impairment of inhibition of subcortical

structures264 but it may in fact be a deficit in control of

the distal musculature. Thorough studies of this be-

havior by Whishaw27” have shown that decorticate

rats are quite capable of excellent forepaw inhibition

when tested in special ways. When he tested animals

in a large circular pool (146 cm diameter), Whishaw

found that forepaw inhibition returned to control lev-

els provided the animals did not swim near the wall of

the pool. A new deficit emerged, however. When

normal animals turned in the pool they made small

rotary or skulhng movements of the paws to aid their

turns. Decorticate rats failed to do this but rather

they paddled with the forepaw contralateral to the di-

rection of the turn. These data suggest that the ab-

sence of forepaw inhibition in alleyway tests may be

an artifact of the testing situation and that the loss of

forepaw inhibition during turning may be due to the

loss of the ability of make small rotary movements of

the distal portions of the limbs. Preliminary studies in

rats with restricted frontal ablations suggest that rats

with ventral frontal lesions have normal forepaw in-

hibition when tested in a large tank whereas animals

with motor cortex or medial frontal lesions behave

more like decorticate rats (Kolb, unpublished obser-

vations). Should further study confirm this obser-

vation, it would provide yet another example of im-

paired use of the distal musculature that may be re-

lated to damage to the secondary forepaw cortex, or

both.

4.2. Response inhibition

Frontal-lobe patients are notorious for their inabil-

ity to inhibit various types of behaviors. This can be

most clearly shown in tests in which there are specific

rules, either implicit or explicit to the task, and fail-

ure to respect the rules results in failure at the

taski*sJ*2. Perhaps the best example of this is seen in

the Wisconsin Card Sorting Task. In this test the pa-

tient is presented with 4 stimulus cards, bearing de-

signs that differ in color, form and number of el-

ements. The patient’s task is to sort the cards into

piles in front of one or another of the stimulus cards.

The only help the patient is given is being told wheth-

er the choice is correct or incorrect. The test works

on this principle: the correct solution is first color;

once the patient has figured out this solution, the cor-

rect solution then becomes, without warning, form.

Thus, the patient must now inhibit classifying the

cards on the basis of color and shift to form. Once the

patient has succeeded at selecting by form, the cor-

rect solution again changes unexpectedly, this time to

number of elements. It will later become color again

and so on. Shifting response strategies is particularly

difficult for patients with frontal lesions, who may

continue responding to the original stimulus (color)

for as many as 100 cards until testing is terminated.

Evidence of a difficulty in response inhibition in

non-human species comes largely from learning tasks

in which the animal is required to learn a particular

solution to a problem and then must later make a re-

sponse that is incompatible with the original learning.

For example, in reversal-type tests the animal learns

to respond to a particular stimulus or to go to a specif-

ic place in order to obtain reward. During the re-

hearsal phase, the task is changed so that reward is

only obtained if the same response is made to a diffeer-

ent stimulus or location. Both rats and monkeys with

prefrontal cortex lesions have difficulty in shifting re-

sponses on reversal-type tests. Similarly. in tests of

response extinction, in which a previously rewarded

response such as pressing a bar is no longer re-

warded, both rats and monkeys with prefrontal le-

sions continue to respond much longer than do nor-

mal control animals. Monkeys with orbital frontal le-

sions and rats with ventral frontal lesions appear to

79

be most affected in reversal and extinction tasks, al-

though medial frontal lesions in rats do also some-

times produce apparent impairments in response in-

hibition, especially in reversal tasks (see Table V).

Although the primary evidence of a deficit in re-

sponse inhibition in non-humans comes from learn-

ing studies, further evidence can be found in studies

of species-specific behavior in rats. One example is

the failure of rats with frontal lesions to inhibit their

forepaws when swimming (see above). More dramat-

ic examples can be seen in more complex behaviors

that require the chaining of discrete behavioral units.

When rats build nests they normally pick up nesting

material in the mouth, carry it to the nesting area,

place the material there, manipulate it into position,

collect more material, etc. Rats with medial frontal

lesions build very poor nests, in part because they ini-

tiate the sequence (collecting material) but fail to

shift to the next behavioral unit. Thus, they can be

seen walking around (apparently aimlessly) with the

nesting material in their mouth. One explanation for

this behavior is that once having initiated a behavior,

the animals are unable to inhibit it to continue to the

next behavior in the chain.

4.3 Serial ordering

One of the most characteristic manifestations of

frontal-lobe damage is in serial organization of be-

havior. This may manifest itself as an inability to

combine a series of actions into an organized se-

quence of movements such as in planning and prepar-

ing a simple mea1210 or in the inability to recall the or-

der of events. Systematic studies of this phenomenon

by Mimer and her colleageus have revealed that fron-

tal lobe patients are unable to keep track of their re-

sponses on a variety of tasks216 and in judging which

of two stimuli, which were previously presented, was

presented most recently4i.I*5.

Evidence of an abnormality in temporal or serial

ordering in non-human species with frontal cortex le-

sions is somewhat more indirect, coming from studies

of delayed response-type learning tasks in both mon-

keys and rats as well as studies of species-typical be-

havior in rats. The original observation of impaired

learning in animals with frontal cortex ablations was

Jacobsen’slo* discovery of impaired learning of de-

layed-response tasks following large frontal-lobe le-

sions in chimpanzees. The inability of animals to per-

form some response normally after a brief delay be-

tween stimulus presentation and the opportunity to

respond has now been replicated in many different

testing situations using many different species, in-

cluding rats (see Table V). For example, in our ex-

periments on the effects of prefrontal lesions on de-

layed response behavior in the ratiss, we used a

scaled-down version of the Nencki Test Apparatus in

which a cue light was presented briefly on one side of

the apparatus or the other, signaling the location of

food reward. The cue light went out and the animal

was released after a delay of O-10 s. Rats, which

were preoperatively trained to mediate delays in ex-

cess of 5 s, were unable to re-master delays of larger

than 1 s postoperatively, whereas control animals, or

animals with ventral frontal lesions, were able to per-

form accurately with delays of up to 10 s. Rats with

medial frontal lesions now have been shown to be im-

paired at various delayed reaction tasks including de-

layed response, delayed alternation, and sponta-

neous alternation. (I am aware of two studies that

have failed to find a delayed-reaction deficit after

medial frontal lesionsioi.275, but both of these experi-

ments tested animals in rather unconventional tasks,

and in the Hannon and Bader experimentloi, many of

the normal animals failed to successfully solve the

task, making interpretation of the results difficult.)

