Table Of ContentTHE PREFRONTAL
CORTEX
Fourth Edition
Joaquín M. Fuster,md, phd
Semel Institute for Neuroscience and Human Behavior
David Geffen School of Medicine
University of California at Los Angeles
Los Angeles, California
AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD
PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
Acadamic Press is an imprint of Elsevier
Contents
Preface xi
1. Introduction 1
2. Anatomy of the Prefrontal Cortex 7
I. Introduction 7
II. Evolution and Comparative Anatomy 7
III. Development and Involution 12
IV. Microscopic Architecture 20
V. Connections 27
A. Afferents 28
B. Efferents 37
VI. Summary 42
References 44
3. Chemical Neurotransmission 59
I. Introduction 59
II. Development and Involution 63
III. Transmitters in the Prefrontal Cortex 65
A. Glutamate 66
B. GABA 68
C. Norepinephrine 70
D. Dopamine 75
E. Serotonin 85
F. Acetylcholine 87
G. Neuropeptides 90
IV. Neuropsychiatric Implications 91
A. Attention Disorders 92
B. Schizophrenia 94
C. Drug Abuse 98
vii
viii CONTENTS
D. Depression 101
E. Neurodegenerative Disease 102
V. Summary 103
References 105
4. Animal Neuropsychology 125
I. Introduction 125
II. Historical Background 126
III. Motility 127
A. Hyperactivity 127
B. Disinhibition 127
IV. Emotional Behavior 129
A. Basic Drives 130
B. Social Behavior 131
V. Cognitive Functions 133
A. Attention: Set 133
B. Discrimination Tasks: Inhibitory Control 135
C. Delay Tasks: Working Memory 138
Anatomical Factors 140
Sensory Factors 143
Spatial Factors 143
Temporal Factors 144
Memory Factors 146
Motor Factors 147
Inhibitory Factors 147
VI. Reversible Lesion 148
A. Prefrontal Cooling on Delay Tasks 150
VII. Development and Involution 153
VIII. Summary 155
References 156
5. Human Neuropsychology 171
I. Introduction 171
II. Historical Background 172
III. Affect, Emotion, and Social Behavior 174
A. Apathy 174
B. Depression 174
C. Euphoria 175
D. Motion and Emotion 175
E. Theory of Mind: Empathy 177
F. Social Behavior 177
IV. Executive Function 178
A. Attention 179
Alertness 180
Set 180
Spatial attention 181
Sustained attention 183
Interference Control 183
CONTENTS ix
B. Memory 184
C. Working Memory 185
D. Planning 187
E. Temporal Integration 189
F. Decision-making 190
G. Monitoring 192
H. Inhibitory Control 192
V. Language 193
VI. Intelligence 195
VII. Prefrontal Syndromes 196
A. Lateral 197
B. Orbital 198
C. Medial/Anterior Cingulate 199
VIII. Development and Involution 200
IX. Summary 205
References 208
6. Neurophysiology 221
I. Introduction 221
II. Historical Background 222
III. Sensory Function 223
IV. Motor Function 226
V. Visceral and Emotional Function 231
VI. Executive Functions 234
A. Attention 235
Expectancy 235
Set 237
B. W orking Memory 239
The Memorandum 240
The Delay: Persistent Neuronal Activity 243
The Choice 247
The Reward 250
C. Mechanisms of Working Memory 251
D. A nticipatory Activity 259
Motor Preparation 259
Rules 260
Reward Value 261
E. Monitoring 266
VII. Summary 267
References 270
7. Neuroimaging 285
I. Introduction 285
II. Functional Imaging: Value and Limitations 286
A. Spatial and Temporal Resolution 287
B. Functional Module or Functional Network 287
C. Interdependence of Cognitive Functions 288
x CONTENTS
III. Imaging Prefrontal Functions 289
A. Attention and Perception 290
B. Working Memory 292
C. Executive Set and Motor Control 301
D. Language 307
IV. Prefrontal Imaging in Neuropsychiatric Illness 310
A. ADHD 311
B. Schizophrenia 311
C. Obsessive-compulsive Disorder 313
D. Depression 314
E. Dementia 315
V. Summary 316
References 318
8. Overview of Prefrontal Functions: The Temporal Organization of Action 333
I. Conceptual Introduction 333
II. Hierarchical Organization of Cognitive Networks 336
A Perceptual Networks in Posterior Cortex 336
B. Executive Networks in Frontal Cortex 340
III. Frontal Action Domains 342
IV. Executive Functions 346
A. Executive Attention 346
Set 347
Working Memory 349
Interference Control 352
B. Planning 353
C. Decision-making 355
V. Emotional Behavior 356
VI. Temporal Organization of Action 357
A. The Perception–Action Cycle 358
Functional Anatomy of the Cycle 358
Temporal Integration 362
B. Language 368
C. Creative Intelligence 369
VII. Alternative Models 371
A. Modular Models 373
B. Network Models 374
VIII. On Consciousness and Free Will 376
IX. Summary 379
References 383
Index 387
C H A P T E R
1
Introduction
The cortex of the anterior pole of the complementing one another in the purpo-
mammalian brain is commonly designated sive behavior of the organism. These will
theprefrontal cortex. Its boundaries have been be outlined in a moment.
