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Placebo Effects
Placebo Effects
Understanding the Other Side of Medical Care
Third Edition
FA B R I Z IO B E N E D E T T I , M D
Professor of Neurophysiology and Human Physiology
University of Turin Medical School, Neuroscience Department, Turin, Italy
Director of Medicine & Physiology of Hypoxia,
Plateau Rosà, Italy/Switzerland
1
3
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries
© Oxford University Press 2021
The moral rights of the author have been asserted
First Edition published in 2009
Second Edition published in 2014
Third Edition published in 2021
Impression: 1
All rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted, in any form or by any means, without the
prior permission in writing of Oxford University Press, or as expressly permitted
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rights organization. Enquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above
You must not circulate this work in any other form
and you must impose this same condition on any acquirer
Published in the United States of America by Oxford University Press
198 Madison Avenue, New York, NY 10016, United States of America
British Library Cataloguing in Publication Data
Data available
Library of Congress Control Number: 2020941678
ISBN 978–0–19–884317–7
DOI: 10.1093/oso/9780198843177.001.0001
Printed and bound by
CPI Group (UK) Ltd, Croydon, CR0 4YY
Oxford University Press makes no representation, express or implied, that the
drug dosages in this book are correct. Readers must therefore always check
the product information and clinical procedures with the most up-to-date
published product information and data sheets provided by the manufacturers
and the most recent codes of conduct and safety regulations. The authors and
the publishers do not accept responsibility or legal liability for any errors in the
text or for the misuse or misapplication of material in this work. Except where
otherwise stated, drug dosages and recommendations are for the non-pregnant
adult who is not breast-feeding
Links to third party websites are provided by Oxford in good faith and
for information only. Oxford disclaims any responsibility for the materials
contained in any third party website referenced in this work.
For Claudia and Federica, with affection and love.
Preface to the Third Edition
The incredible increase in placebo research since the Second Edition of this book has re-
quired an update of many topics related to placebo effects, from neuroscience to the clinic
and from physical performance to ethics. There is, however, a second reason why I decided to
write this Third Edition: over the past few years placebo effects have been regarded not only
from the strict biomedical perspective but they have also been placed into a broader context,
embracing evolution, biology, and the doctor–patient relationship. Accordingly, Oxford
University Press and I decided to merge my two books, Placebo Effects and The Patient’s Brain
(both by Oxford), in a single volume, with the ambitious objective to discuss placebo effects
under a broader and intriguing light, from evolution to the clinic and the therapist–patient
encounter.
As already specified in my Preface to the Second Edition, this book was very well received
by scientists, physicians, psychologists, sociologists, philosophers, and students. Indeed,
there was the need for a book of this kind, in order to improve the description of what pla-
cebo effects are, how they work, and what their meaning is within the clinical context and
more, in general, within the modern biomedical paradigm. This has originated a true science
of placebo, whose study today represents a melting pot of concepts and ideas for neurosci-
ence, ranging from a reductionist to a more integrated approach. I am delighted that many
medical schools, nursing schools, and psychology courses are using this book for teaching
and I am particularly happy that now students and scholars can learn something more about
placebo effects while they are also studying medical and psychological skills and practice.
Within this context, placebo effects represent the hidden and less explored side of medical
care, and this new knowledge needs to be integrated with the knowledge of the classical ma-
teria medica.
In order to comply with the many needs and requests from the many readers, I strongly
believe that merging my previous two books, Placebo Effects and The Patient’s Brain into
a single one, helps improve our understanding of placebo effects from different points of
view. Accordingly, this Third Edition is subdivided into six parts. The first part sets the stage
for and paves the way to a better understanding of placebo effects; it discusses some evolu-
tionary aspects of medical care as well as the neuroscience behind the doctor–patient re-
lationship, thereby preparing the reader firmly to grasp the profound meaning of placebo
effects in medical practice. The second, third, and fourth parts go into the depth of the de-
scription of placebo effects, starting from some general principles and continuing with the
systematic description of placebo effects across different medical conditions. The fifth part
discusses some clinical, ethical, and methodological considerations, whereas the sixth part
goes beyond the healing context, facing some interesting and intriguing issues, ranging from
physical performance and sport to social psychology of everyday life. I hope I was able to
achieve all these goals.
Fabrizio Benedetti
Turin and Plateau Rosà
May 2020
Preface to the First Edition
The progress of modern medicine basically resides in the advancement of anatomy, physi-
ology, molecular biology, and, more in general, a better knowledge of how molecules, cells,
and tissues behave and interact with each other. Within this context, the modern physician
has many effective tools to hand to treat and prevent diseases, from pharmacology to gen-
etic therapy and from physical intervention to surgery. In addition to this materia medica,
the patient’s mind, emotions, and beliefs also matter and play a central part in any therapy,
as emphasized and investigated by different biomedical disciplines like psychosomatics and
psychoneuroimmunology.
With this book on placebo and placebo-related effects, I want to give scientific evidence
to the old tenet that patients must be both cured and cared for. Curing the disease only is not
always sufficient and care of the patient must often be careful and appropriate, as in many
circumstances the patient’s mind really matters. However, maybe paradoxically, anatomy,
physiology, cells, and molecules are all crucial to understand this psychological aspect of
the therapy. In fact, today we know that placebo effects are mediated by many molecules in
the brain which, in turn, may affect the course of a disease and the response to a treatment.
Therefore, this is a biological book which emphasizes the importance of the psychological
component of a therapy by using the same biological tools of the materia medica.
Many misunderstandings and misconceptions about the placebo effect have permeated
the history of medicine. Perhaps the most common resides in its very definition. The in-
appropriate use of the words ‘placebo effect’ and ‘placebo response’ has pervaded the medical
literature for many years, and even today these terms are sometimes confused with other
phenomena. In clinical trials, for example, several authors continue to coin the terms ‘pla-
cebo effect’ or ‘placebo response’ incorrectly when they want to describe the therapeutic out-
come in those groups of patients who received a placebo (an inert treatment). Indeed, the
common and widespread use of ‘placebo effect’ and ‘placebo response’ refers to the outcome
in placebo groups, without considering that many factors are responsible for the reduction of
a symptom when patients take a placebo. Therefore, what most studies deal with when they
talk about placebo effects and placebo responses is actually a complex set of phenomena that
are responsible for the clinical improvement.
For example, when a group of patients takes a placebo and improves, this can be due to the
spontaneous remission of the disease or symptom, to the effects of a co-intervention, to the
biases of the patient who wants to please his doctor, or to a real neurobiological placebo re-
sponse whereby a brain network anticipates a clinical benefit and acts on some physiological
functions. Therefore, when describing the outcome in a placebo group, we must not talk
about ‘the placebo effect’, or ‘the placebo response’ but rather about the improvement that
occurs in the group of patients who received the placebo. Indeed, throughout this book I will
use these definitions carefully in order to clearly distinguish between real neurobiological
placebo effects on the one hand, and improvements in placebo groups attributable to other
factors on the other.
Throughout this book, it will appear clear that a real placebo effect is not spontaneous
remission or the effect of a co-intervention, or the patients’ biases. The placebo effect is a
real psychobiological phenomenon whereby the brain is actively involved and anticipates a
x Preface to the First Edition
clinical benefit. Therefore, this book strives to make it clear that when we study the placebo,
we are actually studying how the brain anticipates an event in the clinical setting.
Another common misunderstanding about the placebo effect is that there is only one
placebo effect. Actually, there is not a single placebo effect but many (Benedetti 2008). The
brain may anticipate a clinical benefit through different mechanisms, such as expectation of
a reward or expectation that reduces anxiety, as well as classical conditioning, and this may
occur in different systems and apparatuses of the body. Therefore, if the main mechanism of
a given placebo effect is reward, one is actually studying reward mechanisms. Likewise, if the
main mechanism is classical conditioning, one is actually studying Pavlovian conditioning.
This is the principal reason why the title of this book refers to the plural (placebo effects).
In recent times, it has also emerged that the term ‘placebo effect’ is too restrictive and
should be extended to related phenomena which share similar mechanisms. Thus, as de-
scribed throughout this book, besides classical placebo effects, today we can describe several
placebo-related effects, the latter being characterized by the fact that no placebo is adminis-
tered. In fact, by adopting a strict definition, the placebo effect follows the administration of
a placebo. If no placebo is given, we cannot call it a placebo effect. I believe that these strict
definitions help us in a number of ways. First, they remind us what a placebo and a pla-
cebo effect are exactly. Second, they underscore that it is not always necessary to administer
a placebo to obtain a therapeutic effect, as sometimes the doctor’s words and attitudes are
enough. Third, these definitions remind us that the psychosocial context can produce thera-
peutic effects in a variety of ways, regardless of the administration of a placebo.
During the many courses I teach at my university, from physiology to neuroscience,
from pain pathophysiology to pain management, and from clinical trials methodology to
the patient–provider interaction, I strive to make the students aware of the placebo phe-
nomenon. Unfortunately, what I have found thus far is only a very limited understanding
and a very restricted usage of the word placebo. What students know about placebos and
placebo effects, from those in the medical schools to those in the nursing schools and to
those in more advanced courses (neurology, surgery, anaesthetics, and such like), is their
use in double-blind clinical trials and its importance in evidence-based medicine, whereby
effective treatments must work better than placebos.
On the basis of these considerations, many years ago I started talking of placebos in more
detail during my lessons to students and to doctors of any kind, until I took the decision to
write this book. I soon realized the difficulty of teaching medical students, and even doctors,
that placebo effects often play a part in treatment. Therefore, this book is directed at medical
students, doctors of every kind, nurses, psychologists, and psychotherapists as well as to all
those neuroscientists and biologists who are interested in understanding the biological link
between a complex mental activity and the body. In other words, this book does not talk of
the most known aspects of placebos and placebo effects, such as clinical trials methodology
and designs, but rather it talks of what is less known about placebos—its psychobiological
aspects and mechanisms.
In an interesting article that was published in 1972 in the Lancet, Blackwell and colleagues
(1972) proposed an experiment to be performed in a class of medical students. With its intri-
guing title ‘Demonstration to medical students of placebo responses and non-drug factors’,
this article is a classic experiment in which medical students participate in a simulation of
a clinical trial that tests the sedative effects of blue capsules (actually a placebo that the stu-
dents believe to be a sedative) and the stimulant effects of pink capsules (a placebo believed
to be a stimulant). I believe demonstrations like this should be more common in medical
schools.
Preface to the First Edition xi
The widespread use of the word placebo in the medical literature, and its use in many
experimental procedures, is evidence of the importance of this phenomenon in modern
biomedical sciences. If one considers the modern clinical approach of evidence-based medi-
cine, which basically relies on the superiority of a treatment over a placebo, the central role of
the placebo emerges even more. Thus the knowledge of placebo effects is essential in modern
medicine, and the crucial questions to be answered are ‘where’, ‘when’, and ‘how’ placebo ef-
fects work. I believe that these questions are worthy of intense scientific scrutiny as they will
lead to fundamental insights into human biology. And, in particular, I hope this book may at
least partially answer some of these questions.
At the beginning of each chapter there is a list of summary points, which are key learning
points; and at the end of each chapter there is a list of points intended to stimulate further
discussion and give an idea of possible future lines of research. I hope these points are of
particular help to readers using this book as a textbook in medical school or studying psych-
ology courses.
References
Benedetti F (2008). Mechanisms of placebo and placebo-related effects across diseases and treat-
ments. Annual Review of Pharmacology and Toxicology, 48, 33–60.
Blackwell B, Bloomfield SS, and Buncher CR (1972). Demonstration to medical students of placebo
responses and non-drug factors. Lancet, 1, 1279–82.
Acknowledgements
I started working on the placebo effect in 1994 and this topic has been for me a fascinating,
challenging, and fertile field of research for many years. Despite the many travels and visits to
foreign institutions, the University of Turin Medical School has been my professional home
for all these years. More recently, I have also been affiliated to the Medicine and Physiology
of Hypoxia at Plateau Rosà in Switzerland, where all my work on oxygen, pain, fatigue, and
physical performance has been conducted. Therefore, I want to thank all my colleagues from
my home institutions who helped and supported me in a number of ways.
In particular, I owe a great debt to Piergiorgio Strata who was for me one of the best ad-
visers and friends, after being an excellent mentor when I was a medical student more than
30 years ago, as well as to Piergiorgio Montarolo, who was partially responsible for the acqui-
sition of my technical skills and for my scientific growth.
Special thanks to all my collaborators who helped me in planning and doing the experi-
ments, analysing the data and interpreting the results. They are: Luana Colloca, Martina
Amanzio, Antonella Pollo, Sergio Vighetti, Elisa Carlino, Elisa Frisaldi, Alessandro
Piedimonte, Diletta Barbiani, Eleonora Camerone, Bruno Bergamasco, Leonardo Lopiano,
Michele Lanotte, Elena Torre, Giovanni Asteggiano, Innocenzo Rainero, Giuliano Maggi,
Catherine Blanchard, Wilma Thoen, Sara Dogue, Jennifer Durando, and Rosalyn Sodaro.
Many colleagues from around the world also helped in many ways, both directly and in-
directly. For example, I will never forget the wonderful experience during the years 2002 to
2004 spent with the ‘Placebo Group’, organized by Anne Harrington as part of the program of
the Harvard University Mind–Brain–Behaviour Initiative. This was one of the most exciting
academic experiences I have ever had, thus I want to thank all members of that group for the
excellent discussions and stimulating exchange of ideas: thanks to Anne Harrington, Dan
Moerman, Howard Fields, Nick Humphrey, Jamie Pennebaker, and Ginger Hoffman.
I would like to mention the many invitations I have had from Stephen Strauss and Linda
Engel of the US National Institutes of Health during the years 2000 to 2004 to discuss and
plan future projects and strategies for a better understanding of the placebo effect. Another
more recent intellectual collaboration with Manfred Schedlowski and Paul Enck, who
stimulated me to co-organize an exciting meeting on placebo and nocebo effects in Tutzing,
Germany, in 2007 and in Tübingen, Germany, in 2013, and with Damien Finniss, Don Price,
Ron Kupers, and Serge Marchand, with whom I co-organized another placebo meeting in
Copenhagen further boosted my desire to publish this book. I also want to highlight the in-
tellectual discussions with Ted Kaptchuk and Jian Kong, who helped me generate new ideas
and hypotheses. I want to thank them all and I apologize if I forget someone.
Finally, my family was crucial in helping me get this book done—both my wife Claudia
and my daughter Federica. My wife has contributed with her continuous, lovely support as
well as in choosing, classifying, and organizing the figures and revising the references. My
daughter has always kept me smiling and has helped me in the first chapters with the diffi-
cult topics of anthropological archaeology and cognitive archaeology while studying at the
University of York. Indeed, she wrote Box 1.1 and Box 7.2.
Contents
List of boxes xxv
1 . T H E PAT I E N T ’ S B R A I N : SE T T I N G T H E S TAG E F O R
U N D E R S TA N D I N G P L AC E B O E F F E C T S
1. A brief evolutionary account of medical care 5