All of the delay tasks require the execution of a re-

sponse that is determined by an event (either a stimu-

lus such as a light or a response such as a turn to the

left or right) that occurred in the recent past. A cor-

rect response is contingent upon responding appro-

priately to that event, a response that is almost al-

ways either to a particular cue presented in the recent

past (cued delayed response) or if no cue is presen-

ted, in the direction opposite of the last response

made (delayed alternation). Thus, the task requires

both a response to a particular place in space as well

as some memory of where this place is. Animals

might be impaired at delayed reaction tasks either

because they have some deficit in spatial orientation

(broadly defined) or because they are unable to re-

call which cue or behavior was the last one they ob-

served or performed. It is safe to conclude that, in

spite of the general consistency of the deficits in de-

layed reaction tasks following dorsolateral frontal le-

sions in monkeys and medial frontal lesions in rats,

80

TABLE V

Summary ofperformance of learning tasks of rats with frontal lesions

Type of test

1. Habituation

2. Motor learning

3. Delayed reaction

4. Spatial

5. Discrimination reversal

6. Aversive

7. Scheduled reinforcement

Task

(a) Heart rate

(b) Flexor reflex (c) Headshake (d) Activity (e) Head poke

(a) Latch puzzles

(b) Bar pressing

(a) Cued delayed response

(b) Delayed alternation

(c) Spontaneous alternation

(a) Lashley III (b) Morris water task (c) Radial arm maze

(d) Nencki task no delay (a) Tactile (b) Object

(c) Spatial

(a) Passive avoidance (b) One-way avoidance (c) Two-way avoidance (a) DRL

(b) FR (c) Extinction of bar pressing (d) Reacquisition of bar pressing

these ablation experiments have failed to explain sat-

isfactorily the basis for the observed deficit or the

neural mechanisms operating in the performance of

delayed reaction tasks’s, Nevertheless, I will take the

performance of rats and monkeys with prefrontal le-

sions to provide a reasonable basis to presume that,

like humans with frontal-lobe lesions, rodents and

primates with analogous lesions are also impaired at

recalling the serial order of past events.

Many species-specific behavioral patterns require

the temporal sequencing of behavior. For example,

rats are energetic hoarders of food and hoarding be-

havior has a distinct sequence. The behavior requires

the animals to engage in a series of motor acts (walk

and find food, pick the food up, walk to the hoarding

location, drop the food, manipulate the food with the

forepaws to form a pile) at particular places in space.

Similarly, nest building maternal behavior and sexual

behavior also require that discrete behavioral acts be

combined sequentially over time to produce an orga-

MF

poor poor poor poor poor

poor

poor normal fail

normal poor

fail normal poor fail poor

normal poor poor

poor normal normal poor poor poor

normal normal normal normal

____ ~ VF Motor

? ‘1 ? ‘7 ‘, ‘,

normal ‘? normal ?

poor poor normal poor normal normal ? normal normal normal

normal ? normal normal ? poor normal very poor normal normal ? ? ‘, ‘7 ‘7

normal normal

normal normal normal ‘1 normal ? normal ?

poor ‘? ? poor slow ‘,

poor ?

80 96

231 123

123 76

142

133,203,236 133, 131.173 101

42.43,63, 112, 153.200, 244,2X,268,281

58 241 256

124, 137,248 6,137

133 7s

5

51, 133. 144,202 101. 137,274 144 131

2.22,23, 131,260 202, 204. 229 133, 198 85. 203

133. 181 199

nized behavior that we might recognize as species-

specific. Damage to the medial frontal cortex of rats

and hamsters interferes with the normal execution of

these behavioral sequences (see Table VI). Thus, in

our studies, mothers with large medial frontal lesions

were poor at retrieving errant pups, built very poor

nests, failed to hoard food, and generally appeared to

be ‘disorganized’ in the care of their pups. Although

it can be argued that the animals are less likely than

normal to initiate the behaviors, when they do per-

form them the behaviors appear poorly organized.

This characteristic has proven difficult to quantify in

rats although it has been somewhat easier to do so in

hamsters with medial frontal 1esionW. By filming

the hoarding and nest building behavior of hamsters

it was possible to show that the frontal hamsters were

capable of each of the individual components of the

behaviors but were impaired at the organization of

these behaviors into long chains of what is sometimes

referred to as ‘goal directed behavior’. Similar be-

havioral disturbances in humans would probably be

called apraxias, but the appropriateness of this term

for non-human species is open to serious questiont40.

In summary, although the interpretation of the ab-

normalities in hoarding, nest building, maternal be-

havior, etc., following medial frontal cortex lesions

in rodents is still uncertain, I believe that one logical

interpretation is that the animals have a deficit in the

serial ordering of behavior. Further, it appears that

the principal focus for this deficit may be in the pre-

limbic region as rats with lesions that spare this zone

often hoard very large amounts of food, although this

observation requires much more study.

4.4 Spatial orientation

Although spatial processing is generally believed

to be a major function of the right hemisphere of hu-

mans, it is reasonable to presume that the frontal and

parietal, and possibIy temporal, regions each con-

tribute to different aspects of ‘spatial behavior’l4s.

Evidence that the frontal cortex might play a signifi-

cant role in spatially-guided behavior first came from

studies of delayed-response type tasks by Mishkin

and Pribram in the early 1950’s. In their studies,

monkeys observed food being placed under one of

two stimuli, which differed only in their position on a

test board. After a delay of some seconds or minutes,

the animals were allowed the opportunity to choose

one of the stimuli and obtain the hidden reward. Al-

though the initial studies confounded the delay and

the spatial component, subsequent studies73J*Jsi

TABLE VI

Summary of species specific behavior of rats with frontal Lesions

81

have demonstrated that the spatial component of the

task was critical for demonstrating a deficit. Since the

correct position of the foodwell was always relative

to the body of the monkey (left, right), if was sug-

gested that the frontal cortex might play a role in ego-

centric spatial orientation. A similar inference has

been drawn from studies by Semmes et al.238 who

found that patients with frontal-lobe lesions had dis-

orders of spatial ability that could be dissociated from

those normally associated with more posterior le-

sions. Thus, patients with frontal lobe lesions were

impaired at a test in which they were required to

point to the location on their body represented by

various numbers on a drawing of a human figure.