traced in various ways, depending on the T he term prefrontal cortex is easily assail-
methodology and criteria of defi nition. Yet, able on lexical grounds. In characterizing
whatever the demarcation, there are hardly the anterior part of the frontal lobe with the
any grounds for a priori regarding this part adjective prefrontal, we make loose, if not
of the cerebral cortex as a structural entity improper, use of the prefi x pre . Nevertheless,
with a unitary function. On morphological that designation has been condoned by so
grounds alone, the anatomical complexity much usage that it now seems unwarranted
of the prefrontal cortex, especially in higher to discard it for semantic reasons. At any
animals, makes its functional homogeneity rate, it is a more acceptable term than two
implausible. Indeed, the behavioral study of others frequently applied to the same part
animals with selective lesions of this cortex of the neocortex: frontal granular cortex and
rules out such homogeneity. Furthermore, a frontal association cortex. The former is based
unitary role for the prefrontal cortex is also on cytoarchitectonic features evident only
inconsistent with clinical fi ndings in patients in primates. The latter is weakened by the
with injuries to this part of the brain. Yet, at ambiguities of the word a ssociation , although
some level, as we shall see, there is certain in a certain sense, as we shall see, the pre-
synergy, if not unity, in prefrontal functions. frontal cortex can be legitimately considered
The precise nature of the apparently cortex of association. Finally, we should note
multiple functions of the prefrontal cor- two additional designations that also con-
tex is still to some extent unclear, and tain ambiguities. In primates the prefrontal
consequently the reviewer of the sub- cortex is commonly referred to simply as
ject is obliged to compile and attempt to frontal cortex, implicitly excluding the motor
relate many diverse and seemingly unre- and premotor cortex of the frontal lobe. In
lated facts. On close analysis, however, rodents and carnivores the prefrontal cortex
the facts can be seen to fall in a sensible has also been called orbitofrontal cortex, a
order. A wealth of experimental evidence term likely to be confused with that of orbital
now indicates that the basic functions of frontal cortex, which in primates applies only
the prefrontal cortex are essentially few to one part of the prefrontal cortex – that of
and represented over the cortical surface the ventral aspect of the frontal lobe.
according to a certain topological pattern. P refrontal cortex is defi ned here as the
Most importantly, these functions seem part of the cerebral cortex that receives pro-
interrelated, mutually supporting and jections from the mediodorsal nucleus of
1
2 1. INTRODUCTION
the thalamus. This anatomical defi nition is the model have gained strength and accepta-
applicable to all mammalian brains. It takes bility, despite some changes in terminology.
into consideration the possibility that the Now, before a brief outline of my ideas
relationship with a well-defi ned thalamic concerning the functions of the prefrontal
nucleus refl ects an identifi able function or cortex, a disclaimer of originality is again
group of functions. Of course, such reason- necessary. Surely, those are ideas that oth-
ing is based on analogy with specifi c tha- ers have expressed before in one form or
lamic nuclei and their cortical projection another, though perhaps referring only to
areas, an analogy that may not be entirely a part of the prefrontal cortex, to a particu-
appropriate. Furthermore, the functions lar cognitive function, or form of behav-
of the mediodorsal nucleus are not well ior, in one or another animal species. My
known, and the prefrontal cortex is also principal endeavor has been to synthesize
connected to many other cerebral struc- a vast amount of prior empirical evidence
tures. On the other hand, the defi nition by into a general construct that has empiri-
relationship has the merit of implying a cally testable components and corollaries.
