Download The Placebo Response

The Placebo Response:
The Psychology of Mind/Body Healing
Richard Kradin, M.D.
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What is the placebo response? Why is it important? How does it contribute to the treatment of
disease? Can the mind influence the body to promote healing, and if so how? The answers to
these questions continue to evade medical science. In fact, medical scientists continue to
disagree about what the placebo response is and as to whether it plays an important role in
therapeutics.
In a recent report (Patterson 2002) Dr. Andrew Leuchther, a psychiatry professor at the
University of California, Los Angeles reported on the results of imaging the brains of patients
with major depression, who had shown positive responses, not to an anti-depressant, but to a
placebo. According to Dr. Leuchter:
We were just looking at the placebo group as a control group. It was really quite a surprise to
us when we....could see that they had significant changes in brain function.
What his research team had discovered was that the brains of the placebo responders showed
comparable changes to those patients who had had a positive response to antidepressants. The
findings appeared to indicate that placebos can change brain chemistry in a similar way to
"active' medications. But as illuminating as the findings were, Dr. Leuchther’s level of surprise
is emblematic of the incredulity that many learned physician scientists express concerning the
ability of placebos to yield substantial and objective changes in the physiology of the body.
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But this surprise is no less than what has been experienced by doctors and patients when wellaccepted therapeutic approaches prove to be no more effective than placebo. Consider a recent
study where a widely known joint surgery procedure was compared with a sham placebo
surgery, in the treatment of osteoarthritis (Moseley, O et al. 2002). In this study, one group
received arthroscopic joint surgery while another group was anesthetized, injected with a local
anesthetic, given three stab wounds in the skin with a scalpel, but subsequently no surgery to
remove arthritic tissue in the joint was performed. Both groups showed comparable levels of
improvement with respect to knee pain at six months following their "surgeries."
Few physicians would be willing to abandon what appeared to them to be an effective and
innocuous means of alleviating patient discomfort. This idea has been seconded by the
following remarks of a seasoned physician (Cassells 2004):
I would happily give up the use of (say) calcium channel blockers, as important as
they have been in the treatment of heart disease, if I could be assured a similar
mastery of the placebo effect; it would be useful in more patients. One would
think that something as potent as the placebo effect would have been subject to at
least as much study as most pharmaceuticals, but that is unfortunately not the
case.
It is fair to say that few clinicians have a clear understanding of what the placebo response is.
This is in part due to the fact that the role of placebos in therapeutics has continued to change
with medical progress. The term placebo was originally coined to denote interventions
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intended to placate patients, but without the expectation that they would provide objective
benefit. In fact, placebo responses precede placebos. Before medicines or surgeries were
conceived, the placebo response was the only healing agent. It represents a mode of healing
unrelated to human technology. It is a part of man's genetic endowment. Like fly-paper, the
placebo response inheres to man-made therapies and placebo effects potentially contribute to
all therapeutic effects.
The history of medicine can be summarized by the following statement:
The “scientific” therapy of today is at risk of becoming tomorrow's placebo.
Healing
All is flux; nothing stays still- Diogenes
If the placebo response is a mode of healing, what exactly is healing? The term healing is from
Old German and is cognate with "wholeness." From this perspective, disease represents a
disruption in mind/body integrity. It implies that something has been lost that requires
restoration. According to the Greeks, the normal function of the body depended on the relative
balance of four humors, blood, choler, phlegm, and black bile (Porter 1997) linked
conceptually to the Aristotelian idea of the four elements-- air, fire, water, and earth-- and to
the quaternity of hot, cold, wet, and dry. Disease was rooted not by a specific defect in
structure but in an imbalance of the humors. Healing was the restoration of optimal
balance.
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Seemingly miraculous healing occurs with regularity in animals. Reptiles can regenerate an
entire limb without ever seeing a doctor. This fact was not lost on early man who must have
wondered at such phenomena. It explains why the caduceus, i.e., a wooden staff entwined by
two snakes, has been the symbol of medical therapeutics since antiquity. While humans do not
have the healing capacities of reptiles, a multitude of physiological restorative processes
operate in the service of health. These including the continuous repair of genetic mutations, the
elimination of infectious agents, and the destruction of incipient neoplasms by immune
mechanisms that serve to maintain health. These processes are highly efficient, automatic, and
occur outside of awareness. They are the reason that we rarely require medical attention. They
are distinct from the placebo response in that they do not occur in a therapeutic setting.