Subsequent experiments by others have revealed a

variety of deficits in spatial processing as required in

finger and stylus maze test&is9 or in limb position-

ingi69. In contrast, frontal-lobe patients are unim-

paired at tasks such as map reading or tests of con-

stru~tiona1 praxis23s. Thus, it is now clear from stud-

ies of both human and non-human primates that fron-

tal-lobe lesions produce some type of disorder of spa-

tial processing or spatial orientation, but the nature

of this deficit is still uncertain.

Studies of spatially-guided behavior in rats have

taken a rather different approach, having largely

been conducted in various mazes, but there is now

compelling evidence of a significant ‘spatial deficit’ in

rats with medial frontal lesions.

I shall define spatial tasks as those in which reward

is contingent upon going to a particular place. The

correct place could be defined by a cue proximal to it

.Behavioral test Medial frontal Ventral frontal Motor cortex Basic references

Food related: (a) Eating and drinking normal transient aphagia normal 130 (b) Food handling abnormal transient abnormal abnormal 124, 142 (c) Food hoarding little normal normal 121,243 (d) Neophobia normal normal normal 55,132 (e) Taste aversion normal normal normal 55,132

Maternal behavior impaired normat normal 145,244,284 Nest building impaired normal normal 145,239 Social behavior normal abnormal ? 122,128 Maie sexual behavior impaired ? ? 154, I83 Female sexual behavior ? ? ? _ Activity and rhythms normal increased activity normal 119,177 Swimming poor forepaw inhibition poor forepaw inhibition poor forepaw inhibition 142 Grooming normal transient disruption transient disruption 142

_

82

(e.g. a black arm in an otherwise white maze), by a

configuration of cues distal to it (e.g. the place has a

constant position in a room with many constant

cues), or by the route taken to get to it (e.g. go left,

go right, go right, etc.). The cortical systems required

to solve each of these types of spatial tasks can be dis-

sociatedi37, and Sutherland has suggested that these

tests can be designated tests of ‘taxis’, ‘mapping’ and

‘praxis’ strategies, respectively*@. It is difficult, how-

ever, to devise pure tests of these processes, since

more than one strategy can be used to solve most

tasks. Nevertheless, some relatively pure tests of tax-

is (Nencki apparatus), mapping (Morris water task;

radial arm maze) and praxis (Lashley III maze) have

been devised. I shah consider each of these sepa-

rately.

1. Taxis. A pure test of taxis would provide a cue

for the animal that, if followed, would lead the ani-

mal to some goal subject such as food. I previously

described the Nencki apparatus as a task used for

studying delayed response learning in the rat. The

task can also be used, however, as a test of taxis. In

this case, the cue light goes on, the restraining cage is

lifted, and the rat’s task is to go to the light to gain

food reward. The only cue to the whereabouts of the

goal object is the light. Rats with either medial fron-

tal or ventral frontal lesions perform normally in this

taski-i-i. A second test of taxis is provided in a varia-

tion of the Morris water task@*. In this task, rats are

released into a large tank of water and must learn to

swim to a black platform to escape the cold water. AI-

though rats with small frontal cortex lesions have not

been studied in this task, Whishawz77 has found that

totally decorticate rats can easily learn this task, so it

is likely that rats with smaller lesions would also have

no difficulty at this task. In summary, it would appear

that rats with prefrontal cortex lesions can normally

solve tests of taxis spatial orientation.

2. Mapping. A pure test of mapping would be a

task in which an animal must learn to go to a point in

space that can only be defined by reference to distal

cues. Thus, in this type of task an animal could be re-

leased from different points and the task would be to

go to the same location in space, regardless of the

starting location, each time. This task requires that

animals cannot be allowed to use any cues at the goal

that might allow them to navigate using a taxis strate-

gy, which would invalidate the test. The best test of

spatial mapping is a version of the Morris water task

described above. in this case, the animal is released

into the water and must swim to the location of a hid-

den, partially submerged, platform. Owing to the ab-

sence of any local cues whatsoever, the animal must

learn the location of the platform relative to distal

cues in the room. Normal rats acquire this task very

quickly so that within 4-8 trials they can swim direct-

ly to the platform, regardless of the starting location

in the task. An extensive series of experi-

ments135,137.13s.*46.24s has shown that rats with medial

frontal lesions are impaired at the acquisition of this

task and, although the animals learn to find the plat-

form rather quickly, they fail to learn to swim directly

to the platform, even with extensive practice. In con-

trast, although rats with ventral frontal lesions are

initially very poor at the taski-17, they can acquire the

task and learn to swim directly to the platform when

given extensive training. The reason for the poor per-

formance of the rats with ventral frontal lesions ap-

pears to be one of initiating appropriate search strat-

egies, rather than a spatial mapping deficit per se as

the animals initially fail to search for the platform but

rather scratch at the tank walls. Once the animals

abandon this strategy they learn the task very rapid-

ly. A second, although less pure, test of spatial map-

ping can be found in the g-arm radial maze2Qs. In this

task rats must learn the location of arms in the maze

that contain food and must learn to enter each re-

warded arm only once since it is only provided there

once per day. Rats with either medial frontal or ven-

tral frontal lesions are very slow to acquire, or to re-

acquire this task5.137. although like decorticate rats,

they are eventually capable of solving the task. The

reason for the deficit in the medial frontal animals is

likely to be the same as the basis of their deficit in the

Morris task, On the other hand, the severe impair-

ment by the rats with ventral frontal lesions may

again be a deficit in initiating a successful search

strategy as the animals race from arm to arm in

search of the reward rather than slowly explorihg the

maze as the normal rats do. Since the use of olfactory

cues in the form of self-induced odor trails cannot be

excluded in the radial arm maze, and rats with ven-

tral frontal lesions have deficits in olfactory-guided

behaviorba, perhaps the slow learning by the ventral

frontal-ablated rats could also be related to an olfac-

tory deficit. This remains to be proven, however.

83

3. Pranis. Tests such as the Lashley III maze pro-

vide a test of praxis spatial orientation since in this

problem the animal must learn to course through a

maze from start box to goal box by following a fixed

route through the maze. Although the Lashley III

maze would seem a good test of praxis orientation, I

am aware of only one study of rats with frontal lesions

in this task: Thomas and Weir256 found rats with me-

dial frontal lesions to be very impaired at the reten-

tion of this task whereas rats with motor cortex le-

sions performed at control levels. Although it thus

would appear that medial frontal lesions disrupt the

acquisition of praxis strategies, it would be unwise to

generalize too far from just one experiment.