Summary points 5
1.1 Simple organisms can take care of themselves 6
1.1.1 Unicellular organisms use simple strategies to protect themselves 6
1.1.2 The withdrawal reflex is present in both invertebrates and vertebrates 7
1.2 From the scratch reflex to grooming 8
1.2.1 The scratch reflex is a simple purposive behaviour 8
1.2.2 Grooming involves a complex behavioural repertoire 11
1.3 Scratching somebody else: a big evolutionary jump to social behaviour 13
1.3.1 Primates spend plenty of time in social grooming 13
1.3.2 From social grooming to altruistic behaviour 14
1.4 Taking care of the sick 17
1.4.1 From early forms of altruism to the emergence of the shaman 17
1.4.2 More rational treatments emerge slowly from prehistoric to
historic medicine 20
1.5 Points for further discussion 21
2. Emergence and development of scientific medicine 24

Summary points 24
2.1 Emerging knowledge and the problem of animal experimentation 25
2.1.1 Scientific medicine requires basic anatomical and physiological
knowledge 25
2.1.2 Acquiring new medical and surgical skills 27
2.1.3 Effective treatments need not be understood but they do
need validation 31
2.1.4 Animal research impacts negatively on most people and raises
many ethical concerns 34
2.2 Biological, psychological, and social factors all contribute to illness
and healing 37
2.2.1 Modern scientific medicine includes a psychosocial component 37
2.2.2 Medical concepts vary across cultures but the psychosocial component
stays the same 40
xvi Contents
2.3 Medical practice meets neuroscience 43

2.3.1 Scientific medicine needs to include the study of the patient’s and
doctor’s brain 43
2.3.2 To become and to be a patient involve four steps and relative
brain processes 43
3. Feeling sick: a combination of bottom-up and top-down events 49

Summary points 49
3.1 The patient feels sick through both bottom-up and top-down processes 50
3.1.1 What is a symptom? 50
3.1.2 Detection of a symptom is a combination of interoception and
other factors 51
3.1.3 Different brain regions respond to interoceptive stimuli 53
3.1.4 The insula plays a crucial role in awareness 55
3.1.5 Interoceptive awareness undergoes a top-down modulation 57
3.2 Bottom-up and top-down processes contribute to the global experience
of pain 58
3.2.1 Pain experience is built up from the periphery to the central
nervous system 58
3.2.2 There is not a single pain centre but a distributed system 61
3.2.3 Pain experience changes across individuals and circumstances 64
3.2.4 A complex neural network is responsible for the top-down modulation
of pain 66
3.3 Emotions influence the perception of symptoms 68
3.3.1 Feeling sick does not necessarily mean physical suffering 68
3.3.2 Positive and negative emotions are processed in the limbic system 69
3.3.3 Anxiety about pain activates brain circuits that increase the pain 70
3.3.4 Anger and depression influence pain perception 75
4. Seeking relief: the activation of motivational and reward circuits 88

Summary points 88
4.1 Suppressing discomfort and seeking pleasure 89
4.1.1 Motivation is aimed at regulating internal states and at getting a reward 89
4.1.2 Suppressing discomfort from hunger, thirst, and thermal variations 91
4.1.3 Seeking the pleasure of sex 92
4.1.4 Reward-seeking behaviours involve the mesolimbic dopaminergic system 94
4.2 Suppressing discomfort from sickness 97
4.2.1 Seeking relief from sickness is a motivated behaviour 97
4.2.2 Motivated behaviour varies according to cultural differences 98
4.2.3 The motivation/reward system is activated when seeking and
expecting relief 99
Contents xvii
5. Meeting the therapist: a look into trust, hope, empathy, and compassion
mechanisms 106
Summary points 106
5.1 Trusting the therapist 107
5.1.1 Trust in doctors can be measured 107
5.1.2 The amygdala is a key region in trustworthiness decisions 109
5.1.3 Oxytocin enhances trust 114
5.1.4 Admiration for virtue and for skills involves two separate neural systems 117
5.2 Sensory inputs can make the difference 118
5.2.1 Subtle differences in verbal communication may lead to different
outcomes 118
5.2.2 Visual stimuli are the basis for nonverbal communication 119
5.2.3 Being touched by a beloved one makes the pain more bearable 125
5.3 The patient wants the future to be better than the present 127
5.3.1 Hope and hopelessness may impact on health 127
5.3.2 Hopelessness/helplessness involve serotonergic and noradrenergic
systems 130
5.4 A look into the doctor’s brain 131
5.4.1 Face expressions of pain are likely to have evolved for eliciting
medical attention from others 131
5.4.2 Empathy and compassion have different meanings and mechanisms 132
5.4.3 There are two different neural systems for empathy 133
5.4.4 Compassion for social and physical pain engages two separate
neural systems 136
5.4.5 Doctors can regulate their emotional responses to others’ suffering 137
5.5 The doctor-patient interaction may have both positive and negative effects 139
5.5.1 A positive interaction may lead to positive outcomes 139
5.5.2 A negative interaction may lead to negative outcomes 142
5.6 Pain can be made a positive experience 143
6. The brain of the demented patient 155

Summary points 155
6.1 Many patients cannot communicate their discomfort 155
6.1.1 Who cannot communicate? 155
6.1.2 Dementia is a major medical problem 156
6.2 How the demented patient feels sick 158
6.2.1 The lateral and medial pain systems are affected differently in
Alzheimer’s disease 158
6.2.2 Vascular dementia may be associated to hyperalgesia 165
6.2.3 Frontotemporal dementia leads to reduced pain responses 166
6.3 The demented patient cannot seek relief 167
6.3.1 Purposive behaviour is impaired in dementia 167
6.4 The demented patient meets the therapist 168
6.4.1 There is no real interaction between the demented patient and the doctor 168
xviii Contents
2 . P L AC E B O E F F E C T S : G E N E R A L C O N C E P T S
A N D M E C HA N I SM S
7. The traditional concept of placebo 175

Summary points 175
7.1 The origin of the placebo concept and methodology 175
7.1.1 Many bizarre ineffective therapies were developed over the past centuries 175
7.1.2 When doctors became aware of the ineffectiveness of many therapies 178
7.1.3 The traditional concept of placebo effect is a first source of confusion 179
7.2 The placebo in clinical trials and medical practice 181
7.2.1 Placebos are the tenet of the randomized double-blind
placebo-controlled trial design 181
7.2.2 Placebos may be used with other experimental designs 182
7.2.3 Placebos are widely used in routine medical practice 186
7.2.4 Psychologists consider the placebo effect as an example of the
power of mind 187
8. A modern view of placebo and placebo-related effects 193

Summary points 193
8.1 What they are not 194
8.1.1 Many phenomena are mistakenly taken for placebo effects 194
8.1.2 Spontaneous remission is frequently and erroneously defined
as placebo effect 194
8.1.3 Regression to the mean is common in clinical trials 197
8.1.4 Signal detection ambiguity can sometimes explain symptom ‘reduction’ 197
8.1.5 Sometimes patients and doctors give biased reports of the
clinical condition 199
8.1.6 Co-interventions can sometimes be the cause of improvement 199
8.1.7 Classical clinical trials are not good for understanding placebo effects 200
8.2 What they are 203
8.2.1 Is the placebo effect different from the placebo response? 203
8.2.2 The psychosocial context around the therapy is the crucial factor 204
8.2.3 Placebo and nocebo effects occur when inert treatments are given 209
8.2.4 Placebo-and nocebo-related effects do not involve the administration
of inert treatments 210
8.2.5 Are subjective outcomes different from objective outcomes? 211
8.3 How they work 212
8.3.1 There is not a single placebo effect but many 212
8.3.2 Expectation of a future outcome is one of the principal mechanisms 213
8.3.3 The placebo effect is a learning phenomenon 216
8.3.4 Some personality traits may be associated with placebo responsiveness 221
8.3.5 Genetics may affect placebo responding 222
8.3.6 Other possible explanations have been proposed 224
8.3.7 Placebo effects are also present in animals 225
8.3.8 What is the difference between placebo responders and non-responders? 226
Contents xix
8.4 Why they occur 227

8.4.1 Expectation-mediated placebo effects may be related to other
self-regulatory processes 227
8.4.2 Are placebo and placebo-related effects a product of evolution? 229
8.4.3 Open-label placebos: why are they effective? 231
8.4.4 Do placebo effects occur on pre-existing nocebo effects? 232
9. Placing placebo effects within the context of the doctor–patient
relationship as a defence mechanism 244
Summary points 244
9.1 A variety of defence mechanisms are present in living organisms 245
9.1.1 Cells respond to invaders and to damage 245
9.1.2 Living organisms protect themselves from a variety of dangers 247
9.2 Defence mechanisms can also involve cultural and social aspects 248
9.2.1 Thermoregulation as an example of physiological and
cultural mechanism 248
9.2.2 Social groups can be advantageous to health in a number of ways 249
9.3 The doctor–patient interaction is a social mechanism of defence 250
9.3.1 The system works regardless of effective therapies 250
9.3.2 Why does the system work this way? 252
9.3.3 The doctor himself belongs to the system 253
3 . D I SE A SE - B A SE D C L A S SI F IC AT IO N O F P L AC E B O E F F E C T S :
M O S T S T U D I E D C O N D I T IO N S
10. Pain 259

Summary points 259
10.1 Placebo analgesia 259
10.1.1 Placebo analgesia is the most studied type of placebo effect 259
10.1.2 Many factors influence the magnitude of placebo analgesia 260
10.1.3 Expectations of improvement may lead to analgesia 265
10.1.4 Painkillers are much less effective when administered covertly 267
10.1.5 Placebo analgesia is today the best model for studying endogenous
mechanisms of analgesia 269
10.1.6 Some types of placebo analgesia are mediated by endogenous opioids 270
10.1.7 Some types of placebo analgesia involve the endocannabinoid system 275
10.1.8 Placebo analgesia is related to a reward dopaminergic system 277
10.1.9 Imaging the brain during placebo-induced expectations of analgesia 277
10.1.10 No prefrontal control, no placebo response 281
10.2 Nocebo hyperalgesia 282
10.2.1 Expectations of worsening may lead to hyperalgesia 282
10.2.2 Learning nocebo effects through observation 285
10.2.3 Negative expectations spread across different individuals 285
10.2.4 Nocebo hyperalgesia is mediated by cholecystokinin 288
10.2.5 Imaging the brain when expecting hyperalgesia 290
10.2.6 Positive mood can reduce nocebo effects 292
xx Contents
11. Diseases of the nervous system 303

Summary points 303
11.1 Parkinson’s disease 303
11.1.1 Parkinson patients who receive placebo show a high rate
of improvement 303
11.1.2 Expectations modulate Parkinsonian symptoms 304
11.1.3 Dopamine depletion in the striatum is the cause of Parkinson’s disease 307
11.1.4 Placebo administration induces dopamine release in the striatum 309
11.1.5 The subthalamic nucleus neurons of Parkinson patients show
abnormal activity 311
11.1.6 Placebos restore the normal activity of subthalamic nucleus neurons 312
11.1.7 Expectations of benefit can be as powerful as half dose of L-dopa 315
11.2 Deep brain stimulation and emotional processing 315
11.2.1 Expectations enhance the excitability of some limbic regions 315
11.2.2 Expecting an emotion may change its intensity 317
11.3 Migraine and headache 320
11.3.1 Subcutaneous placebos are better than oral placebos 320
11.3.2 Substantial clinical improvements occur in placebo groups in
clinical trials of anti-migraine agents 321
11.4 Fatigue 323
11.4.1 Fatigue is very sensitive to placebo treatments 323
11.5 Sleep 324
11.5.1 Placebos for insomnia may induce behavioural and
physiological changes 324
11.5.2 Restless legs syndrome shows improvements in placebo groups 325
11.6 Neurological disorders with a few or no available data 325
12. Mental and behavioural disorders 333
Summary points 333
12.1 Depression 333
12.1.1 The rate of improvement in placebo groups is high and has
increased over the past years 333
12.1.2 Placebos and antidepressants affect similar areas of the brain 336
12.1.3 Some genetic polymorphisms are involved in the antidepressant
placebo response 339
12.2 Anxiety 340
12.2.1 Anti-anxiety drugs are much less effective when given covertly 340
12.2.2 Imaging anxiety reduction after placebo administration 340
12.3 Dementia 343
12.3.1 Intensive follow-up can improve cognition in demented patients 343
12.3.2 Loss of prefrontal executive control affects placebo responsiveness 344
12.4 Addiction 346
12.4.1 Expecting a drug of abuse makes it more pleasurable 346
12.4.2 There is no definitive role of placebo and placebo-like effects in
alcohol abuse 348
12.4.3 Tobacco smoking and nicotine intake show large placebo effects 350
12.4.4 Placebos can mimic and replace caffeine 351
12.4.5 Placebo response rates from cessation trials may inform on
strength of addictions 352
Contents xxi
12.5 Psychotherapy 352