When we fall ill, a variety of physiologic processes are automatically activated. Scientists have
coined the term sickness behavior to describe the isolation, weakness, fatigue, and anorexia
that characterize illness. Cytokines, small proteins are released by immune and other cells in
response to infection and cell injury and they serve as bidirectional signals between the
nervous and immune systems during illness. The release of cytokines, including interleukin-1
(IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), and a host of others, result in the
fevers, malaise and fatigue that characterize sickness (Kluger, Kozak et al. 2001). However,
the same cytokines serve to limit microbial infection. In other words, the healing response is
Janus-faced, as it is both the cause of sickness and its potential cure.
From the perspective of the placebo response that is activated within an interpersonal
therapeutic milieu, sickness behavior is an important non-verbal communication. Social
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animals, like primates, can readily identify when a member of the group is sick. However, the
response to sickness is tentative as it can include either concerned attentiveness or aversive
avoidance.
This dichotomous response to sickness is seen in man, so that according to Roy Porter (Porter
1997) the sick persons was either:
treated as a child, fed, and protected during illness or incapacity.
or alternatively:
ritually expelled, becoming culturally dead before they are biologically dead.
Hunter-gatherer bands were more likely to abandon their sick than to succor
them.
Where then does the motivation to care for the sick arise? There is prima facie evidence that
compassionate concern is primarily rooted in mammalian mother-child dynamic (Katz 1984).
The uncertainty of eliciting therapeutic responses within early male-dominated hunter-gatherer
groups may explain why the responsibility for medical care was eventually assumed by
specific individuals within the group (Fabrega 1997). Medical professionalism helped to insure
that therapeutic attention and expertise would be reliably available to early man. These early
shamans combined availability, knowledge, and what appeared to be supernatural powers to
heal. In other words, they had mastered the capacity to evoke the placebo response.
In the ancient Greek Asklepian healing ritual, the sick patient was isolated from everyday
activities, perhaps in an effort to recapitulate sickness behavior. The prescription for healing
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was transmitted via a dream, recognized at the time as a message from the gods, or from what
today we would term the unconscious. The physician's primary role was to attend to the patient
and assist in enacting the prescribed cure. But the cure was invariably the result of the placebo
response.
As far as can be ascertained, as late as the 17th century, the therapeutic armamentarium
included no specifically active treatments for disease. Therapies were based primarily on
complicated systems of bleeding, diuresis, and purgings, none of which would pass muster as
therapies today. An increasingly enlightened population viewed physicians as either
meddlesome or frankly dangerous. The deathbed scene of King Charles II of Great Britain
highlights this situation (Shapiro and Shapiro 1997)
Sixteen ounces of blood were removed in his right arm with immediate good
effect… They ordered cupping glasses to be applied to his shoulders forthwith,
and deep scarification to be carried out by which they succeeded in removing
another eight ounces of blood.. Strong purgatives were given, and supplemented
by a succession of clysters. The hair was shorn close and pungent blistering
agents were applied al over his head; and as though this were not enough the redhot cautery was requisitioned as well.
Suffice it to say, the King died. It was not until the 18th century that a truly non-placebo drug
was identified (Shapiro and Shapiro 1997).
Medicine and Uncertainty
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In the 19th century, Claude Bernard introduced experimental medicine as the basis for medical
practice (Bernard 1878). This unquestionably led to progress in the treatment of a host of
disorders . But there are important differences between the experimental approach in the clinic
and that adopted by the physical sciences, e.g. physics and chemistry. In the physical sciences,
all aspects of nature are potentially targets for experimentation. A dispassionate scientist
develops a hypothesis and then devises a well-controlled experimental design, in order to test
it. By contrast, clinical research is driven by medical practice, and its aims are biased towards
promoting the well-being of the public.