In summary, lesions of the medial frontal cortex

disrupt the acquisition of spatial mapping, and per-

haps praxis strategies, in spatial orientation, while

having no obvious effect upon the use of taxis strate-

gies. Sutherland244 has suggested that the medial

frontal cortex may be more important for the acquisi-

tion than the retention of mapping strategies, as defi-

cits in retention of the water task and radial arm maze

appear to be small or negligible compared to the defi-

cits in acquisitiorG.t37,246. This distinction stands in

contrast, however, to the performance of spatial de-

layed-reaction tests in which acquisition and reten-

tion deficits appears to be of a similar magnitude (see

above).

4.5. Socialand affective behavior

One of the most obvious and striking effects of

frontal-lobe damage in humans is a marked change in

social behavior and personality. Although most re-

ports have been purely descriptive’s, systematic stud-

ies have shown frontal-lobe patients to have impaired

perception of affective states in othersrss, reductions

in facial expressionsi26, alterations in levels of spon-

taneous talking, with left frontal ablations producing

significant decreases and right frontal ablations pro-

ducing significant increasesi39, and a tendency to-

ward social isolation50.

Similarly, monkeys with frontal-lobe lesions, es-

pecially orbital frontal lesions, have a wide variety of

abnormalities in social behavior. For example, in one

study Butter and Snyder31 removed the dominant

(so-called alpha) male from each of several groups of

monkeys, subsequently removing the frontal lobes

from half the monkeys. When the animals were later

returned to their groups they all resumed the position

of dominant male, but within a couple of days all of

the frontal monkeys were deposed and fell to the bot-

tom of the group hierarchy. Analogous studies of

wild monkeys have shown similar results: frontal

monkeys fall to the bottom of the group hierarchy

and eventually die, because they are helpless alone.

It is not known exactly how the social behavior of

these animals has changed, but there is little doubt

that it is as dramatic as the changes in the social be-

havior of humans.

The species-specific social behavior of rats is ob-

viously very different from that of primates, but to

the extent that rats engage in behavior which influ-

ences, or is influenced by, other members of their

species, social behavior is clearly class-common and

we might expect the frontal cortex to play some role

in rodent social behavior.

Although there have been several detailed ac-

counts of the social behavior of normal rats3+93=94,

there have been surp~singly few studies of the effects

of cortical ablations on these behaviors in rats. Since

social behavior is not a unitary behavior with a uni-

tary neurological basisiss, we examined the behavior

of rats with media1 or ventral frontal ablations in

male rats in several settings including: (1) free inter-

actions in both large and small enclosures; (2) shock-

induced aggression; (3) territorial aggression; and

(4) predatory aggressioni22J2s. Our results showed

that ventral frontal lesions increased fighting in re-

sponse to either mild shock or to dominance displays

(e.g. social grooming), possibly because these ani-

mals might be hyperreactive to certain types of stim-

uli, a result we have seen in other situations as well.

In contrast, we found no effect whatsoever of medial

frontal removal. In another far more ambitious

study, Lubar, Hermann, Moore and Shousei’* stud-

ied the behavior of rats with medial frontal lesions in

a large colony situation. Although their data are very

complex, they did find that medial frontal-operated

male subjects engage in more fights and more homo-

sexual mounting. They did not study rats with ventral

frontal lesions. In summary, although descriptions of

human patients with frontal lobe lesions would lead

one to expect changes in social behaviors in rats,

there are disappointingly few studies of changes in

social behavior in rats with lesions of the frontal cor-

84

tex. In view of the importance of olfaction in rodent

social behavior, and the anatomical connections be-

tween the ventral frontal cortex and the olfactory

cortex and amygdala, it would seem worthwhile to

study olfactory-related behaviors of rats with frontal

cortex lesions, especially since there is evidence that

frontal lesions in cats disrupt olfactory components of

social behavio9.

4.6 Behavioral spontaneity

A little studied. but extremely salient, characteris-

tic of frontal-lobe patients is their apparent lack of

spontaneous behavior. For example, according to

ZangwW~, such authors as Feuchtwanger and Kle-

ist observed that, although patients with left frontal

lesions anterior to Broca’s area were not aphasic,

they did have a type of verbal deficit. Zangwill de-

scribed it as a ‘certain loss of spontaneity of speech’.

Subsequent studies have been able to quantify this

verbal deficit as patients are greatly impaired at word

fluency tasks in which they must write as many words

beginning with a particular letter as they can think of

in five minutestsg.2”. More recently, it has been

shown that frontal-lobe patients are devoid of spon-

taneous conversational speechrss, spontaneous facial

expressionr’h. and abstract design fluency such as is

seen in doodlingrrJ.

I am unaware of any studies using either monkeys

or rats that have specifically looked for changes in be-

havioral spontaneity, but there is evidence for both

species that such changes do in fact occur. First, in his

study of the social behavior of monkeys with large

prefrontal lesions Myers’94 found that the lesions led

to a significant decline in the number of spontaneous

facial expressions and vocalizations. Lesions in the

precentral gyrus did not have this effect. Although

Myers interpreted his observations as changes in so-

cial behavior, they can be described as changes in be-

havioral spontaneity, and, indeed, it was Myers’ ex-

periment that led me to study spontaneous faciat ex-

pressions and speech in patients with frontal-lobe le-

sionsr26~l”Y. Evidence of reduced behavioral sponta-

neity in rats will obviously not be found in studies of

facial expression and I am unaware of any studies of

vocalizations in rats. Nevertheless, I did find a signif-

icant reduction in the number of spontaneous vocali-

zations in guinea pigs with ventral frontal lesions

(Kolb, in preparation). One of the most striking as-

pects of the behavior of rats with ventral frontal ie-

sions is their apparent inability to initiate new re-

sponse strategies in novel situations. This appears as

‘hyperreactivity’ in some situations but in settings

such as the Morris water task this is very maladaptive

as the animals have a very slow latency to initiate a

search pattern for escape from the cold water. This

symptom may be conccptuaiIy simitar to the reduced

behavioral fluency of human frontal-lobe patients,

but a more convincing demonstration requires tests

for rats in which behavioral fluency is more directly

assessed.