12.5.1 Does psychotherapy work through a benign human relationship? 352
12.5.2 It is difficult to disentangle placebo effects from psychotherapy 353
12.5.3 The neural mechanisms of some psychotherapies differ from
those of the placebo effect 355
12.5.4 Methodological recommendations for randomized controlled
trials of psychological interventions have been proposed 355
12.6 Premenstrual dysphoric disorder 356
12.6.1 Placebos may reduce symptomatology through endogenous opioids 356
12.7 Attention-deficit hyperactivity disorder 357
12.7.1 Reducing drug intake through conditioned placebo responses 357
12.8 Mental disorders with no available data 357
13. Immune and endocrine systems 366
Summary points 366
13.1 Immunity and hormone secretion are subject to psychosocial
influences 366
13.2 The immune system 367
13.2.1 Immune responses can be conditioned 367
13.2.2 Can conditioning of immune placebo responses affect the course of
autoimmune diseases and allergies? 371
13.2.3 Specific and discrete neural networks are responsible for immune
placebo effects 373
13.2.4 Several neurotransmitters are implicated in conditioned immune
placebo effects 375
13.2.5 Inducing nocebo allergic reactions and adverse events 376
13.3 The endocrine system 377
13.3.1 Insulin conditioning can induce both hypoglycaemic and
hyperglycaemic placebo responses 377
13.3.2 Inducing placebo insulin secretion 379
13.3.3 Hypothalamic–pituitary–adrenal activity can be conditioned 380
13.3.4 Conditioning but not expectation induces growth hormone
and cortisol placebo responses 381
4 . D I SE A SE - B A SE D C L A S SI F IC AT IO N O F P L AC E B O
E F F E C T S : L E S S S T U D I E D C O N D I T IO N S
14. Cardiovascular and respiratory system 393

Summary points 393
14.1 The cardiovascular system 393
14.1.1 There are a few and contrasting placebo studies in
cardiovascular health 393
14.1.2 Some cardiac effects can be conditioned 395
14.1.3 Placebo-induced activation of endogenous opioids may affect
heart activity 396
14.1.4 Side effects are common in placebo groups of cardiovascular
clinical trials 399
xxii Contents
14.2 The respiratory system 400

14.2.1 Placebos can mimic the depressant effects of narcotics on ventilation 400
14.2.2 Placebos reduce bronchial hyper-reactivity in asthma 402
14.2.3 Cough is powerfully reduced by placebo treatments 405
15. Gastrointestinal and genitourinary disorders 411
Summary points 411
15.1 Gastrointestinal disorders 411
15.1.1 Reduction in gastrointestinal symptoms is common in patients
who receive placebo treatments 411
15.1.2 Increasing the frequency of placebo administration increases clinical
improvement 413
15.1.3 The placebo responses in irritable bowel syndrome can be imaged
in the brain 415
15.1.4 Salivary secretion can be conditioned 417
15.1.5 Gastrointestinal symptoms can be learned 417
15.1.6 Placebo-and nocebo-induced expectations may lead to clinical
improvement and worsening respectively 418
15.2 Genitourinary disorders 420
15.2.1 Reductions of subjective lower urinary tract symptoms are larger
than reductions of objective symptoms in placebo groups 420
15.2.2 Sexual function may improve after placebo and worsen after nocebo 421
16. Special medical conditions and therapeutic interventions 427
Summary points 427
16.1 Oncology 427
16.1.1 Placebos may induce symptom reduction but not cancer regression 427
16.1.2 Cancer chemotherapy induces conditioned nocebo responses 428
16.2 Surgery 431
16.2.1 Patients undergoing placebo surgery show a high rate
of improvement 431
16.2.2 Improvement may occur in those who believe they have received
transplantation 432
16.3 Physical therapies 434
16.3.1 It is difficult to devise placebo physical therapies 434
16.4 Complementary and alternative therapies 435
16.4.1 Do complementary and alternative therapies work through
placebo effects? 435
16.4.2 Acupuncture is likely to work through both specific and
placebo effects 436
16.4.3 Expectations in acupuncture clinical trials can make a
big difference 437
16.5 Itch 438
16.5.1 Substantial placebo and nocebo effects are present in itch 438
16.6 Other conditions with no available data 438
Contents xxiii
5 . C L I N IC A L , E T H IC A L , A N D M E T HO D O L O G IC A L
C O N SI D E R AT IO N S
17. Clinical–ethical implications and applications 447

Summary points 447
17.1 Assessing the effectiveness of new therapies 447
17.1.1 The debate of using placebos in clinical trials is still open 447
17.1.2 Two examples of the ethics of placebo trials: surgery
and schizophrenia 456
17.1.3 New designs can be envisaged that increase the sensitivity of the trial 458
17.1.4 The new insights into placebo mechanisms lead to an
uncertainty principle 460
17.2 Harnessing placebo and placebo-related effects in the clinic 465
17.2.1 Drug-like effects can be obtained without drugs 465
17.2.2 When doctors should treat their patients with placebos 468
17.2.3 Patients with prefrontal impairment need larger doses of analgesics 469
17.2.4 There is a danger behind the corner: does the science of placebo boost
pseudoscience? 470
18. How to run a placebo study: a closer look into complex
experimental designs 478
Summary points 478
18.1 What are we looking for? 478
18.2 Many arms are better than two 480
18.2.1 The 12-arms experiment with placebo, naloxone, and proglumide 480
18.2.2 The 12-arms experiment with placebo, naloxone, morphine,
and ketorolac 482
18.2.3 The 6-arms experiment on the somatotopic effects of placebo
and naloxone 484
18.2.4 The 4-arms experiment with nocebo, diazepam, and proglumide 485
18.3 Investigating sequence effects and learning 487
18.3.1 The design of expectation versus conditioning effects 487
18.3.2 The conditioning procedure for intraoperative recording 490
18.3.3 The experiment on learning 491
18.4 Comparing expected versus unexpected therapies 493
18.4.1 How to compare an open with a hidden treatment 493
18.4.2 The open–hidden paradigm in Alzheimer patients 494
18.4.3 The experiment with deep brain stimulation 495
6 . B EYO N D T H E H E A L I N G C O N T E X T
19. Physical and cognitive performance 499

Summary points 499
19.1 Physical performance 499
19.1.1 Placebos boost physical performance 499
19.1.2 Should opioid-mediated placebo responses be considered doping? 504
19.1.3 Nocebos can counteract good physical performance 504
xxiv Contents
19.2 Performance at high altitude 505

19.2.1 High altitude is a model for both performance and hypoxia 505
19.2.2 Placebos work at very high altitudes under severe hypoxic conditions 508
19.2.3 Nocebo effects explain the interaction between biological
and psychosocial factors 511
19.3 Cognitive performance 512
19.3.1 Placebos boost performance within the cognitive domain 512
20. Everyday life 519
Summary points 519
20.1 Halo effects are similar to placebo effects 519
20.2 Expectations modulate hunger and satiety 520
Index 523
List of boxes
1.1. Understanding human behaviour and emotions of the past 19

2.1. Statement of the World Medical Association on the use of animals in biomedical research 36
3.1. A closer look at pain processing 60
3.2. Co-expression of opioid and CCK receptors in the medulla 74
4.1. The experiment by Olds and Milner 94
5.1. The oxytocin system 115
5.2. The response of a mirror neuron 124
5.3. Identifying the patient’s cognitive and emotional needs 141
6.1. Prevalence of dementia worldwide 157
6.2. The Mini Mental State Examination (MMSE) test 160
6.3. The Frontal Assessment Battery (FAB) test 166
6.4. The Pain Assessment in Advanced Dementia (PAINAD) scale 169
7.1. Healing recipes in ancient Rome 176
7.2. The shamanic ritual of the Saami drum 177
7.3. Run-in and enriched clinical trials 184
8.1. Factors that can cause the false impression of a placebo effect 195
8.2. Moerman’s meaning response 205
8.3. Therapeutic rituals in medical practice 206
8.4. The ‘blocking’ experiment and the cognitive reinterpretation of conditioning 219
8.5. Single-nucleotide polymorphisms 223
8.6. Movies and open-label placebos 232
9.1. What is the best definition for the medical encounter? 250
10.1. The opioid and cannabinoid systems 274
10.2. Prefrontal executive control 281
11.1. Parkinson’s disease and pathological gambling 308
11.2. Electrical stimulation of the human limbic system 319
11.3. International Headache Society classification of headache 321
12.1. Some definitions of positive and negative emotions 334
12.2. Selective serotonin reuptake inhibitors (SSRIs) 339
13.1. A quick overview of the immune system 368
13.2. Hypersensitivity 369
13.3. Autoimmune diseases 372
13.4. The hypothalamus–pituitary system 381
14.1. Extracting sympathetic and parasympathetic activity from the electrocardiogram 398
14.2. Forced expiratory volume in one second 404
xxvi List of Boxes
15.1. Irritable bowel syndrome 412