reasonable principle: the physiology of a Thus, my original construct of prefrontal
cortical region can be meaningfully studied functions, shaped as it was by both induc-
and understood only in the context of its tive and deductive reasoning, remains alive
anatomical connections with other struc- though subject to refi nement, especially
tures ( Creutzfeldt, 1977) . Nevertheless, in with regard to the n eural mechanisms behind
primate studies the use of the cytoarchitec- those functions.
tonic criterion is sometimes more practical T he entirety of the frontal cortex, includ-
than that of the connectivity criterion; the ing its prefrontal region, is “ action cortex ”
two are equally valid, at least inasmuch as in the broadest terms. It is cortex devoted
the frontal granular cortex is the part of the to action of one kind or another, whether
neocortex receiving afferent connections skeletal movement, ocular movement, the
from the mediodorsal nucleus. expression of emotion, speech, or visceral
W e shall examine the topic of this book, control; it can even be the kind of internal,
the prefrontal cortex, by systematically mental, action that we call reasoning. The
reviewing data from each of the contribut- frontal cortex is “ d oer” cortex, much as the
ing methodologies. The reader will note posterior cortex is“ sensor ” cortex. Most cer-
that, as the review proceeds from the basic tainly, however, the frontal cortex does noth-
facts of anatomy to neuroimaging, my con- ing by itself; all it does is in cooperation with
ceptual point of view will become progres- other cortices, with subcortical structures,
sively more explicit. In any event, there now and with certain sectors of the sensory and
appear to be more reasons to support that motor apparatus and of the autonomic sys-
point of view, as it is formally presented in tem. Surely also, there is considerable spe-
the last chapter, than there were twenty- cialization of action within the frontal cortex
eight years ago, when the fi rst edition of (action domains ). Thus, there are in it areas
this book was published. Of course, since for eye movement, for skeletal movement
that time some of my ideas have changed of various body parts, for speech, for emo-
in the face of confl icting empirical evidence; tional expression, etc., though there is also
however, the main ones have survived, considerable functional cooperation between
and today they seem even more plausible them. More importantly for what concerns
than they did in 1980. A theoretical model us here, the specialized areas within the pre-
is as good as the means to prove it right or frontal cortex, whatever their action domain
wrong, and in recent years the means to do may be, contribute their share to the com-
it with my model have become ever more mon cognitive and emotional functions that
accessible. As a result, substantial parts of characterize this part of the neocortex as a
1. INTRODUCTION 3
whole. Those functions are essentially inte- of the competitive interference – a source of
grative and goal-directed. uncertainty and ambiguity – between two
As organisms evolve, their actions alternative cues that succeed each other at
become more complex and idiosyncratic, random from one trial to the next.
their goals more remote in space and time, T ime, however, is the single most impor-
and their reasons or motives for attaining tant attribute placing a complex and novel
them more covert, less transparent, more sequence of behavior under the physiologi-
based on prior experience than on peremp- cal purview of the lateral prefrontal cortex.
tory instinctual need. Furthermore, action in Only this part of the cerebral cortex can pro-
general becomes more deliberate and volun- vide that“ temporal gestalt ” with the coher-
tary. With this evolution of biological action, ence and coordination of actions that are
and presumably because of it, the most essential for the organism to reach its goal.
anterior sector of the frontal cortex, which Both coherence and coordination derive
we defi ne as the prefrontal cortex, grows from the capacity of the prefrontal cortex
substantially – in relative size – as evolu- to organize actions in the time domain , which
tion progresses, and so does its functional in my view is the most general and charac-
role. In both respects, growth reaches its teristic of all prefrontal functions in the pri-
maximum in the human primate. The phy- mate (Fuster, 2001). The importance of this
logenetic growth of the cortex of the frontal temporal organizing function in mamma-
lobe, however, is not uniform. Thus, the pre- lian behavior cannot be overstated. Without
frontal cortex of the lateral or outer frontal it, there is no execution of new, acquired,
convexity, which is essential for cognitive and elaborate behavior, no speech fl uency,
functions and intelligent behavior, under- no higher reasoning, and no creative activity
goes greater development than that of the with more than minimal temporal dimen-
medial and inferior (orbital) surfaces, which sion; only temporal concreteness is left, the
is critically involved in emotional behavior. here and now, in anything but instinctual
Though their functions are interdependent sequence or automatic routine.