4.7 O(faction

Although olfaction is seldom studied in human pa-

tients, behavioral evidence from studies of non-hu-

man subjects led Potter and Butter@ to investigate

olfactory detection and discrimination in frontal-lobe

patients. Their results showed that, although the

threshold for olfactory detection was still within nor-

mal limits, olfactory discriminatory ability was se-

verely impaired in their patients with large frontal-

lobe lesions. Owing to the nature of their patients’ le-

sions they could not localize their behavioral change

to the orbital cortex but the orbital frontal cortex of

other species is known to have significant olfactory

input and cells there are known to respond to specific

odors so it is a reasonable supposition that the same is

also true in humans. As with humans, there are few

studies of olfactory-guided behavior in either rats or

monkeys with frontal lesions, but it has been shown

that both species are severely impaired at odor dis-

criminations following ventral frontal or orbital gyrus

albations, respectiveIy~~~2sO. Taken together, the

data from all 3 species (humans, monkeys and rats)

imply that the ventral aspect of the prefrontal cortex

may be the core olfactory neocortex. I return to this

point later.

4.8 Habituation

Habituation is one of the simplest forms of learning

studied by psychologists. The term is applied to a

gradual quantitative response decrement that is the

result of repeated exposure to a standardized stimu-

luG*. Although many authors appear to assume that

85

the prefrontal cortex is involved in behavioral habit-

uatiotW, there are no unambiguous demonstrations

of this in humans. Several Russian investigators have

provided evidence of siow electroenaephalogra-

phically-inferred habituation of an orienting re-

flexi’s, and Luria, Pribram and Homskayai76 de-

scribed a patient with a left frontal-lobe tumor in

whom psychophysiological measures failed to show

any orienting response at all. These studies provide

at least tentative evidence of the presumed role of the

prefrontal cortex in habituation, but stronger support

comes from studies with monkeys and rats. On the

basis of earlier work by Pribraam, Butter30 showed

that lesions of either the dorsolateral orbital regions

of the frontal lobe of monkeys retarded habituation

to a novel tone presented in the course of lever pres-

sing for reward. On any given day the animals habit-

uated at the same rate as control animals to the tone,

but over days the monkeys with orbital frontal remo-

vals were particularly slow at habituating to the stim-

ulus. Similar results have been found with rats. As

summarized in Table V, rats with medial frontal le-

sions exhibit very poor habituation on a variety of be-

haviors ranging from flexor reflexes to investigatory

head poking behavior. Griffin and Glaser79.*a79s.96

have argued that the prefrontal cortex participates in

the habituation process by accelerating plastic

changes occurring elsewhere in the central nervous

system, although the prefrontal cortex itself is not as-

sumed to be the actual site of these changes. Their

evidence in support of this hypothesis is that: (1)

frontal lesions retard or prevent habituation of a vari-

ety of behavioral responses; (2) stimulation of the

prefrontal cortex accelerates habituation; but, (3) re-

moval of frontal cortex fails to affect previously sta-

bilized habituation. It is unclear from Griffin and

Glaser’s discussion exactly what function the pre-

frontal cortex performs in habituation but perhaps it

is related to Teuber’s concept of corollary dis- charge253.254.

4.9 Associative learning

It has commonly been reported that patients with

large frontal-lobe lesions are unable to regulate their

behavior by external stimuli. Thus, for example, Lu-

ria and Homskaya 17s described patients with massive

frontal-lobe tumors who could not be trained to re-

spond consistently with the right hand to a red light

and with the left hand to a green light, even though

the patients could indicate which hand was which and

could repeat the instructions. As with many other

frontal-lobe symptoms, however, there are very few

experimental studies of this phenomenon in patients

with more restricted cortical injuries. Nevertheless,

there is a good deal of research on the effects of fron-

tal cortex lesions in non-human species on the acqui-

sition of conditional learning tasks in which arbitrary

stimuli become associated with responses bearing no

natural relation to the stimuli (e.g. Go-No Go, see

below). Furthermore, PetrideW has recently found

that frontal-lobe patients are impaired at learning ar-

bitrary associations between colors and spatial loca-

tions, or colors and hand postures, a result that ap-

pears analogous to Luria’s earlier observations in pa-

tients with far larger lesions.

Like humans with frontaI-robe lesions, monkeys

are impaired at Iearning arbitrary associations be-

tween a set of stimuli and a set of responses. In a

monkey analogue of his associative learning task, Pe-

tridesZ*s trained monkeys to make different move-

ments of a manipulandum when presented with dif-

ferent objects. In contrast to his control monkeys

who rapidly acquired the task, monkeys with pre-

frontal lesions including area 8 and part of area 6

were unable to learn it, although they were able to

master unrelated tasks. I am unaware of any compa-

rable studies of associative learning in rats, but such

experiments would seem worthwhile.

4.10 Other symptoms of frontal-lobe lesions in hu- mans

The first symptom of frontal cortex damage to be

described was the disturbance of language following

damage to the left frontal lobe (Broca, 1861). Cu-

riously, although this symptom of frontal-lobe dam-

age was the first to be described, it remains the most

controversial as some question its existence287,

whereas others question its natureill. Nevertheless,

there are consistent abnormalities of language from

left frontal-lobe excisions, especially if the damage

includes the motor representation of the face area.

TayloW reports that patients with relatively small

removals, which respect Broca’s area but include the

face area, result in chronic impairments in spelling,

86

as well as impaired phonetic discrimination. The ori-

gin of these deficits is unexplained to date. Finally, it

has been proposed by a number of authors*so that

frontal-lobe patients, especially those with right fron-

tal-lobe lesions, exhibit a form of dysprosody. That

is, there is a loss of tone to their speech. This is really

only a clinical impression to date, however, and

awaits more rigorous evaluation.

4.11 Other symptoms of prefrontal lesions in rats and

monkeys

Three other symptoms have been thoroughly stud-

ies in rats and monkeys with lesions of the frontal cor-

tex: activity, feeding and sensory neglect. I shall con-

sider each separately.