16.1. Spontaneous regression of cancer 429
17.1. World Medical Association Declaration of Helsinki—Ethical principles for
medical research involving human subjects 449
17.2. The sequential parallel comparative design 462
18.1. The experimental design devised by James Lind 479
19.1. The central governor 503
19.2. Subdivision of the high-altitude zones 507
20.1. The hormone ghrelin 520
PART 1
T HE PAT IE N T ’S BR A I N:
SET T ING T HE STAG E F OR
UNDER STA N DING PL AC E B O E F F E CT S
This first part is not specifically aimed at discussing placebo effects but rather at setting the
stage for and paving the road to a better understanding of what will be covered throughout
the book (Parts 2, 3, 4, 5, 6). In fact, here some basic concepts of medical care and the
doctor–patient relationship will be described with a main emphasis on the neuroscientific
perspective, namely, the therapeutic encounter investigated through neuroscience. In the
next few chapters, the evolution of medical care (Chapter 1) and of scientific medicine
(Chapter 2) will be discussed, then the neuroscience behind the doctor–patient interaction
will be approached by using the biological and psychological approaches of modern science
(Chapters 3, 4, 5, 6). Therefore, this part will lead the reader to more specific topics related
to placebo effects through a general overview of the setting within which placebo effects
take place.
Why is Part 1 important? There is a vast amount of literature on what has often been called
‘doctor–patient relationship’, ‘patient–provider interaction’, ‘therapist–patient encounter’,
and such like. This special and indeed intriguing social interaction has been analysed from
different perspectives so that today the medical, psychological, social, philosophical, and
even socioeconomic and health policy literature is full of accounts and essays that deal
with this topic. This literature has provided valuable information to physicians, health pro-
fessionals, psychologists, philosophers, and policy-makers. Basically, what has emerged in
the course of the years is that not only should health professionals develop and take care of
their own technical skills but they also should strengthen their social skills in order to better
interact with their patients. This might seem quite obvious, nonetheless a large amount of
scientific investigation has provided compelling evidence that not only is a good doctor–
patient relationship desirable because politeness is better than rudeness but also because
the former may have beneficial effects on health whereas the latter may lead to negative
outcomes.
In addition, with the recent advances of neuroscience, I believe we are in a good position
today to describe and discuss the biological mechanisms that underlie the doctor–patient
relationship. No attempt of this kind has been made thus far and the task is not an easy one.
Many neuroscientific facts must be put into the context of the clinical setting, routine med-
ical practice, social issues, and psychological theories in order to provide evidence that the
doctor–patient relationship can indeed be approached in neurobiological terms.
Neuroscience is a very broad discipline, and many sub-disciplines exist, like molecular
and cellular neuroscience as well as cognitive neuroscience. Social and cognitive neurosci-
ence are well placed to take on the doctor–patient relationship from a biological perspective
2 The patient’s brain
because many neurobiological underpinnings of complex social interactions have been un-
ravelled in recent years and many neuroscientific hypotheses have been put forward. For ex-
ample, we now know that different physiological and biochemical mechanisms play a part in
complex functions like trust, hope, empathy, and compassion, all of which are key elements
in the therapist–patient encounter. If on the one hand the patient must trust and hope, on the
other hand the therapist must be empathic and compassionate.
Neuroscientific facts should also be put into an evolutionary context. Neuroscience inves-
tigates biological systems, and any simple or complex neurobiological system is a product of
evolution which has emerged in animals and humans with a precise and specific purpose.
For example, brain circuits subserving trust have emerged in the course of evolution in order
to strengthen social interactions. Trustworthy behaviour is a prosocial behaviour, and if the
patient who seeks relief does not trust therapists and therapies, the doctor–patient encounter
has no meaning to exist at all. Therefore, an evolutionary understanding of why and how
these social mechanisms have emerged and evolved is of paramount importance. They give
us insights into the evolutionary emergence of altruism and subsequent medical care.
In this Part 1, I want to offer scientific facts about the most recent discoveries and ad-
vances of neuroscience that can explain the biological systems involved in the doctor–patient
interaction, and their evolutionary meaning as well as the biological and evolutionary bases
of placebo effects. The basic concept is that from a neuroscientific perspective, I aver, the
doctor–patient relationship can be subdivided into at least four steps. The first is ‘feeling
sick’, a key starting point that triggers the subsequent behaviour. Neuroscience has a lot to
say about feeling sick. It involves sensory systems and cortical areas that generate conscious
awareness, and indeed the perception of a symptom, like pain, is the product of bottom-up
processes and top-down modulation. The second step is ‘seeking relief ’, a kind of motivated
behaviour which is aimed at suppressing discomfort. This behavioural repertoire is not very
different from the one aimed at suppressing hunger or thirst, and the brain reward circuits
are of great importance in this regard. The third step is ‘meeting the therapist’, a special and
unique social encounter whereby the therapist represents the means to suppress discomfort.
Here many intricate mechanisms are at work, such as the patient’s trust and hope and the
therapist’s empathy and compassion. Neuroscience is beginning to understand these com-
plex functions and, interestingly, not only can we study the patient’s brain but we can also
have a look into the doctor’s brain, in which many regions are responsible for empathic and
compassionate behaviour. Finally, the fourth step is ‘receiving the therapy’, the final act of the
doctor–patient interaction. The mere ritual of the therapeutic act may generate therapeutic
responses (placebo responses) which sometimes may be as powerful as those generated by
real medical treatments.
I believe these four steps, as described from a neurobiological point of view, represent a
social-neural system which has evolved as a defence mechanism in all respects. In the same
way as cellular immune responses evolved for protecting living organisms from external
microinvaders, and the fight-or-flight response evolved for tackling environmental dangers,
so the ‘sick–healer interaction’ emerged for providing psychological and social support to
the weak, the sick, the elderly, and for guaranteeing suppression of discomfort by a mere
social event; that is, meeting the healer. A person whose brain is capable of shutting down
pain when the presence of medical help is detected may have an advantage over someone
whose brain lacks this capacity. This system is always at work, regardless of effective or inef-
fective therapies. Even if the therapy is totally ineffective, expectation of benefit (the placebo
response) may be sufficient to inhibit discomfort and eventually to influence the course of
illness. What makes the difference between shamans and modern doctors is that whereas
The patient’s brain 3
shamanic procedures are likely to lack specific effects completely, at least in most circum-
stances, modern doctors rely on effective procedures and medications with specific mechan-
isms of action. But this social-neural system is always there, as an ancestral system which is
ready to emerge, both with shamans and with doctors.
Is there any advantage to approach the doctor–patient relationship from a neuroscientific
perspective? I believe so, for a number of reasons. The first is obvious. Neuroscience is inter-
ested in understanding how brains work, and this special social encounter may uncover the
mechanisms of higher brain functions, such as trust and hope. The second reason is that
physicians, psychologists, and health professionals can better realize what kind of changes
they can induce in their patients’ brains. With this neuroscientific knowledge in their hands,
health professionals ‘see’ directly how their words, attitudes, and behaviours activate and
deactivate molecules, cortical areas, and sensory systems in the brains of their patients. I be-
lieve that this ‘direct vision’ of the patient’s brain will hopefully boost health professionals’
empathic and compassionate behaviour further. The third reason is related to the second
one. I believe that doctors, nurses, and other medical personnel would benefit from the
teaching of neuroscience of the doctor–patient relationship in medical schools and schools
of nursing, as well as in psychology courses. Including this sort of teaching in the education
of health professionals, as we are trying to do in our medical school, would lead to a better
awareness of the potential influence that the doctor’s behaviour may have on the patient’s be-
haviour and capacity to recover from illness. Last but not least, understanding the neurobio-
logical underpinnings of the doctor–patient relationship may lead to better medical practice
and clinical work as well as to better social/communication skills and health policy.
Therefore, placebo effects are generated from and indeed thrive on this biological–
evolutionary background. Understanding this Part 1 means grasping the real and profound
meaning of placebo effects and why they exist at all.
1
A brief evolutionary account of medical care
Summary points
• In this chapter, medical care is approached from an evolutionary perspective. It

represents a complex form of social behaviour that is aimed at taking care of the
weak, the sick, the elderly, and, more in general, the individual who needs help.
Understanding the evolution of medical care paves the way to a better understanding
of several aspects related to placebo effects.
• This evolutionary account starts from unicellular organisms. These simple forms of
life are capable of taking care of themselves through a variety of mechanisms which
are often aimed at tackling harsh environments. Mechanisms of self-care and self-
protection then evolved in more complex forms, such as the withdrawal reflex, the
wiping reflex, and the scratch reflex.
• Grooming is somehow more complex than these simple reflexes, and involves
scratching, rubbing, licking, and the like. It is not triggered by peripheral stimuli on
the skin but rather it is generated in the central nervous system through a complex
concertation of neural, hormonal, and genetic events, which take place mainly in
subcortical areas. There is however a similarity between grooming and the simple
scratch reflex: both are directed towards one’s own body.
• The big evolutionary step that is relevant to the mechanisms of the doctor–patient re-
lationship occurred when animals started grooming others rather than themselves.
Grooming others, so-called social grooming or allogrooming, is one of the first ex-
amples of social interaction. It represents a very elementary form of medical care
whereby the groomer takes care of the groomee.
• Social grooming in apes and early hominids was likely to pave the road to altruistic
behaviour. In real altruism, the conscious intentions to help other individuals are
critical, the so-called psychological altruism. There are many examples of supposed
altruistic behaviour in Homo erectus and in Neanderthal man.
• Whereas the very early forms of altruism and medical care in a social group relied on
the involvement of many members of the group, in the course of evolution a single
individual started taking care of the sick: the shaman. Shamans have then been re-
placed with doctors, such as in Ancient Greece, but a real scientific medicine has
emerged only very recently.
• It is important to look at the doctor–patient relationship from an evolutionary per-
spective because it reminds us that it is a sort of social interaction aimed at taking
care of the members of a social group, and thus at protecting both the single indi-
vidual and the social group from possible dangers and damages. Therefore, the
doctor–patient relationship is a product of the evolution of the nervous system and
behaviour and can be studied with a neuroscientific and evolutionary approach.
Placebo Effects. Fabrizio Benedetti, Oxford University Press (2021). © Oxford University Press.
DOI: 10.1093/oso/9780198843177.003.0001.
6 1. Evolutionary account of medical care
1.1 Simple organisms can take care of themselves
1.1.1 Unicellular organisms use simple strategies to protect themselves
Living organisms take care of themselves and others for better survival, and in so doing they
adopt different strategies, from the shape of intracellular organelles and the movement of the
cilia in unicellular protists to the verbal communication between members of a social group.
Of course, we should not conceive of a phylogenetic scale, from unicellular mechanisms of
self-defence to human social interactions, whereby the amoeba is at the bottom and primates
at the top. There is today compelling evidence for an extensive divergence of evolutionary
lines which involves both parallel evolutionary lines and extinction of intermediary lines
(Simpson 1949). Therefore, some of the strategies adopted by simple organisms, for example
unicellular ones, do not necessarily mean that these have then evolved into those strategies
that are used by higher mammals. Nevertheless, it is crucial to understand that both simple
and complex organisms can take care of themselves at different stages of evolution, and this
occurs on the basis of different physiological mechanisms and behavioural repertoires.
Some relatively simple mechanisms and strategies are already present in unicellular or-
ganisms, such as the paramecium, also known as the Lady Slipper, a freshwater protist found
particularly in scums. The paramecium takes care of itself in different ways. For example, it
contains intracellular organelles, the contractile vacuoles, which are used to pump excess
water out of the cell (Wichterman 1986). These intracellular structures are surrounded by
several pores that absorb water from the cytoplasm by osmosis. If there is an overload of
water in the cell, the contractile vacuole can expel it through a pore that can be opened and
closed (Figure 1.1A). Without such a mechanism, the paramecium would explode when ex-
cess intracellular water is present.
The paramecium, like many other unicellular organisms, can also solve simple problems
of locomotion when, for example, it hits an obstacle. It has a series of cilia on the membrane
surface that allow movements in the water (Wichterman 1986). When the cilia beat back-
ward simultaneously, the paramecium moves forward with a spiral trajectory. However, it
may run into an obstacle. If so, the cilia change their direction and beat forward, causing the
paramecium to move away from the obstacle. After a while, the cilia beat backward again,
and the paramecium moves forward again. If it hits the obstacle again, this process will con-
tinue until the obstacle is overcome.
Other unicellular protists show similar mechanisms. The amoeba has vacuoles that can
regulate intracellular osmosis by expelling excess water through exocytosis (Jeon 1973). In
this case, the overloaded vacuole moves toward the surface of the cell in order to expel the
water into the extracellular environment. The amoeba can also face harsh conditions, such
as an acid environment. In this case, it turns into a dormant state, whereby the metabolic
activities, feeding, and locomotion are slowed down, the so-called state of microbial cyst
(Figure 1.1B). In a microbial cyst, a wall surrounding the cell membrane is built up, and this
wall increases the resistance of the organism to the new harsh environment. For example, the
wall of the Entamoeba histolytica contains sialic acid which confers a negative charge to the
cyst. This negativity, in turn, prevents the attachment of the cyst to the intestinal wall, thus
facilitating its elimination with the faeces and its passage to a more favourable environment.
These forms of self-protection are crucial to survival, of course. Both the paramecium and
the amoeba use strategies that allow them to take care of themselves so as to tackle difficult
conditions and environments. Therefore, at these very early stages of evolution, we already
Simple organisms can take care of themselves 7
(A)
Contractile
vacuole
Contractile
vacuole
H 2O
H2O
Paramecium
(B)
Favourable environment Harsh environment
(low pH )
Sia
lic
aci
d
cid
lica
Sia
Amoeba Microbial cyst

Fig. 1.1 Two examples of self-defence mechanisms in unicellular organisms. (A) In the
paramecium, excess water is pumped out by means of the so-called contractile vacuoles. (B) In
harsh conditions, such as low pH, the amoeba turns into a microbial cyst. Its wall may become
negatively charged, due to sialic acid, thus preventing its attachment to the intestinal wall and
facilitating its passage to a more favourable environment.
observe simple mechanisms of self-care, although they do not require a nervous system.
Unicellular organisms do not have neurons but only specialized intra-and extra-cellular
structures which confer some self-defence properties to the cell. Without such specialized
structures, these cells would have not survived throughout evolution.
1.1.2 The withdrawal reflex is present in both invertebrates

and vertebrates
Withdrawal reflexes are common in those organisms with a nervous system. The withdrawal
reflex is a somatic-motor reflex act which protects some parts of the body from threatening
stimuli. In general, when a body part is touched by a potentially threatening stimulus, be it
non-painful or painful, it is suddenly withdrawn so as to warrant protection from possible
damage. This reflex is present in both invertebrates and vertebrates, including man. Without
it, an organism would be exposed to a number of noxious environmental stimuli, with no
possibility to retract from them.
In the marine snail Aplysia, the neuronal organization of the withdrawal reflex has
been analysed in detail. In particular, Aplysia shows two interesting reflexes, the siphon-
withdrawal reflex and the gill-withdrawal reflex (Kandel 1976). A tactile stimulus to the
siphon or mantle causes the gill to contract and withdraw into the mantle cavity and the si-
phon to contract beyond the parapodia, thus preventing from potential damage. A relatively
simple circuit is needed for this reflex (Figure 1.2A). Basically, the reflex arc that has devel-
oped in Aplysia is represented by an afferent pathway, a centre in the nervous system, and
an efferent pathway. The afferent pathway is made up of sensory neurons innervating both
siphon and gill which, in turn, make synapses with several clusters of motor neurons in the
abdominal ganglion of the snail. On the whole, there are about 24 identified sensory neurons
innervating the siphon, whilst there are 13 identified motor cells (Kandel 1976). Although
most of the connections between sensory and motor neurons involve one synapse only, it
should be noted that some of these connections are not direct as they occur via either excita-
tory or inhibitory interneurons.
The circuit depicted in Figure 1.2A is sufficient to guarantee the efficient withdrawal of
both siphon and gill. It can be explained in terms of the features of its components. First,
the afferent discharge is in fact proportional to the intensity of the stimulus. Second, there
is a linear summation of the synaptic actions induced by the sensory afferents onto motor
neurons. Third, the frequency of the action potentials is a linear function of the amplitude
of the excitatory post-synaptic potential. Fourth, the motor response, that is the muscle con-
traction of siphon and gill, is linearly related to motor cell discharge (Kandel 1976).
Withdrawal reflexes are present in vertebrates as well. They are somehow more complex
in mammals, including man, than in invertebrates, as they involve different muscles for
the maintenance of posture (Sherrington 1947). The withdrawal reflex in mammals obeys
the law of reciprocal innervation whereby the flexor muscles of the stimulated limb con-
tract whereas the extensor muscles of the same limb are inhibited (Figure 1.2B). Along with
these effects in the stimulated limb, this reflex yields opposite outcomes in the contralat-
eral limb: extensor muscles are excited while flexor muscles are inhibited. These opposite
effects in the two limbs, for example the legs, strengthen the postural adjustment during the
withdrawal of the stimulated leg from the noxious stimulus. In fact, posture is maintained
through the extension of the non-stimulated leg.
Due to the complex nature of the flexor–extensor reciprocal innervations for the with-
drawal and the postural maintenance, the withdrawal reflex in man and other mammals
is polysynaptic, as it involves a number of interneurons (Kandel et al. 2000) (Figure 1.2B).
Nonetheless, the withdrawal reflex is a relatively simple neuronal circuit that warrants self-
protection from environmental noxious stimuli. Without it, the organism would be exposed
to possible damage of different parts of the body.
1.2 From the scratch reflex to grooming
1.2.1 The scratch reflex is a simple purposive behaviour
Like the withdrawal reflex, the scratch reflex has a purpose because the movement is aimed at
protecting against potential damage. However, from an evolutionary perspective, the scratch
reflex is particularly interesting because the reflex movement seeks to target the potential
noxious stimulus and remove it from the body. The wiping reflex in the frog is similar to the
scratch reflex, with the notable difference that in the former there is no rhythmic activity.
From the scratch reflex to grooming 9
stimulus stimulus
(A)
siphon gill
Sensory
neuron
Motor
neuron
(B)
Sensory
neuron Interneurons
− + − + Interneurons
Motor neurons
Ext
Extensor
Flex
ens
Flexor
or
or
Cutaneous Left leg