Furthermore, it is a cardinal rule in the natural sciences that experimental results are only
accepted as accurate if they can be reproduced by other scientists. These experiments are
conducted at standardized temperatures, pressures, and under other rigorous environmental
conditions. In addition, they are repeated manifold.
Compare this scenario with that of present day clinical trial, the approach via which new drugs
and procedures are evaluated. As might be expected, it is far more difficult to control for the
individual differences between patients and the environment in which these trials are
conducted. As a result, clinical experimentation is rarely rigorous. As a result, the chances that
the results obtained via medical experimentation will be generally reproducible are diminished.
Medical science also views biological phenomena as linear events, when, in fact, they often are
not. Instead, they are complex and may require different experimental design and analysis in
order to be optimally interpretable.
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For instance, take the current controversy concerning the potential side effects of popular
arthritis drugs called COX-2 inhibitors. These drugs interfere with prostaglandins, a molecules
that cause inflammation, fever production, and blood clotting. Doctors are presently unable to
agree about the possible cardiac risks of these drugs, precisely because the results of clinical
trials differ substantially(Ozols 2004). But such differences are the rule, not the exception.
How placebo responses contribute to this confusion has not been fully considered. It is clear
that they virtually always occur in clinical trials, and sometimes at very high rates, but why this
should be the case is generally ignored. What has plagued understanding of the placebo
(Harrington 2002) is the fact that it represents the ambiguous border between subjectivity and
objectivity. But placebo responses are not imaginary. They yield specific changes that can be
observed and quantified. As Jay Katz notes in his text The Silent World of Doctor and Patient
(Katz 1984):
Modern medicine remains caught between science and intuition. This is not
necessarily bad; indeed, medicine may have to be ruled by both science and
intuition for a long time to come. What is disturbing though is that physicians are
so reluctant to acknowledge to themselves and their patients which of their
opinions and recommendations are based on science and which on intuition.
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Physicians on the front lines of medicine, and daily faced with sick patients demanding relief
from their ailments, have always shown an inclination towards therapeutic improvisation.
Furthermore, medical science has, since its inception, been confounded by a sizable population
of patients with psychosomatic disorders, whose complaints defy scientific explanation (Kradin
1997). Many of these patients were and continue to receive placebos.
The Randomized Controlled Clinical Trial
Prior to the 1930's medical therapeutics were based exclusively on the anecdotal observations
of astute clinicians. Harry Gold, a clinical pharmacologist, recognized that the scientific
evaluation of a new therapy could not be left to this practice (Shapiro and Shapiro 1997),
precisely because placebos were also therapeutic. According to Gold, a bona fide therapy
should be superior to placebo.
Patrick Wall, an anesthesiologist has outlined the design of the randomized controlled clinical
trial (RCT) succinctly (Wall 2000):
A group of patients with some definite problem, e.g. a wisdom tooth extraction,
are asked to volunteer for a trial. They are told that they will receive the new
tablet(to relieve pain) or one that looks exactly the same. Then the patient, who
does not know which tablet he received, tells an observer, who is also unaware of
the nature of the tablet, whether the tablet reduced his pain. Finally after all the
data has been collected, the code is broken and it is calculated whether the new
drug is superior to placebo.
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In theory, the design is sound. But in practice, problems, both of a scientific and ethical nature,
have haunted this approach since its inception. Some interventions, e.g., surgeries, and a host
of alternative/complementary therapies, including yoga or acupuncture, psychotherapy, etc.,
are notoriously difficult to randomize, accounting in no small way for their continued but
unsubstantiated therapeutic claims. In addition, the groups being tested in RCTs are rarely
large enough to include all of the types of people who might eventually receive the therapy.
With the advent of the RCT, placebos, previously the basis of all medical therapeutics, were
radically transformed from benign interventions aimed at placating patients into undesirable
therapeutic confounders.
But if placebos are "inert," one might expect that effective therapies should have no problem
outperforming them. This is not the case. In an oft-quoted paper entitled the "Powerful
Placebo," Henry Beecher, a Harvard anesthesiologist concluded that placebos were
therapeutically effective approximately 35% of the time (Beecher 1955). And in certain
disorders, e.g., mild major depression, placebo response rates in RCTs can be so high as to
preclude the ability to establish superiority of the drug being examined (Zimbroff 2001)
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Placebo Effects- Who Gets Them?