Activity and rhythms

Perhaps the oldest established effect of frontal cor-

tex removals in both rats and monkeys is an increase

in activity67.225. This phenomenon has now been well-

studied in the rat, leading to several conclusions. (1)

Ventral frontal lesions produce an immediate and

chronic increase in daily wheel runningrzs-177. (2)

Treatments that normally increase wheel running in

rats (e.g. amphetamine, starvation, oestrous) poten-

tiate increases produced by ventral frontal le-

sions1*3,177. (3) Medial frontal lesions produce mild-

er, but reliable, increases in wheel running activity’*”

and larger increases in stabilimeter activity than ven-

tral frontal lesionsr77. (4) Increases in activity in-

duced by medial frontal lesions are also potentiated

by starvationtrrJ**. (5) Ventral frontal lesions disrupt

normal circadian rhythms by increasing activity dur-

ing the light cycle, an effect that is potentiated by

starvationtzs. In attempting to interpret these data,

Lynch177 was guided by earlier proposals that the

frontal cortex (especially the orbital cortex) of pri-

mates provides significant input to the hypothalamus

in order to attenuate the effects of changes in internal

homeostatic balancetr5. Hence, Lynch demonstrated

that lesions along the anterior medial forebrain bun-

dle produced increases in wheel running activity simi-

lar to those resulting from ventral frontal lesions. It

may be, however, that the ventral frontal cortex

functions to modulate responses to changes in both

internal or external environment since rats with ven-

tral frontal lesions are hyperreactive in many situa-

tions (e.g. male-male social interaction, open

fields), as well as to treatments such as starvation or

amphetamine.

Feeding

Lesions of the ventral frontal region of both mon-

keys and rats disturb normal feeding behavior. Al-

though this has not been extensively studied in mon-

keys, one can find many ‘clinical’ statements of ab-

normal feeding behavior in monkeys with posterior

orbital frontal lesions. For example, Butter and Syn-

dersl state: ‘For a period of 12 days to 3 weeks follow-

ing surgery, these animals were lethargic, drowsy

and quite unreactive to most forms of stimulation;

they also showed marked anorexia, although follow-

ing this initial depressive stage they showed pro-

nounced oral tendencies’. Similarly, damage to the

ventral frontal cortex of rats produces a lethargic pe-

riod including transient aphagia that is most severe if

the lesion includes underlying white matter or ex-

tends into the sensorimotor representation of the ~n~~t1Y-21,82-84,I21,129,13~~,134,146,19CJ~ This aphagia ap-

pears to be related to at least 3 factors. First, these le-

sions produce a transient disruption of the ability to

chain together the sequences of movements nec-

essary for eatingr46. Second, ventral frontal ablation

produces chronic impairment in lickinglJ”.*QJ78.

Third, ventral frontal ablation appears to reduce the

resting body weight, or so-called ‘set point’lsJ34.146.

Thus, rats dieted preoperatively show very little

aphagia postoperatively, although they still have the

motor impairments, whereas rats fattened preopera-

tively show prolonged aphagia postoperatively such

that both groups eventually attain an equivalent body

set point that is about 15% below normal control lev-

els. This body weight drop is still unexplained but is

consistent with the idea that the ventral frontal cor-

tex is closely associated with the limbic system and

may play some role in the regulation of visceral or ho-

meostatic mechanismsrs.

Neglect

Although there are scattered reports of visual neg-

lect following frontal-lobe lesions in humans”6,‘04. I

am unaware of any systematic studies of this phe-

nomenon in patients with surgically-induced lesions

restricted to the grey matter of the frontal lobe. Nev-

ertheless, there are many studies purporting to show

87

a polysensory neglect following damage of the region

of the frontal eye fields of both monkeys and rats. In

a series of rigorously controlled experiments, Latto

and CoweyssJss-162 have unequivocally demon-

strated that unilateral frontal cortex lesions in mon-

keys produce transient field defects during central

fixation, oculomotor defects, and severe disorganiza-

tion in visual search patterns, symptoms that have

largely disappeared within about one month of sur-

gery. Analogous results have also been reported for

rats with frontal eye field lesions. For example, in a

series of experiments Crowne and his colleagues

have shown that removal of the presumed homolo-

gue of the frontal eyefield of rats (roughly including

the regions PrCm and ACd in Fig. 1) produces a defi-

cit in orienting to stimuli impinging upon the contra-

lateral side of the body or in that half of extraperso-

nal space, even though the animals can avoid shock

on the basis of cues presented in the ‘neglected

world’46.47.70. Parallel data have been reported by

other laboratories4.44. Although the phenomenon of

contralateral neglect is far form understood, the re-

sults from studies of both rats and monkeys can be

taken as tentative evidence that some portion of the

medial frontal cortex (possibly the frontal eye fields)

has a significant role in directing behavior, and subse-

quently the sensory systems, towards novel stimuli,

possibly via some interaction with brainstem mecha-

nisms believed to function in this capacity (e.g. colli-

culi).

5. THE EFFECTS OF FRONTAL CORTEX DAMAGE IN INFANCY

The functions of the frontal lobes have primarily

been studied in adults with acquired lesions whereas

comparatively little attention has been paid to the ef-

fects of similar injury in infancy or childhood. The

study of patients with disease of the frontal cortex in

infancy is particularly imporant, however, since it al-

lows an assessment of the ability of the brain to com-

pensate for the loss of the frontal cortex since the in-

fant brain is generally assumed to be more ‘plastic’

than the adult brain. Presumably functions that can

only be mediated by the frontal cortex will show little

sparing or recovery of function as compared to func-

tions that can be mediated by other cerebral struc-

tures.

Although there are little data from the human li-

terature to support it, there is a general belief in the

non-human literature that infant brain damage is as-

sociated with dramatic sparing and recovery of func-

tion. This belief is presumably reinforced by the con-

sistent observation of apparently complete recovery

from aphasia in children with early left hemisphere

damagelee, whether it be in the anterior or posterior

speech zones. Nevertheless, there is accumulating

evidence that sparing of function is not a salient char-

acteristic of early brain injury in humans as there may

be a general lowering of intelligence223Jss and no evi-

dence of sparing whatsoever on many tests sensitive

to frontal-lobe damaget31ss. These results are impor-

tant, both in terms of the medical and behavioral

treatment of patients with frontal-lobe injuries, but

also in terms of the now extensive literature on the ef-

fects of ablation of the frontal cortex of monkeys and

rats in infancy.

The initial studies of both rats and monkeys with

neonatal frontal cortex removal reported apparently

complete recovery of function on what appeared to

be a very broad range of neuropsychological t&slO*,l31.*57.