receptor
Right leg
STIMULUS
Fig. 1.2 Organization of the withdrawal reflex in the snail Aplysia (A), and in mammals,
including man (B). In the simple circuit in A, sensory neurons innervating both siphon and gill
make synapses with motor neurons which innervate the muscles of siphon and gill. In the more
complex circuit in B, the reflex is governed by the law of reciprocal innervation, which warrants
postural adjustment while the stimulated leg is retracted. In fact, the reciprocal innervation of
flexor and extensor muscles guarantees that while a limb is withdrawn, the other is extended to
maintain the posture.
In the frog, the wiping reflex only requires the spinal cord, even for some complex fea-
tures of this purposive behaviour (Figure 1.3). For example, if a weak acid solution is placed
on the forelimb of a spinalized frog, the hindlimb is moved towards the irritated skin so as
to wipe the acid solution away. However, if the position of the forelimb is changed, but the
irritated skin is always the same, the direction of the movement of the hindlimb changes so
stimulus
SECTION SECTION
Spinal cord
Spinal cord
stimulus
Fig. 1.3 In the frog, the neuronal circuits in the spinal cord are sufficient to guarantee even
complex motor reflexes. In the wiping reflex of the spinalized frog, whereby the hindlimb
movement is aimed at removing a noxious stimulus from the forelimb (left), the spatial position
of the forelimb is critical. In fact, if it changes its position (right), the hindlimb movement is
adjusted so as to reach the new spatial location of the noxious stimulus.
as to reach the new spatial position of the irritated skin. Therefore, the spatial characteristics
of the wiping reflex depend on the joint position at the moment of the application of the acid
solution, and these spatial coordinates and relative adjustments are specified in the spinal
cord (Fukson et al. 1980).
The scratch reflex differs from the wiping reflex because in the former the spinal cord is
capable of generating rhythmic movements. This reflex is typical of those animals with a fur,
and is clearly aimed at removing the bothering stimulus produced, for instance, by a flea’s bite.
It starts with a movement of the hindlimb which is positioned in proximity of the stimulus.
Then the rhythmic movements take place. It is crucial that the upright position of the body be
maintained, thus the contralateral extensor muscles are excited (Sherrington 1947). In this
case also, the spinal cord is sufficient in evoking this reflex. If a stimulus, such as a mild elec-
trical shock, is applied to a side of the body of a spinalized animal, the features of the reflex
response depend on both intensity and duration of the stimulus. By increasing the intensity
of stimulation, the latency of the reflex decreases and the strength of the muscle contractions
as well as the number of alternated movements increase. Interestingly, the rhythm of these
movements is independent of the stimulus. Thus the frequency of the rhythmic movements
stays the same when stimulus duration and intensity change. The neuronal circuits that are
responsible for the alternated flexor and extensor movements during scratching are located
in the spinal cord, and they require neither descending influences from supraspinal centres
nor ascending influences from the periphery, such as muscles and joints (Sherrington 1947).
From the scratch reflex to grooming 11
The scratching reflex is present not only in animals with a fur, such as mammals, but
in other species as well. For example, the semi-aquatic turtle Trachemys scripta elegans
shows a typical scratch reflex whose spinal circuits are partially understood. First of all, it is
interesting to note that those neurons involved in scratching are also involved in other motor
behaviours, like swimming. Therefore, a given cluster of spinal neurons, both interneurons
and motor neurons, has not developed to give rise to a single and unique behavioural rep-
ertoire, but rather different motor patterns (scratching and swimming) share common
neuronal circuits (Stein 2005). In addition, there is experimental evidence for a modular
organization of turtle spinal networks. For example, during scratching, hip-extensor motor
neurons are active when hip-flexor motor neurons are silent. The same holds true for inter-
neurons, which suggests a population of hip-extensor motor neurons and interneurons, the
hip-extensor module, during scratching. This holds true for knee-extensor and knee-flexor
modules as well (Stein 2005).
Therefore, both the occurrence of the wiping and scratch reflexes and the adaptability of
the wiping reflex are warranted by circuits in the spinal cord. A purposive behaviour of this
kind does not require a complex nervous system. During evolution, simple networks in the
spinal cord have acquired the capability of generating a behavioural repertoire that is aimed
at preventing damage of a body part. In so doing, relatively elementary circuits subserve
a very elementary form of self-care which involves the removal of the potentially noxious
stimulus from the body.
1.2.2 Grooming involves a complex behavioural repertoire
Whereas scratch and wiping reflexes are triggered by cutaneous stimuli, such as a bug’s bite, a
quite different motor behaviour emerged during evolution in order to take care of one’s own
body. Grooming is a self-directed behaviour which represents a biological function aimed
at caring for the body surface (Spruijt et al. 1992). It has an important role in the control of
ticks and ectoparasites across many animal species, and is characterized by a complex be-
havioural repertoire involving scratching, preening, rubbing, nibbling, wallowing, as well
as dust, sand, and mud bathing. Even insects show some forms of simple grooming, such
as rubbing of the wings. Interestingly, ants spread antibiotic secretions over their body, thus
self-protecting against bacteria and fungi (Spruijt et al. 1992).
Although grooming behaviour is concerned with care of the body surface, there is compel-
ling experimental evidence that, in contrast to scratch and wiping reflexes, it is not triggered
by cutaneous stimuli but it is generated centrally in the brain. In fact, grooming is usually
not associated with a particular stimulation of the skin but rather with a given state of the
animal. Therefore, the structure and initiation of grooming bouts seem to be independent of
any particular stimulus (Spruijt et al. 1992). In addition, peripheral deafferentation, such as
sectioning of the trigeminal nerve in mice, does not abolish grooming behaviour, which sug-
gests centrally generated grooming acts (Berridge and Fentress 1987).
The big evolutionary step from the peripherally driven scratch reflex to the centrally
driven grooming behaviour helps us understand how the nervous system developed from
a simple form of reflex act aimed at preventing potential damage of the skin to a more
complex motor pattern aimed at taking care of the whole body surface. Grooming motor
pattern is controlled by at least two mechanisms: on the one hand, it is modulated by sev-
eral hormones, on the other hand, it is generated by some specific regions of the brain
(Figure 1.4).
Hormonal Neural
control control
Substantia nigra
ACTH Periacqueductal grey
Oxytocin Cerebellum
Prolactin Striatum
TRH Hypothalamus
CRF
Hoxb8
Grooming
behaviour
Fig. 1.4 Grooming behaviour is under hormonal and neural control. It is induced by several
hormones as well as by the activation of a variety of brain areas. Hoxb8 genes may take part in
the genetic programme of grooming. ACTH: adrenocorticotropic hormone. TRH: thyrotropin-
releasing hormone. CRF: corticotrophin-releasing factor.
The most effective hormone that induces grooming behaviour is the adrenocorticotropic
hormone (ACTH). Intracerebral administration of ACTH induces excessive grooming in
the rat (Ferrari 1958; Ferrari et al. 1963; Gipsen et al. 1975), an observation that has been
confirmed by many subsequent studies. However, it should be noted that other peptides
have been found to produce grooming, like vasopressin, oxytocin, prolactin, substance P,
bombesin, somatostatin, thyrotropin-releasing hormone, corticotrophin-releasing factor
(Spruijt et al. 1992). ACTH-induced grooming is mediated by endogenous opioids, as it can
be prevented by the opioid antagonist naloxone (Gispen and Wiegant 1976). In addition,
dopamine, gamma-aminobutyric acid (GABA), and serotonin have been found to take part
to ACTH-induced grooming, which indicates the high complexity of the endocrine control
of grooming behaviour (Spruijt et al. 1992).
As far as specific brain regions are concerned, it is now clear that grooming behaviour is
still present in the decerebrated animal, thus showing that it is a subcortical function. There
is not a single area involved in the motor pattern but many. Lesions of the substantia nigra
and of the dorsal periaqueductal grey in the rat are crucial in suppressing ACTH-induced
grooming (Gispen and Isaacson 1986; Spruijt et al. 1986), and stimulation of the cerebellum
in the cat induces grooming bouts (Berntson et al. 1988). The striatum and hypothalamus are
also involved. For example, the stimulation of some hypothalamic areas induces grooming
in the cephalo-caudal direction, which is characterized by licking paws and fur, and washing
movement over the head (Kruk et al. 1998).
Knock-out mice with disruptions of Hoxb8 show excessive grooming, without any sign
of abnormality in the skin or peripheral nerve fibres (Greer and Capecchi 2002). Hoxb8 is a
member of the mammalian Hox complex, a group of 39 transcription factors known for their
role during development. Interestingly, Hox genes are expressed in the adult brain and, in
Scratching somebody else 13
particular, Hoxb8 is expressed in those regions that are implicated in the control of grooming
behaviour in rodents. This suggests that the innate pre-programmed grooming behaviour
involves neuronal networks that are specified using a genetic program, in which Hoxb8 may
take part.
1.3 Scratching somebody else: a big evolutionary jump