Health that mocks the doctor's rules, knowledge never learned of schools- John Greenleaf Whittier
It has long been assumed that certain types of patients are prone to developing placebo
responses. During the 1960s and 1970s, investigators made efforts towards determining the
personality traits that might predispose one towards being a placebo responder.
Arthur Schapiro, a psychiatrist at the New York Hospital-Cornell University and Mt. Sinai
Medical Centers, devoted his career to investigating placebo responses. He noted that the
presence of chronic anxiety and mild depression both predicted positive responses to placebo.
But he added that
In our studies and others there appear to be no consistent data relating these variables
or demographic variables such as age, sex, intelligence, race, social class, ethnicity,
religiosity, or religious background to placebo reaction. (this author's underlining)
Despite long standing beliefs to the contrary, there were no specific traits that reproducibly
characterized placebo responders. Rather, the findings appear to suggest that placebo responses
might be a shared human potential that is variably evoked within a therapeutic relationship.
A number of studies have demonstrated that the attitude of caregivers can yield significantly
different results. In the 1930's, W.R. Houston (Houston 1938)” reported on how physician
behavior influenced therapeutic outcomes in a paper entitled, “The Doctor Himself as a
Therapeutic Agent.” In a 1994 article in the Lancet, K.B. Thomas (Thomas 1994). showed
that the patient’s perception of the clinician as optimistic, experienced, and competent,
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influenced the outcome of therapy. In another study, Thomas (Thomas 1987) demonstrated that
the level of attention paid towards the patient, as judged by the number of visits with health
care professionals, was the most significant factor in predicting placebo responses.
Psychotherapists have long recognized the therapeutic importance of concerned attention, but
modern medical science has been reticent to credit human interactions with therapeutic effects.
In the 1960s, Michael Balint, a psychoanalyst, championed the idea of introducing
psychoanalytical theory and techniques into the delivery of primary medical care. Balint
summarized the state of medical practice as follows (Balint 1972):
Nowadays with more and more of us becoming isolated and lonely, people have
hardly anyone to whom they can take their troubles. It is undeniable that fewer
and fewer people take them to their priests. The only person who is available ... is
the doctor. In many people, emotional stress is accompanied by or tantamount to
bodily sensations. So they come to their doctor and complain.
Approximately 63% of patients with anxiety or depression, with or without physical
symptoms, are treated by their family doctors (Shorter 1985). And a substantial percentage of
patients have given up on traditional medicine altogether, preferring instead to seek out
alternative/complementary modes of treatment (Eisenberg, Davis et al. 1998). This group may
be justified in their choice, as the average consultation with a family doctor in the U.S.A. is
eleven minutes; and this is twice as long as a visit in the UK! Obviously, this is hardly
sufficient time for most patients to communicate their concerns.
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Psychotherapy and Placebo
As psychological factors contribute to the development of placebo effects, one might wonder
whether the beneficial effects of psychotherapy may be attributable, at least in part, to the
placebo response. In a meta-analysis of 25,000 patients treated with 78 forms of
psychotherapy, psychotherapy did prove to be more effective than wait-list controls, but there
were no differences attributable to either the method of psychotherapy, therapeutic setting,
duration of treatment, types of patients or the training of therapists (Smith, Glass et al. 1980).
Some have concluded from these results that psychotherapy is basically ineffective (Eysenck
1994).
Placebo and Meaning
Definition in experimental psychology is a difficult problem. In an effort to operationalize
thoughts, affects, and behaviors, cognitive and behavioral scientists may compartmentalize
mental factors in ways that are frankly artificial. So one might be understandably confused
concerning the fine and overlapping distinctions between expectancy, hope, beliefs, and
meaning. Daniel Moerman, a medical anthropologist, has stressed the critical role of meaning
in his studies of the placebo response (Moerman 2002). He argues that the idea of the placebo
as an inert substance does not jibe with their efficacy in practice. Moerman further suggests
that meaning is so critical in determining the outcome of therapeutic interventions that the term
meaning response should replace placebo response in the literature.