This result was consistent with the general belief in

the literature that brain injury in infancy was less de-

bilitating than similar injury in adulthood, but

seemed to stand in contrast to the far less than com-

plete recovery observed in humans with naturally oc-

curring brain injury in infancy. Over the last decade,

however, further research on both rats and monkeys

has shown that recovery is far less complete than it

appeared: sparing is absent or very poor in tests of

species-specific behavior or fine motor control, even

though it is rather good on many tests of learn-

ing17.72.86.90.124.2~. Table VII summarizes the data,

showing the clear parallel between the results from

rats and monkeys. Performance on tasks such as de-

layed response typically show virtually complete

sparing of function after infant frontal lesions where-

as fine motor skills are permanently lost. Although

not illustrated in the table, it is now also established

that age, gender, postoperative experience and pre-

cise locus of the lesion all affect the degree of sparing

following frontal cortex damages9,90.276. Some of

these variables (age and lesion locus) are known to

affect the degree of sparing from damage to the frontal

speech area in humans224 and there would seem to be

88

TABLE VII

Summary of fhe effects of frontal lesions in infant monkeys and rats

Inferred function Monkey

1. Motor: (a) Loss of distal movements (b) poor execution of chains of complex movements

2. Response inhibition:

(a) impaired performance on learning tasks requiring changes in behavior

(b) Impaired performance on species-specific behaviors requiring behavioral inhibition

3. Temporal ordering: (a) difficulty in separating discrete trials

4. Spatial orientation: (a) poor performance on spatial learning tasks

5. Social and affective behavior: (a) abnormal social interaction

6. Behavioral spontaneity 7. Olfaction 8. Habituation 9. Activity

(a) hyperactivity 10. Homeostasis:

no sparing (209) ?

sparing (85)

7

sparing (86)

partial sparing (86)

partial sparing (72) ? 3 ‘1 7 ‘) ‘P ‘>

partial sparing (17,72) sparing (199. 144)

(a) reduced body weight (b) transient anorexia

sparing (72) sparing (72)

every reason to expect that the remaining factors are

important for predicting recovery in humans as well.

The apparent parallel between humans, monkeys

and rats regarding the general phenomena of sparing

following infant frontal lesions suggests that rats may

provide a good model for the study of reorganization

of cortical functions in primates with early brain inju-

ries. Further, since it now appears that removal of

the frontal cortex in infant rats124.130.13s.141 and mon-

key@ is associated with a series of abnormalities in

cortical morphogenesis, studies of the anatomical ef-

fects of early frontal cortical injury in rats may have

important clinical implications related to the surgical

treatment of early frontal lobe injury in humans.

6. DISCUSSION

My review of the literature has summarized the an-

atomical origin of the frontal cortex of the rat and has

identified the major behavioral changes observed

following frontal cortex lesions in rats. The compari-

sons between the effects of frontal cortex lesions in

rats, monkeys and humans have shown that the be-

havioral symptoms are remarkably similar. Recog-

nizing that other authors might group the behavioral

changes somewhat differently, I have compared the

Rat

no sparing (124) no sparing (14.5)

sparing (131)

no sparing (144)

sparing (131)

partial sparing (268, 199, 138)

sparing (129) sparing (129)

behavioral effects of frontal cortex lesions in rats to

those in monkeys and humans and have shown that

there is a striking similarity among the 3 species. I

conclude that in spite of the tremendous difference in

the relative volume of frontal neocortex in humans

versus the other species, and particularly rodents,

there appears to be a remarkable unity in frontal cor-

tex function across mammals. In order to consider

the possible bases for this functional similarity across

mammalian taxa I will first begin with a consideration

of a potential general function of the frontal cortex

that would likely be found in animals with a neocor-

tex.

Historically, claims about the functions of the fron-

tal lobes have been extravagant and extreme. From

the time of Gall until the 193Os, the frontal lobes

were thought by most to be the seat of highest intel-

lect. Functions as varied as ‘abstract behavior’, fore-

sight, intellectual synthesis, ethical behavior, affect

and self-awareness were proposed by a variety of

writers. Two discoveries were particularly influential

in challenging the prevailing view of frontal lobe

functions. First, Jacobsenl’Js described the dramatic

deficits in performance of delayed response tasks fol-

lowing large frontal removals in chimpanzees. Sec-

ond, Hebbl”” administered standard intelligence

89

tests to patients with frontal-lobe removals for treat-

ment of epilepsy, and found their IQ was not lowered

by frontal lobe lesions, and sometimes may actually

have been raised. These two studies led to a re-exam-

ination of frontal lobe function in non-human and hu-

man species, respectively, a re-examination that con-

tinues today.

Although a uniform consensus of prefrontal cortex

function has yet to be found, several important theo-

retical monographs have been published in the last 20 years27,73,147,217,219.220,228,251.252,260~

Each of these reviews has made significant and

novel points regarding frontal cortex functioning but

there is one idea that underlies most of the theories

and has recently been most thoroughly pursued by

Fustero. This view argues that, although there is un-

doubtedly heterogeneity in prefrontal function, there

is one overall function that characterizes the prefron-

tal cortex: it functions to provide flexibility and unity

in behavior by providing a kind of temporal structure

in which behavior is organized over time into a mean-

ingful whole. At first blush this type of argument ap-

pears overly broad and simplistic, but it does provide

a useful conceptualization from which to view the un-

derlying function of the prefrontal cortex. In order to

realize this type of argument, we need to consider the

nature of .a ‘behavior’. When describing behavior,

there is a tendency to describe it with English words

that describe the apparent purpose or function of the

behavior (e.g. grooming, maternal, spatial, etc.).

Such behaviors are obviously not a single entity,

however, but are better described as a collection of

units of movement that are joined together in time.

Further, a given ‘behavior’ may be composed of

many series of such units, much as a musical score is

composed of many sub-groupings of notes into

phrases or movements, and so on. In order for behav-

ior to be directed toward some ‘goal’, it is necessary

for these units of behavior to be integrated not only

within and between one another over time, but also

in response to the particular demands of the past and

current situations. Lashley stated this problem an-

other way in his now classic consideration of the

problem of serial ordering of behaviori57. How is it,

he asked, that a violinist can play an arpeggio so

quickly and flawlessly? Clearly, each note is not

‘thought’ of separately and yet the movements are in-

tegrated so precisely over time, and in relation to

what has been played previously by the musician, and

to what is being played by other musicians at the

same time.