and to some degree integrated in the behav- All cortical functions take place on a neu-
ior of the organism, lateral and orbitomedial ral substrate of representation, that is, on a
prefrontal cortices require somewhat differ- neuronal repository of permanent, though –
ent methodologies for their study. by experience – modifi able, long-term mem-
Any series of purposive actions that ory. The functions of any area of the cortex
deviates from rehearsed automatic routine make use of whatever part of that memory
or instinctual order necessitates the func- substrate that area stores, which is the infor-
tional integrity of the lateral prefrontal mation contained in the neuronal networks
cortex. The longer the series, the greater of the area. That information is defi ned by
is the need for that cortex. Time is only the neuronal constituents of those networks
one factor, however, among those deter- and by the connections between them. In
mining that need; other factors include any event, the study of the physiological and
the complexity and novelty of the actions cognitive operations of any cortical region
and of the information on which they are must take into account its representational
based, and still another the uncertainties or substrate. The representational substrate
ambiguities in that information. There is of the prefrontal cortex, in particular its lat-
considerable trade-off between those fac- eral sector, is made of networks of e xecutive
tors. For example, a monkey with prefrontal memory , which extend into other cortical
defi cit may fail at a simple and thoroughly areas and have been formed by prior expe-
rehearsed task, such as delayed response, rience. The executive functions or operations
not only because of the interval of time of the prefrontal cortex essentially consist
between cue and response, but also because of the utilization of that substrate (a) for the
4 1. INTRODUCTION
acquisition of further executive memory and Working memory is the kind of active
(b) for the organization of behavior, reason- memory, i.e., memory in active state, which
ing, and language. the animal needs for the performance of
My use of the preposition f or , in the last acts in the short term. This is why it is often
sentence above, points by itself to the cen- called also “ short-term memory. ” It is not
tral position of teleology in the physiology to be confused, however, with short-term
of the prefrontal cortex. As we all know, memory as the precursor stage of long-
teleology is anathema in the scientifi c dis- term memory. According to the “ dualis-
course, if nothing else because it blatantly tic ” concept of memory, before memories
defi es the logic of causality. Yet in the dis- become established they pass through a
course on prefrontal physiology, g oal is of short-term store. In any case, that concept,
the essence. All cognitive functions of the which is based on the assumption of sepa-
lateral prefrontal cortex are determined, rate neural substrates for the two forms of
we might say “ caused, ” by goals. If there memory, is gradually being replaced by a
is a unique and characteristic feature better supported unitary view of memory
of that part of the brain, it is its ability to with a common cortical substrate. In accord
structure the present in order to serve the with this view, working memory is the
future, by this apparently inverting the temporary activation of updated long-term
temporal direction of causality. Of course, memory networks for organizing actions in
this inversion is not real in physical terms. the near term.
It is only real in cognitive, thus neural, The content of working memory may
terms inasmuch as the representations of the be sensory, motor, or mixed; it may consist
goals of future actions antecede and cause of a reactivated perceptual memory or the
those actions to occur through the agency motor memory of the act to be performed,
of the prefrontal cortex. Teleology thus or both. It may also consist of the represen-
understood is at the basis of planning and tation of the cognitive or behavioral goal
decision-making, which are two of the major of the act. Inasmuch as the content is selec-
executive functions of the prefrontal cortex. tive and appropriate for current action,
A third major prefrontal function is exec- working memory is practically inextricable
utive attention, which in many respects, as from attention. In fact, working memory
we will see, is indispensable to the fi rst two: is essentially sustained attention focused
planning and decision-making. Executive on an internal representation. In primates,
attention has three critical components, all working memory, depending on its content,
three direct participants in the goal-directed engages a portion of lateral prefrontal cor-
temporal organization of action: (1) working tex and, in addition, related areas of poste-
memory, (2) preparatory set, and (3) inhibi- rior (i.e. postcentral, postrolandic) cortex.
tory interference control. All three have The selective activation of posterior cortical
somewhat different though partly overlap- areas by the prefrontal cortex, in that proc-
ping frontal topographies and a different ess of internal attention that we call working
cohort of neural structures with which the memory, is a major aspect of the neural basis
prefrontal cortex cooperates to implement of what has been called “ cognitive control ”
them. Strictly speaking, none is localized in ( Miller and Cohen, 2001) .
this cortex, but all three need their prefron- Preparatory set is the readying or priming
tal base to operate. The prefrontal cortex of sensory and motor neural structures for
performs its executive control of temporal the performance of an act contingent on a
organization by orchestrating activity in prior event, and thus on the content of the
other neural structures that participate in working memory of that event. Set may be
executive attention. rightfully viewed as “ motor attention. ” In