to social behaviour
1.3.1 Primates spend plenty of time in social grooming
Not only do animals scratch, rub, and lick themselves, but they scratch and rub their com-
panions as well, devoting as much as 20% of their total day to this one activity, depending
on the animal species. This social grooming, or allogrooming, represents an important step
in the evolution of social behaviour, and is present in many mammals, such as kangaroos,
antelopes, horses, dogs, cats, and rodents; however it is typical, above all, of primates (Spruijt
et al. 1992). It is important to realize that allogrooming has a function in the regulation of
social relationships, and it is not only involved in the care of body surface. One of the major
forms of social grooming is maternal grooming, whereby the relation between mother and
pups is cemented as well as the body surface of the offspring is maintained.
Although social grooming may have a function in the care of the skin of the companions
and may help groom areas that cannot be easily reached by the animal itself, in primates it
should be noted that individuals who are virtually free of parasites still solicit grooming and
submit themselves to being groomed. Therefore, the social functions of allogrooming ap-
pears to be as important as, or even more important than the cleaning function of the skin.
For example, if grooming were purely hygienic in function then one should expect a cor-
relation with surface area, but it does not. Moreover, social grooming time correlates with
social group size, which suggests that allogrooming has to do with intense social relation-
ships (Dunbar 2010).
There is thus compelling evidence that social grooming serves to establish, renew, main-
tain, and strengthen social bonds. It may also regulate social tension and reconciliation
among the members of a group and may also play a role in consolation behaviour. For ex-
ample, there is some evidence in chimpanzees that relatives or allies of a victim are capable
of restoring his emotional balance by soothing him (de Waal and van Roosmalen 1979). It is
also worth noting that relationships established by social grooming may have lifelong con-
sequences. In fact, among wild gelada baboons, the likelihood of a female going to the aid of
another female when the latter is under attack is significantly correlated with the amount of
time the two of them spend grooming with each other, and the reproductive success of wild
female savannah baboons is correlated with the number and intensity of their grooming-
associated relationships (Dunbar 2010).
In contrast to scratch reflexes and self-grooming, which require neuronal circuits in the
spinal cord and in the brainstem, respectively, allogrooming is tightly linked to social inter-
actions, a complex function that requires a complex integration in the cerebral cortex (Figure
1.5). The relative neocortex volume in primates in fact correlates with several behavioural
indices of social complexity (Dunbar 1998; Dunbar and Shultz 2007). In the social brain hy-
pothesis, brain size is correlated to social group size and social relationships (Dunbar 2010).
Bonded relationships are cognitively very demanding and a large increase in the develop-
ment of the neocortex should be expected in these cognitive/social activities.
Fig. 1.5 The evolutionary steps from the care of oneself to the care of others. (A) The neuronal
circuits in the spinal cord warrant the simple sensory-motor integration of the scratch reflex.
(B) Centrally (subcortical) generated grooming behaviour is aimed at the care of one’s own
body. (C) The neocortex, together with some hormones, like oxytocin (Oxy) and vasopressin
(Va), endogenous opioids (EO), and Hoxb8 genes, are crucial to generate social grooming,
whereby the grooming behaviour is directed towards other members of the social group.
Being groomed is physiologically relaxing, as shown by the decrease of heart rate, the
reduction of some indices of stress, and sometimes falling asleep (Dunbar 2010). A role for
endogenous opioids has been suggested in these effects. For example, the opioid blocker nal-
trexone has been found to increase the frequency with which monkeys solicit grooming from
others (Keverne et al. 1989). Similarly, oxytocin and vasopressin, two neuropeptides widely
distributed in the brain, have been found to have prosocial effects (see also section 5.1.3). In
particular, oxytocin receptors can be found in the nucleus accumbens, a region involved in
reward mechanisms, thus suggesting that oxytocin may be involved in reward. Massage-like
stroking in rats raises plasma oxytocin, and increases pain tolerance, which indicates that
the mechanical stimulation of the skin affects oxytocin secretion (Agren et al. 1995). More
interestingly, vasopressin has been found to affect social memory in male mice: vasopressin
V1a receptor knockout males show a marked impairment of social, but not spatial, memory
(Bielsky et al. 2004).
An important aspect of Hoxb8 mutant mice (see section 1.2.2) is that they show both ex-
cessive self-grooming and excessive allogrooming. Therefore, Hoxb8 excessive grooming in-
cludes a social component. In fact, when Hoxb8 mutants are caged with control littermates,
the control animals show bald patches over the body and the head (Greer and Capecchi
2002). These findings suggest that genetic programs specify the neuronal networks for both
self-and allogrooming (Figure 1.5).
1.3.2 From social grooming to altruistic behaviour
In social grooming, there are at least two actors: the one being groomed and the groomer.
Whereas the former benefits from it in a number of ways, such as touch-induced pleasure,
relaxation, and hygiene, it is less clear what the benefits are for the latter. Indeed, there are no
Scratching somebody else 15
immediate benefits to the groomer because he spends energy and time to the advantage of
others. The act of grooming can thus be considered an altruistic behaviour.
In the strict biological sense, altruistic behaviour benefits other organisms at a cost to
itself. What counts in biological altruism is not so much the intention to be altruistic but ra-
ther the consequences of an action. Indeed, altruism is common in many animals but most
of them, if any, are not capable of conscious intentions at all. For example, in social insects,
such as ants, bees, and termites, sterile individuals devote their lives to caring for the queen,
and vampire bats regurgitate blood and give it to other members of the group who have failed
to feed that night. It is hard to believe that insects or bats have conscious altruistic intentions.
Therefore, the biological notion of altruism has to do with the action itself, not with what
causes that action. Through the altruistic act, the altruist reduces the number of offspring it
is likely to produce itself, but boosts the number that other organisms are likely to produce.
Self-sacrificial behaviour, though disadvantageous for the individual altruist, might be bene-
ficial at the group level (Darwin 1871).
The role of the groomer and the groomee are related, of course. Any individual can be ei-
ther a groomer or a groomee, depending on the circumstances. Thus altruism is reciprocal
and, if there is no immediate advantage to the groomer, the service can be returned by the
one who is being groomed. This idea of reciprocal altruism was introduced to explain cases
of altruism among unrelated organisms (Trivers 1971). If the groomer scratches the back of
the groomee, the groomee will eventually return the same service to the groomer in the near
future. In other words, it may pay an organism to help another, if there is an expectation of
the favour being returned in the future.
The main objective of the theory of reciprocal altruism is to explain why some altruistic
acts are performed towards non-kin. Indeed, kin selection theory explains altruism when the
altruistic action is toward kin. It predicts that animals are more likely to behave altruistically
towards their kin than towards unrelated members of their species, and that the closer the re-
lationship, the greater the degree of altruism (Hamilton 1964). Indeed, grooming behaviour
often takes place among relatives, like in chimpanzees, macaques, and baboons. However,
this is not a general rule, and in many species of primates grooming occurs between both kin
and non-kin (Spruijt et al. 1992). Thus kin selection alone cannot explain grooming among
non-kin.
In primates, complex patterns of grooming behaviour have been described. In a study
in chimpanzees (Nakamura 2003), these included 27 types of grooming cliques and the
largest one consisted of seven individuals. The proportion of multi-interaction grooming
cliques was more than 25% compared to less than 10% in other primate species. Overlap
of grooming interactions, such as grooming and being groomed simultaneously or being
groomed by multiple individuals, accounted for about 20% of individual grooming, and
the maximum number of interactions for one individual at one time was four. Grooming
clusters of two to 23 individuals were observed, and clusters of three or more members ac-
counted for about 70% of total duration.
By taking this study as an example, it is clear that the roles of the groomer and the groomee
overlap, and any member of the group can be both a groomer and a groomee. Thus, any indi-
vidual experiences the pleasure and relaxation of being groomed and eventually adopts the
altruistic act of grooming the companions. These continuous exchanges of roles boost social
interactions and promote reciprocal social behaviour. In the course of evolution, these social
interactions are accompanied by a dramatic increase of the neocortex, thus warranting a
social brain specifically aimed at boosting sociality (Dunbar 1998, 2010).
Altruistic behaviour and sociality are far from being understood in humans. For ex-
ample, reciprocal altruism is clearly the antithesis of real altruism because behaving nicely
to someone in order to procure return benefits from them in the future is just delayed self-
interest. Adoption is a special case whereby reciprocal altruism does not seem to apply to
Homo sapiens. Biological fitness is reduced in parents who adopt children because these chil-
dren are usually unrelated to their adoptive parents. Adoption as well as other human altru-
istic acts seem to obey neither kin selection nor reciprocal altruism, so they probably need to
be treated as real altruistic actions.
All those human altruistic acts that seem to be at odds with the evolutionary theory, are
clearly related to conscious intentions. In contraposition to biological altruism (i.e. kin se-
lection and reciprocal altruism), psychological altruism is used to mean the conscious in-
tention of helping somebody else. Psychological altruism may represent a form of genuine
altruism whereby individuals may indeed care about helping others. Many directed altruistic
behaviours in humans are based on empathy, that is, the capacity to share the emotional state
of another and to adopt his perspective. In this sense, the altruistic act may represent a self-
reward because it is aimed at placating the altruist’s internal state.
A possible origin of empathy may be represented by the evolution from emotional con-
tagion, whereby the emotional state of a subject is matched with an object, to sympathetic
concern, whereby both concern about another’s state and the attempts to ameliorate it are
present (de Waal 2008) (see also section 5.4). In the latter, sympathy consists of feelings of
sorrow for a distressed other. The best example of sympathetic concern is consolation, which
is widely present in apes and humans but not in monkeys, and which may consist of putting
an arm around a companion who has been defeated in a fight, as shown in Figure 1.6 (de
Waal 2008). The next evolutionary step occurs when the capacity to take on another’s per-
spective has emerged, the so-called empathic perspective-taking (de Waal 2008) (see also
section 5.4). In Homo, and particularly in Homo sapiens, the groomer and the groomee, with
their sympathetic concern and empathic repertoire, were likely to evolve into those who
helped each other in a number of circumstances, including the care of the sick.
Fig. 1.6 An ape soothing a companion who has been defeated in a fight, a good example of
consolation emerged in non-human primates during evolution.
Taking care of the sick 17
1.4 Taking care of the sick
1.4.1 From early forms of altruism to the emergence of the shaman
The evolution of prosocial behaviour in early hominids went on in a number of ways. One
of these is certainly the care to the weak, the sick, the elderly, and, more in general, the
individual who somehow needs help. For example, in order to survive in harsh condi-
tions, it was crucial for our ancestors to obtain a daily nutritious diet of meat and other
food. However, this daily provision was not guaranteed because of the high variability
of hunting success. Therefore, there were days with a food excess and days with a food
shortage. Although the first altruistic exchanges were likely to occur among relatives,
thus favouring kin selection, in the course of evolution further food exchanges occurred
with non-kin that were less lucky on that particular hunting day. These non-kin recipients
eventually returned this favour, according to the reciprocal altruism theory (Van Vugt and
Van Lange 2006).
Living in social groups is advantageous to individuals and sharing food and other goods
may be critical for survival. This is nicely shown by some social decision dilemmas, such
as the ultimatum game or the prisoner’s dilemma, whereby the individual has to choose
among different possibilities that can be either advantageous or disadvantageous to him. In
such social dilemmas, cooperation turns out to be the best choice. In the example offered
by Van Vugt and Van Lange (2006), two subjects, A and B, share a house together. Each of
them would be better off if they relied upon the other to clean the house (assuming that
for most people cleaning is time-consuming, energy-consuming, and tiring). However, if
neither of them makes an effort to clean the house, the house becomes a mess and they will
both be worse off. The altruistic or cooperative choice (C choice) in this example stands
for cleaning the house, whereas the defecting choice (D choice) stands for not cleaning the
house. If A cleans the house by himself, but B does nothing, the outcomes for B are very
good (e.g. 10 on a personal satisfaction scale), but they are poor for A (e.g. 0). Conversely,
if B cleans by himself, but A does nothing then the outcomes for A are good (10), but
for B they are bad ( 0). If A and B share the cleaning, the outcomes for both of them are
moderately good (e.g. 5 each), which is not as good as when the other subject does all the
cleaning. The gist of the social dilemma is that, if neither A nor B cleans the house, their
outcomes will be relatively poor (e.g. 2 each), which is worse than their outcomes had they
both shared the cleaning (5 each). Altruism and cooperation is thus advantageous in a so-
ciety. Once the members of a social group understand that their interests are at least partly
overlapping, and that they have some sense of a shared future, they will tend to act benevo-
lently towards each other.
By taking kin selection, reciprocal altruism, psychological altruism, and social dilemmas
into account, in a social group it is very important to help and support the weak, the sick,
and the elderly. Individuals who cannot hunt and feed themselves are not abandoned but
rather they are looked after and fed. The first example of human compassion may well be
represented by a toothless skull that was found at the site of Dmanisi in the Eurasian republic
of Georgia (Lordkipanidze et al. 2005). It belongs to a Homo erectus dating back 1.7 million
years who had lost all but one tooth several years before death. This specimen represents
the earliest case of severe masticatory impairment which raises questions about subsistence
strategies in early Homo. In fact, it may attest to evolution's oldest known example of some
kind of altruism and compassion for the elderly and handicapped in the social group. As all
his teeth, except the left canine, were missing at least two years before he died, it would have
been difficult for him to survive that long, unable to chew the food of a mainly meat-eating
society. Companions might have helped him in finding soft plant food and hammering raw
meat with stone tools.
There are other examples of this kind in Homo erectus, such as the one who presented se-
vere bone lesions that were attributable to hypervitaminosis A (Walker et al. 1982). These
lesions were likely to be due to the high dietary intake of animal liver and were painful and
disabling. In this case also, surviving for weeks or months in these conditions requires help
from the group to which the individual belongs.
Neanderthal man has been found to show signs of compassion towards companions as
well, dating back to about 60,000 years ago. For example, due to the many lesions to the
bones, the La Chapelle-aux-Saints and Shanidar individuals must have been severely in-
capacitated and would have died even earlier without substantial help and care from the
group to which they belonged (Klein 1989). The analysis of undeveloped bone structure
indicates that a man at Shanidar caves was a severe cripple from birth. His right upper limb
was entirely useless and may have been amputated just above the elbow. Extensive bone scar
tissue indicates that he was blind in his left eye. He was apparently cared for by his com-
panions until his death at age 40, which represents a very old age by Neanderthal standards
(Wiester 1983).
Although at the very beginning of human evolution these altruistic acts were probably
adopted by different members of the groups, in the course of evolution a single member
of the group assumed the role of the one who takes care of the sick. This member is usually
named the shaman, and represents a very important component of any social group, in pre-
historic, historic, and modern times. Although there are plenty of variations of shamanisms
throughout the world, there are some common factors that are present in virtually all kinds
of shamanism (Eliade 1964). For example, the shaman can communicate with the spirit
world, in which spirits can be good or evil, and ecstasy, trance, and altered states of con-
sciousness are central to shamanistic practices. A typical feature in all forms of shamanism is
that the shaman can treat sickness caused by evil spirits and to do this he adopts a number of
procedures that vary from culture to culture, such as the evocation of animal images as spirit
guides or the use of different symbolic objects and rituals.
Shamanistic practices are likely to date back to the Paleolithic, and certainly to the
Mesolithic and Neolithic. For example, a shamanic figure was found in Les Trois Freres cave
in France, dating back to approximately 13,000 BC. This is a therianthropic figure, part man
and part beast, which is likely to represent a sorcerer, or magician, wearing a horned mask
and costume and in the process of transforming into an animal, as drawn by Henri Breuil
(Boyle 1952). Prehistoric shamanism represents the first example of real medical care. This
is a form of good relationship between the sick and the shaman. The sick individual trusts
the shaman and has strong beliefs in his therapeutic capabilities; thus he refers to him for
any kind of psychological, spiritual, or physical discomfort. In this way, the shaman became
a central figure in any social group and acquired more and more prestige and a higher social
status over the centuries and across different cultures.
In general, the complex emotional human behaviour can be inferred through the study of
either the prehistoric or historic archaeological finds, which tell us something of how ancient
populations experienced the world. Although this approach through archaeology is subject
to plenty of biases and mistakes, it provides some important pieces of information about the
very nature of the interaction between the mental world of our ancestors and the physical
world (Box 1.1).
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power has generally been considered essential; namely, in the
sonatas. Of these there are three: an early one in C minor, published
posthumously; one in B-flat minor, opus 35; and one in B minor, opus
58.
The first of these is almost in no way representative of the composer.