The temporal control of movement requires at

least 5 components. First, there must be an ongoing

record of what movements are being produced by the

‘motor system’ at any given moment. Teuberzsz re-

ferred to this process as corollary discharge. The

principal idea here is that it is only with the knowl-

edge of what is ongoing that new units or series of

units can be initiated. For example, grooming move-

ments cannot be initiated until a rat has stopped

walking and assumed an ‘upright pattern’. Second,

there must be a record of those behaviors that are al-

ready executed. For example, if a rat attempts to pick

up food in its mouth when the mouth is full, it will be

unable to do so. Third, there must be inhibition of

some motor impulses and excitation of others in or-

der to produce appropriate behavioral sequences.

For example, in order to swim efficiently, rats inhibit

the movements of their forepaws and make large

strokes with their rear legs. Failure to properly inhib-

it and excite the appropriate systems will disorganize

the behavior. Fourth, behavior must be flexible with

respect to both the internal and external environ-

ment. Sexually related behaviors (darting, ear wig-

gling, lordosis, etc.) should be initiated by female

rats when they are receptive and when males are

present. Further, as Pribram and his colleagues have

nicely demonstrated (e.g. Brody and Pribram*s), be-

havior must be flexible to changes in the internal or

external environment. Thus, animals must be able to

adjust behavior when the context changes. For ex-

ample, for the rat swimming in the Morris water task,

spatial cues based upon body position in the swim-

ming tank are unreliable since the starting location

varies on each trial. To correctly solve the task the ani-

mal must disregard the unreliable information, focus-

ing instead upon those cues that predict the location

of the hidden platform. Similarly, when the frontal-

lobe patient must unexpectedly change strategy to

correctly solve a card sorting task, it is necessary to

generate a flexible response pattern in the face of

changing environmental demands. An inability to

show this flexibility results in a striking behavioral

impairment. Finally, there must be some monitoring

of the consequences of behavior. If food is found in

association with one particular series of movements,

90

but not with another, then the association between

movements and consequences needs to be made.

Whereas the principal of temporal organization of

behavior provides a basis for the unity in prefrontal

function, the necessary components for such a func-

tion provide a basis for the diversity in its function.

At the risk of grossly oversimplifying, it is possible to

distinguish the respective roles of the medial and ven-

tral subfields of the frontal cortex in the control of

movement. The medial cortex appears to have a spe-

cial role in the temporal ordering of movements in

the execution of complex chains of behaviors, espec-

ially if the movements require movement from one

place to another. Thus, medial frontal lesions in rats

disrupt behaviors that require a series of movements

in extrapersonal space as well as movements directed

towards places in space in which direction of move-

ment is dependent upon orientation to distal cues

(i.e. mapping strategy, see above). In contrast, the

ventrai frontal cortex appears to have a special role

in the initiation of movements at the correct time and

place, especially in relation to internal cues. Ventral

frontal lesions thus disrupt behavioral rhythms, feed-

ing, and responses to stimuli such as hunger. This

dorsal-ventral dichotomy is not restricted to rats but

as we have seen, it is also true of monkeys and proba-

bly humans (see Tables II, 111 and IV), and formed

the basis of Rosvold’s”i concept of frontal subsys-

tems.

This distinction between the functions of the frontal

subfields has emphasized the efferent role of the

frontal cortex but it is likely that the frontal cortex

has also a ‘sensory’ role. Indeed, the reliable deficits

in the perception of species-typical releasers such as

facial expressions in humansis”, visual and olfactory

nonspecific signals in catsI”‘, and olfactory stimuli in

rats63 imply that the frontal cortex does indeed play

some role in ‘sensory processing’. The intriguing idea

has been proposed that the specific subdivisions of

the prefrontal cortex of mammals may have evolved.

in part, as extensions of specific sensory pathway+.

To extend the argument further. the medial cortex in

the rat may be an extension of the visual, auditory,

tactile and kinesthetic systems, whereas the ventral

cortex in the rat may be an extension of the olfactory,

gustatory, and autonomic systems. The deficits in

spatial orientation and contralateral neglect from

medial lesions and altered feeding and olfactory-re-

lated behaviors from ventral lesions would seem con-

sistent with this interpretation.

7. SUMMARY

This review summarizes the anatomical and func-

tional organization of the frontal cortex of the rat in

comparison to primates. Lesions of the primary mo-

tor or of the prefrontal cortex of both primates and

rodents produce a consistent constellation of symp-

toms that are strikingly similar across species as di-

verse as rats and humans. Thus, in spite of the tre-

mendous difference in the relative volume of the

frontal cortex of mammals, as well as the obvious di-

versity of behavioral repertoires across mammalian

phylogeny, there appears to be a remarkable unity in

frontal cortex function across the class mammalia.

Hence, motor and prefrontal lesions produce analo-

gous alterations in motor control in rodents and pri-

mates even though humans walk upright and have

fine control of digit movement and rats walk on all

fours and have less dextrous control of distal move-

ments. Similarly, there are analogous changes in be-

haviors that can be labeled response inhibition, tem-

poral ordering, spatial orientation, social or affective

behavior, behavioral spontaneity. olfaction and ha-

bituation following prefrontal cortex lesions in both

primates and rodents. Finally, it is proposed that the

principal function of the prefrontal cortex of mam-

mals is the temporal organization of behavior.

This research was supported by a Natural Science

and Engineering Research Council of Canada grant

to the author. 1 wish to thank Brian Bland, Jill Beck-

er, Terry Robinson, Robert Sutherland, Richard

Tees, and Ian Whishaw for comments on an earlier

version of this paper and Adria Allen for typing.

91

LIST OF ABBREVIATIONS

A

AC, AC,

AI,

AI, AI,, AM B BL Ce

CL co F

FR G

H

HPC I

IL L La LD

LG, LG, LHa LO LP M

MD,

auditory cortex dorsal anterior cingulate cortex ventral anterior cingulate cortex dorsal agranular insular cortex posterior agranular insular cortex ventral agranular insular cortex

anterior medialis whisker barrels basolateral amygdala central medial nucleus

central lateral nucleus cortical amygdala somatosensory forelimb cortex

fasciculus retroflexus gelatinosus nucleus of thalamus

somatosensory hindlimb cortex

hippocampus insular cortex infralimbic cortex lateral nucleus lateral amygdala

lateral dorsal nucleus dorsal lateral geniculate nucleus ventral lateral geniculate nucleus lateral habenula lateral orbital cortex lateral posterior nucleus

motor cortex mediodorsal nucleus, central segment

Nomenclature from Jones and Leavittti3 and Krettek and Priceis

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