It was completed by 1828 and sent to Vienna for publication; but it
did not appear in print until two years after Chopin’s death. Neither in
melodiousness nor in harmonic richness does it show the mark of his
genius. It is ordinary in treatment of the piano. One can hardly attach
even an historical significance to it, since works composed at or
about the same time give more than a suggestion of his future
greatness. For example, it was in connection with the contemporary
variations on Mozart’s aria, La ci darem la mano, that Schumann
wrote, ‘Hats off, gentlemen: a genius!’ It is true that the return of the
first theme, at the beginning of the last section of the first movement,
in B-flat minor instead of C minor, is at variance with conventional
usage; but this was by no means unprecedented. The 5/4 rhythm of
the Largo is evidently an attempt at originality; but it is self-
conscious, not spontaneous. In spite of these features the work goes
to prove only one thing: that in such a familiar and well-established
form as the sonata, Chopin at that time either dared not or felt he
should not trust to his own instinct, even as to the treatment of the
instrument.
But the other two sonatas are worthy of his full maturity, and they
show, like the Études, the Scherzi and the Ballades, the perfection
and sureness of his art of self-expression. And in thus revealing
himself he could not but be an innovator. He brought something new
to the sonata. Consequently the opinion that he is ill at ease in the
form, which may be interpreted to mean (or generally is so
interpreted) that he had not the intellectual grasp of music necessary
to the composing of a great sonata. This, it is to be feared, is one of
the ready-made opinions in music. There are many such at hand. A
few great critics have given the hint. Liszt, in writing of the concertos,
ventured to say that they showed plus de volonté que d’inspiration.
The remark has been applied to explain the uneasiness of the two
great sonatas. Mr. J. S. Shedlock in his book on the pianoforte
sonata wrote that ‘the real Chopin is to be found in his nocturnes,
mazurkas, and ballads, not in his sonatas.’ But, though it is nearly
absurd to pick from many supremely great works one that is superior
to the others, and we do not in the least wish to infer that Chopin’s B-
flat minor sonata is his masterpiece, we think it may be fairly
questioned whether he ever wrote anything greater. It is thoroughly
impregnated with his unique spirit. There is not a note of it that is not
of the ‘real’ Chopin. Furthermore, the B minor sonata is not less
thoroughly Chopin.
It may be reserved to the trained critical mind to decide what is great

art of any kind; but the decision as to what is great music must
ultimately rest with time and its changing voice of expression—the
general world. Upon no sonatas, except some of those of
Beethoven, does the public set such store as upon these two of
Chopin. The sonatas of Weber, Schubert, Schumann and Brahms
hold no such place in the general favor. In the case of the first three
of these men a looseness in the grasp of form is responsible for the
gradual degradation of their long works. It is logical to infer, then, that
a similar looseness is not evident in the sonatas of Chopin. At any
rate it has not yet become palpable to the public, whatever critics
may have said. And the sonatas have undergone and are still
undergoing a tremendous test. Therefore, however much men may
declare the intellectual weakness in Chopin’s music, one must
conclude that his instinct gave sufficient vitality even to his sonatas
to enable them, alone among sonatas, to hold their public place with
those of Beethoven. And it would seem that the undisputed
intellectual power of Brahms failed where the instinct of Chopin
succeeded.
Of course it will be urged in explanation of the popular acceptance of

the sonatas of Chopin, that they are eminently gratifying to the
pianist, suitable to the instrument, and consequently delicious to the
public. At the most this is but a grace which no other sonatas have in
so great measure. It is not a virtue by which alone music endures.
Music cannot last without a positive strength of form; and this, no
matter what the source of it, the Chopin sonatas have.
So then, what do men mean when they state, in the face of the
enduring strength and beauty of these works, that Chopin has shown
himself ill at ease in them? Chiefly that these sonatas are different
from those of Beethoven. For the most part they choose to condemn
the difference, rather than to understand and appreciate it. But if the
verdict of time is worthy of consideration, this difference is not
condemnable, and an analysis of it will bring us face to face with
Chopin the innovator, not Chopin the insufficient.
It is usually in the first movement of a sonata that a composer either

proves his skill or discloses his weakness. It is the first movements
of these two sonatas that are brought into question before the courts
of theory. They will be found to differ in at least two distinct if not
radical features from movements of similar form by Beethoven. First,
in the self-sufficient breadth and splendor of the second themes.
Through these themes the composer speaks with his most intense
meaning; on them the music soars to its highest, flaming pinnacle of
beauty. This is obviously at variance with what we may call the
classical procedure. Early in the evolution of the triplex form, a
powerful tendency became evident to give to the first theme a
vigorous, declarative character, and to the second a softer, more
songful one. The first theme usually dominated the movement, and
the development of its significance was the life and flow of the music.
Generally the second theme, by reason of its contrasting character,
served to accentuate the meanings of the first. Chopin handled his
material otherwise. Though he preserved in a measure the
conventional character of the two themes, the first undergoes no
logical development, but whirls here and there in a sort of
tempestuous chaos for which the second theme offers sublime
justification. Except in the opening measures, the first theme is given
no definite shape. Neither in the B-flat minor sonata nor in the B
minor sonata does it reappear at the beginning of the third section. In
the development section of both sonatas it is but a fragment tossed
here and there on stormy harmonies.
The result is of course a lack of logical coherence. But one may well
ask if the hot intensity of utterance has not welded the notes and
parts of these movements into a complete fusion, if there is need of
logic in such molten music.
In the second place, the Chopin sonatas owe not a little of their
unique appearance to the composer’s great gift of harmony. The
foundation of the classical sonata form was harmonic, and, be it said
with due regard to exceptions, was rigid. Nothing was more
characteristic of it, both in the early and late stages of its use, than
the harmonic clearness of what one may call the approach to
themes, episodes, or sections, and the sharp definition of these
sections by what were fundamentally conventional cadences. Chopin
in his sonatas obliterated at least one of these sectional lines. It is
impossible to decide in the first movements where the middle section
ends and the last section begins. It is not only that the first theme
fails to make its reappearance. The harmonies surge on from the
development section into the last section with no trace of break in
their current. Even the cadences at the end of the first sections are
incomplete, and the modulations by which they progress sudden and
remote. Such procedures foretell unmistakably the endless
harmonies of Wagner. So does the treatment of the development
section in both sonatas, with the scattering of motives over never-
ending progressions of chords.
No sonatas, not even those of Beethoven, present such radical

variations from the accepted form; and naturally the question arises
whether such movements as these of Chopin’s are properly in
sonata form at all. One can only answer that Chopin named them
sonatas, and that they represent at least what he felt a sonata
should be. Mr. Shedlock has said of Beethoven that in aiming at a
higher organization, he actually became a disorganizer. One cannot
attribute such a conscious aim to Chopin; yet it is plain that his
instinct led him to the complete demolition of one or two of the
conventional restrictions of the sonata form.
Before leaving the sonatas there is a word to be said of Chopin’s
comprehension of the group of four movements as a whole. It is
such a comprehension on the part of a Beethoven that makes many
of his later sonatas and a few of his earlier ones indisputably grand.
In his case the successive dependence of the various movements on
each other is often made plain either by the actual merging of one
into the other, or by the employment of the same or cognate thematic
materials in all. Of such structural unity there is no trace in the two
great sonatas of Chopin. The separate movements are formally
complete in themselves, and not materially related. Any other union
between the separate movements of suite, sonata, or symphony, if,
indeed, it is not a matter of familiarity with the whole work, or of
respect for the composer, exists only in the mind of the hearer
according to his or her sensibilities. Of the Chopin sonatas that in B-
flat minor will probably impress most people as an impassioned and
powerful whole; that in B minor as less unified.
The Funeral March of the former has a double existence, one within
and one without the sonata. It is known that it was completed
perhaps before the sonata was thought of; and that certainly the
other movements were written in some sort of relation to it. The
finale which follows it cannot possibly be dissociated from the
sonata; and the first and second movements share a common
intensity of passion. Organic unity the series may not have, but its
phases of emotion lead, and almost blend, one into the other.
The two concertos, written as Chopin was on the verge of manhood,

have evidently not held, if ever they won, so high a place in
pianoforte literature as the two great sonatas. For one thing,
Chopin’s treatment of the orchestra is, according to most critics,
uninspired and unsatisfactory. But for another thing, their form is
conventional, and in submitting to a conventional ideal Chopin is
unquestionably ill at ease. Ten years later when he wrote the B-flat
minor sonata he was all past his age of submission, and made of the
form something new, shaped it fearlessly to his need of self-
expression. The Fantasia in F minor, written about this time (1840),
is longer than any single movements in the sonatas. Though
unconventional in structure it is none the less faultless.
There still remains a profoundly moving work of Chopin’s, which,

from the point of view of form, is astonishing. This is the Polonaise-
Fantaisie, opus 61, seemingly his last work for the piano in large
proportions. The Barcarolle, opus 60, was written probably about the
same time; and it is worthy of note that this perfect piece escapes
the grasp of most who would play it—i.e., interpret it in the only way
that music can be truly interpreted. The difficulty is usually ascribed
to its apparently rambling structure. But here, as in most cases
where the composer may seem to be at fault, the imperfection exists
in the player, not in the music. The right touch and the right quality of
fervid yet delicate poetic imagination will reveal in the Barcarolle a
poem in music of the most exquisite proportions. It is a work of
matchless beauty. But the Polonaise-Fantaisie is not lyrical; it is
intensely dramatic. It builds itself out of the strength, the weakness,
the despair of unnamed forces in conflict. It is the cry of Poland in
her agony, the pride of her people, crushed and tormented, in a
broken voice.
The clashing moods of the piece are not of the sort that can be
regulated and made orderly within even the expanded forms of
conventional art. The grief and despair, the wrath, the pity, the
unconquerable pride and hope of Chopin, shuddering like a great
harp in the wind of destruction that has swept over his country, here
demand and take on unfettered freedom of expression. The result is
a work which reaches over Liszt to the symphonic poems of modern
writers. It is probably not of historical importance; but it is of great
significance as testimony to Chopin’s constructive originality. Liszt
said of it that because of its ‘pathological contents,’ it must be
excluded from the realm of art. If Chopin had chosen to supplement
the piece with a few words as to its meaning, a program, as the
phrase goes, Liszt would have had to judge differently, or else by the
same token exclude other great works from the hallowed aristocracy
to which he denied this one entrance.
At the other extreme of Chopin’s achievements stand the twenty-four
Préludes. Some of these, like the eighth, fifteenth, sixteenth,
nineteenth, for example, are well-rounded and completed pieces,
which have not more of the spirit of improvisation which one
associates with the term ‘prelude’ than his longer works. But many
others are hardly more than fragments, or sketches, or
instantaneous impressions. In pieces of such length, form is of no
importance. What is perhaps unparalleled is their vividness. They
seem now like a veiled glow, fading into darkness, now like a
momentary flash from that region of secret fire in the light of which
Chopin ever lived.
So Chopin’s power of expression showed itself new, fine, and broad.

He is a master of presentation. There are but three or four of his
considerable works of which one may say that they show uncertainty
in judgment, an awkwardness in line, a clumsiness in balance. The
vast majority of his compositions are perfect in shape and form, and
flawlessly put together. If only we at this day might hear them unfold
through his magic fingers! For, no doubt, what seems weak or
unstable to the cautious judgment that relies upon standards of more
rational genius, seems so only because the key is lost that will open
to view the delicate machinery in all its perfect assemblage.
III
Chopin is second to no composer as a harmonist. In this respect, it
now seems he stands directly in line with Bach and Mozart. The
fabric of the music of all three is chromatic; but it is usually so
delicately woven that its richness is accepted almost unconsciously
by the listener. Like Bach, Chopin wanders where he will in the
harmonic field. Like Mozart, he is ineffably graceful and subtle. The
foundation of his music is a series of widely varied, yet blending
chords. He is rarely startling. His modulations are swift and flashing;
but they seldom if ever seem abrupt.
On the whole his music has few conspicuously unusual chords. The
crashing dissonances just before the end of the Scherzo in B minor
are exceptional. So are the wild bursts in the prelude in D minor. But
there are sequences of chords which, when analyzed, show an
amazing boldness. For example, the opening measures of the
scherzo in the B-flat minor sonata; the middle section of the study in
C minor; the swirl of chords before the coda in the F minor Ballade;
the long modulating passage between the A major and E-flat major
portions of the G minor Ballade; the whole of the study in broken
chords; and countless others.
He is fond of shifting the harmony down through chromatic steps, as

in the prelude in E minor and the mazurka, opus 17, No. 4. Rushes
of chromatic sixths and fourths, such as are in the E minor concerto,
at the beginning of the great polonaise in A-flat major, and the
scherzo of the B-flat minor sonata, are effects of color more than of
harmony. But he gets magnificent harmonic effects by sending wide,
whirring chords through half-steps down or up the scale, as in the
first meno mosso section of the scherzo in C-sharp minor, or in the
cadenza-style passage of the study, opus 10, No. 3. Yet again,
before the return of the first motives in the study, opus 25, No. 6,
there is a long cascade of diminished seventh chords. Sometimes he
leads his music through broader progressions, which are in effect
diatonic. The dropping of the music from its dramatic height in the C-
sharp minor portion of the ballade in A-flat major, the long
descending play with the triplet motive in the middle section of the
second scherzo, and all the second part of the scherzo in the B-flat
minor sonata offer examples of this bold harmonic stride.
One may take up a handful of Chopin’s music almost at random and

find signs of his harmonic boldness, and there is hardly a line of it
which does not reveal his ever subtle power over chromatic
alterations. This is so fine and really so ever present as almost to
defy analysis. Yet one or two pages in which it is unusually
suggestive may be cited. All the first part of the scherzo in B minor,
particularly the second section of it, is but a play with chords which,
but for the unpleasant connotation of the word, might almost be said
to writhe, so are they twisted and interwoven by a ceaseless
alteration of their fundamental notes. By reason of this same
chromatic litheness, both the study in C major, opus 10, No. 7, and
the coda of the second ballade take on a shimmer of harmonic light.
The chromatic scale has often been used for a sort of windy or
surging effectiveness in pianoforte music. Witness the first
movement of Beethoven’s concerto in G major, Weber’s Rondo in C
major. But rarely in any music has it been used so melodiously as in
Chopin’s. Sometimes it is but a strand over which other strands are
woven, as in the colossal Étude in A minor; but even more
remarkable are those cases in which he contented himself with the
unadorned scale. The studies in A minor, opus 10, No. 2, and G-
sharp minor, opus 25, No. 6, rest upon the ordinary familiar
chromatic scale, perhaps the gaudiest of the virtuoso trappings; yet
even the first of these, in its frankly étude manner, has an
uncommon beauty, and the second has more than an earthly charm.
Neither study depends upon a vague, windy effect. Both demand
rather a distinct touch. We have then a chromatic scale in which the
separate notes are constantly audible throughout the entire piece, a
chromatic scale, turned by some alchemy of which Chopin alone
possessed the secret, into graceful melody.
It is in a sense this power in Chopin to turn every note to melody that

is the secret of the perfection of his style. We may pass over his
characteristics in the broader melody. These, like the qualities of
Bach’s, Mozart’s and Schubert’s melodies, are of an essence that
escapes words. The metaphor is perhaps sickly—but one may as
well attempt to catch firmly in words the fragrance of flowers. But the
power over a more subtle melody, what one might call an inner
melodiousness, is so striking in Chopin that it may not be passed at
least without special comment. Bach and Couperin possessed the
same kind of skill; and this, though manifested in almost radically
different forms, and applied upon a wholly different instrument,
makes their music unqualifiedly welcome upon the modern
pianoforte. In the case of Chopin, it was brought to bear upon our
own instrument, and wrought the perfect style for pianoforte music, a
style which conforms to the special qualities in the instrument of
which we have elsewhere spoken at length. (See Introduction.)
In Chopin accompaniment figures for the piano are brought to their

highest perfection. It may be fundamentally his choice of harmonies
that gives them a richness not to be found so generally in any other
music for the instrument. Here must lie the secret of the beauty of
certain passages, like that of the melodious second theme in the
scherzo in B-flat minor, where the accompaniment is only a series of
chords, the movement or rolling of which is not at all unusual. But in
the formation of figures there is often a distinction peculiar to Chopin
alone.
First one notices the wide spacing of the notes, the avoidance of all
thickness such as often makes the pianoforte music of Brahms
unsatisfactory from the point of view of the pianist. By means of
these widely spaced figures he obtains a sonority of after-sounds
from the piano in which the overtones and sympathetic vibrations
play a great part. It is never muddy or thick. There are many pages
of his music which show group after group of these figures employed
to give only a shimmering, not a distinct harmonic background to the
melody which he wishes to set forth. One remembers the nocturnes
in C-sharp minor and D-flat major, the study in A-flat major, opus 25,
No. 1, and countless passages in other works.
Frédéric Chopin.
After the portrait by Ary Scheffler.

These undulating figures are no more than the Alberti bass,
developed to suit the piano. To the student they offer little more than
an example of wholly satisfactory spacing of notes on the keyboard.
But Chopin is rarely so simple. In almost all his accompaniments
based on broken chords he introduces something of an independent
spirit. This shows itself either in the suggestion of an inner melody
which here and there joins richly with the chief subject; or in the
accentuation of certain notes of harmonic significance. In neither
case does the accompaniment take on a definite line, as it so often
does in the music of Brahms. Particularly in the latter case, the
accompaniment is still vaguely sonorous, the separate notes not
more distinct than they must be to preserve a sense of gentle or
vigorous movement.
It must not be supposed that these notes, which accentuate

harmonic coloring, are literally to be emphasized. They are rarely
marked with accent signs. But Chopin has so placed them at the
height of the figure that they must stand out, even if played more
lightly than the notes with which they are associated. The
accompaniment of the second theme in the sonata in B minor,
especially the later portions of it where it is broken into groups of
sixteenth notes, offers proof of a subtlety in awakening a sensuous
volume of sound out of the piano which is at once vague and distinct,
that can hardly be matched.
As for the flashes of counter-melodies, of hidden strands of music

which enrich his accompaniments, we approach here into one of the
mysteries of Chopin’s genius. It is in suggesting these that the
technique of the pianist frequently fails. There is need of a touch at
once pointed and yet often as gentle as a breath. Sometimes these
magical notes are at the extremity of a wide space. Chopin has
written a study—opus 10, No. 9—which deals almost wholly with this
difficulty. Again they are concealed in the very middle of the figure,
as in parts of the accompaniment of the nocturne in D-flat major.
Finally there are accompaniments which are all elusive melody. How
many melodies are there, for example, within the accompaniment, if
so it may be called, of the nineteenth prelude; in the magnificent
passages of the fourth ballade, before the coda; in the first E-flat
major section of the first ballade? Even where figures have given
way in passages of utmost sonority to chords, there is a full melodic
life here and there. The accompanying chords in the big passages of
the Barcarolle, just before the end, have indeed almost a polyphonic
significance.
Here then is that inner melodiousness of Chopin’s music which goes

far towards making it the great work of art that it is. It is so little
explicit, often hardly more than suggested, so delicate and so
infinitely varied that one must for ever question just what the nature
of it is. Yet if one tries to analyze Chopin’s style, his treatment of the
keyboard, his unmatched grace and elegance and fervor, it is
precisely against this inner musical life that one must ultimately
come to pause. There are conceptions of emotion expressed in
pianoforte music which are perhaps grander than his because less
personal; there are other works for the piano that are more abstract
and seemingly therefore less capricious; but there is perhaps no
music which quite like his has called forth the full spirit of the most
mechanical of the string instruments.
Is it essentially polyphonic music? The first canon of the pianoforte

style is movement. That is a mechanical necessity. The strings must
be kept in vibration, constantly touched. In music so fine as Chopin’s
this movement must be found to have a beauty in itself. It must be
ever varied. It must take on an independent character of its own. So
far, in studying accompaniment figures, one finds in them an almost
never-absent suggestion of such a life. Perhaps one of the greatest
proofs of Chopin’s skill is that he rarely attempted more than to
suggest it. For he knew above all things his piano. He knew its great
power over chords and harmony, that music for it must first of all
bring out this richness of vibration of which it was capable. He knew
that the logical, consecutive movement of the polyphonic style left
his piano more than half dumb. Polyphony was no outlandish book to
him. Many an anecdote testifies to his worship of the ‘Well-Tempered
Clavichord’; many to his ability to reveal as few, perhaps no others,
have been able to do, the beauty of the preludes and fugues in it.
But in his own music he submerged polyphony, so to speak, just
beneath the sea of moving harmonies. Over and through the fine
silver network his harmonies swirl and flow like waters. Only now
and then a strand of it shines clear; but always its presence may be
seen, though its lines quiver and break.
Now and again one comes across measures in his music which do
more than hint at the sterling imitative style of the old masters, or
that show a grasp of that sort of logical technique which is able to
weave a single motive or two into various shapes, a highly
concentrated sort of music. These are neither more nor less beautiful
than other measures, and surely their value is the value of all his
music, not enhanced by the evidence of a highly respected technical
skill. The fourth ballade gives surprising examples of this intensive
art. The few measures in canonic style which bring back the principal
subject are worthy of study; but even more remarkable is the page of
music which precedes them. Here, following an episode in which the
steady rhythm of the whole great work takes on almost the gaiety of
a dance, we come upon music of the most profound character, fully
and sonorously scored, rich in harmony, expressive of passion. The
bass part is one variant of the chief subject, the treble part is
another. Here is skill of the sort that brings praise to Brahms; but in
the music of Chopin to mention it is hardly worth while, so little,
rather so entirely not at all, is it an end in itself.
Finally there are pages of his music in which the movement of his
accompaniment are so free and extended, or so interwoven with
what seems the chief idea, that one is at loss to classify them as to
style. These it seems to us are the result of his finest art of writing for
the piano. In some cases it is easy to speak of the accompaniment
as an arabesque, with the implied meaning that, delicately and
carefully as it has been shaped and perfected, it remains of
secondary importance. So, for instance, with the little prelude in G
major, and, to a somewhat greater extent, the study in C minor, opus
10, No. 12. But the prelude in D major is a net of sounds from which
nothing but shimmering harmony shines out, though there are two
voices for ever entwining about each other. Which is melody and
which accompaniment in the prelude in F major? What is going on
within the prelude in F-sharp minor, that outwardly seems but a
broad melody with whirring accompaniment? At last, in the later
works, one comes across accompaniments running from top to
bottom of the keyboard, every note of which is but part of a melody.
Take as examples of this art the following passages from the fourth
scherzo:
These few measures are typical of the essence of the keyboard,

rather the pianoforte, style of Chopin, a style showing a grace and
flexibility highly characteristic of his music in general. One finds such
art only very rarely in the works of other composers since the time of
Bach and Couperin, as, for example, in the second Intermezzo in the
second number of the Kreisleriana and at the end of Brahms’
Caprice in F-sharp minor, opus 76, No. 1. It is the sort of music
which sounds best on the pianoforte, which cannot give the same
effect on any other instrument nor by any combination of
instruments. There are the constant movement which is necessary to
keep the piano vibrating, and the richness of harmony which belongs
to no other single instrument except the organ. The homogeneous
nature of the scale gives to the runs a continuity of line and of color
that is almost uniquely proper to the piano. The single notes of the
runs drop with the bell-like quality which likewise belongs only to this
instrument. At last it must be noted how the sound of it all floats and
changes. This is strikingly a sonority of after-sounds.
In the case of the above selection from the Scherzo this is obtained
by the arrangement of chords with the broad melody of the left hand.
Of the six chords that are struck four are left to vibrate during two
measures; that is to say, that five-sixths of their value is given only in
after-sounds. Against this tonal background are arranged the rapidly
moving notes of the right hand, which a careful study will show
accentuates in varying fashion the floating harmonies of the left. So
that the whole passage has not only a vague shimmer but a
sparkling radiance as well.
In the following selection from the same piece it will be noticed that
this sonority is built up by the movement of the accompanying
figures which at the same time sprinkle their own mist with sparks. It
is like the passage of a faint comet through the sky, leaving a trail of
apparently substantial light. And here this drifting light of sound
resolves itself into definite harmonies, in the third, fifth, seventh,
ninth, fourteenth and fifteenth measures. The substantial harmonies
of the passage are very obviously established by the chords in the
left hand part; but it is the movement of the right hand that makes
them glow and darken as it were. In those measures not mentioned
above, this movement seems to weave a mist about these
harmonies, which, in the measures we have numbered, clears for an
instant and lets the light through. And that the notes in this
movement which have such an harmonic clarity may be not so much
emphasized as retained is one of the fine points in the playing of
Chopin which the unskilled player is likely wholly to miss, and with it
the elusive subtlety of Chopin.
The ordinary pianoforte style of running figuration generally is made

up of simple arpeggios or scales. Liszt does not often show himself
master of more than such. It is only Chopin who envelopes his
harmonies in such an exquisitely spun thread of melody. The last
measures of the Barcarolle show such a thread of pure gold, woven
and twisted as no other composer for the piano has been able to
spin.

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Placebo effects : understanding the

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List of boxes xxv

1. A brief evolutionary account of medical care 5

2. Emergence and development of scientific medicine 24

2.3 Medical practice meets neuroscience 43

3. Feeling sick: a combination of bottom-​up and top-​down events 49

4. Seeking relief: the activation of motivational and reward circuits 88

6. The brain of the demented patient 155

7. The traditional concept of placebo 175

8. A modern view of placebo and placebo-​related effects 193

8.4 Why they occur 227

10. Pain 259

11. Diseases of the nervous system 303

12.5 Psychotherapy 352

14. Cardiovascular and respiratory system 393

14.2 The respiratory system 400

17. Clinical–​ethical implications and applications 447

19. Physical and cognitive performance 499

19.2 Performance at high altitude 505

1.1. Understanding human behaviour and emotions of the past 19

15.1. Irritable bowel syndrome 412

• In this chapter, medical care is approached from an evolutionary perspective. It

1.1 Simple organisms can take care of themselves

1.1.1 Unicellular organisms use simple strategies to protect themselves

Amoeba Microbial cyst

1.1.2 The withdrawal reflex is present in both invertebrates

1.2 From the scratch reflex to grooming

1.2.1 The scratch reflex is a simple purposive behaviour

Cutaneous Left leg

1.2.2 Grooming involves a complex behavioural repertoire

1.3 Scratching somebody else: a big evolutionary jump

1.3.1 Primates spend plenty of time in social grooming

1.3.2 From social grooming to altruistic behaviour

1.4 Taking care of the sick

1.4.1 From early forms of altruism to the emergence of the shaman

The first of these is almost in no way representative of the composer.

It may be reserved to the trained critical mind to decide what is great

Of course it will be urged in explanation of the popular acceptance of

It is usually in the first movement of a sonata that a composer either

No sonatas, not even those of Beethoven, present such radical

The two concertos, written as Chopin was on the verge of manhood,

There still remains a profoundly moving work of Chopin’s, which,

So Chopin’s power of expression showed itself new, fine, and broad.

He is fond of shifting the harmony down through chromatic steps, as

One may take up a handful of Chopin’s music almost at random and

It is in a sense this power in Chopin to turn every note to melody that

In Chopin accompaniment figures for the piano are brought to their

After the portrait by Ary Scheffler.

It must not be supposed that these notes, which accentuate

As for the flashes of counter-melodies, of hidden strands of music

Here then is that inner melodiousness of Chopin’s music which goes

Is it essentially polyphonic music? The first canon of the pianoforte

These few measures are typical of the essence of the keyboard,

The ordinary pianoforte style of running figuration generally is made

3. Feeling sick: a combination of bottom-up and top-down events 49

8. A modern view of placebo and placebo-related effects 193

17. Clinical–ethical implications and applications 447