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Cultural, societal, and religious differences all contribute to how meaning is construed by
individuals. Furthermore, as Bootzin and Caspi have suggested, placebo responses are not
static(Bootzin and Caspi 2002):
They evolve and change in response to biological and psychological signals that
play a role in the therapeutic process...The placebo effect always interacts to an
unpredictable degree with other elements of the therapeutic intervention... Albeit
methodologically very complex and difficult to test, the interaction implies that
even in experimental arms of randomized controlled trials the placebo effect may
account for some of the outcome we measure.
Consider the large numbers of treatments that were at least partially effective in ancient times.
It is difficult to imagine that a sophisticated urban dweller would derive substantial therapeutic
benefit from “eye of newt.” Placebo responses occur within a specific therapeutic setting, but
their potential meaning is also dependent on a host of other societal factors.
So far, arguments with respect to the role of meaning in placebo responses are compelling. But
the term meaning respons does not clarify how placebo acts. It furthermore loses precision
when one begins to inquire as to what specifically is meant by "meaning"?
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Mechanisms of Placebo Response
The fact that laboratory animals could develop conditioned responses that mimicked placebo
responses in the medical literature prompted Hernstein in 1962 (Hernstein 1962) to publish an
article entitled Placebo Effects in the Rat. Hernstein reasoned that if rats could develop placebo
responses, then placebo effects must be the result of conditioned responses. He argued against
the prevalent notion that placebo responses were a function of symbolic thought and
challenged the notion that they were based on the relationship between patients and their
doctors.
Elements of Hernstein’s argument are undoubtedly correct. Carefully designed “placebo”
experiments with ethanol, nicotine, and a variety of drugs, support the conclusion that prior
conditioning and expectations may contribute to placebo responses. But how can these findings
and the time-honored importance of the doctor-patient relationship be reconciled?
The problem may reflect how psychology and neurobiology overlap. Conditioning, meaning,
expectation,etc., are all dependent on learning and memory. As will be discussed, conditioning
represents a specific linking of learned neural pathways in the nervous system. Hernstein's
argument is valid, but it is too limited because the range of human memory includes
relationships with early caregivers, and these include conditioned emotional and mind/body
states that may be recalled in the context of the therapeutic situation.
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In a series of elegant experiments, the placebo researchers Price and Benedetti independently
demonstrated that placebo analgesia is dependent on opioid pathways (Benedetti and Amanzio
1997). These researchers have extended their observations to explain how conditioning and
expectancy might both contribute to placebo analgesia.
Placebo and Memory
Any convincing theory of the placebo response must address how the mind and body are
physiologically integrated. I propose that memory provides the basis for how placebo
responses are generated. The psychologist Daniel Siegel has suggested that memory can be
defined as the way that past events determine future behaviors (Siegel 1999). From a neural
Darwinian perspective, what has been repetitively learned has an adaptive advantage of being
recalled precisely because the probability of accessing a previously selected pathway of
memory is increased. The essence of memory is a neural reconstruction of experience that can
be retrieved precisely because it has an increased chance of being so. The probability of a
certain neural pathway being remembered is the result of strengthened connections between
distributed neurons. Memory storage represents stable synaptic connections within the nervous
system that in some cases are maintained over the life of the individual.
Memory can be categorized in a variety of ways. Memories can be termed as either explicit or
implicit, i.e., one either consciously or explicitly recalls what was previously learned, or it
becomes part of implicit memory that can be retrieved without conscious recall. Explicit
memory can be further subdivided into declarative semantic and episodic memories. Semantic
memory is the information that one attempts to recall, e.g., when taking a school exam. It
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includes previously learned names, dates, places, and ideas. Semantic memory requires
conscious attentiveness both to what is being learned and recalled. In the brain, it depends on
activation of an area called the hippocampus both during encoding and retrieval (Siegel 1999).
Unlike semantic memory, episodic memory is the autobiographical recall of one’s life
experiences. It is linked to the "tensing" of time, into past, present, and future, a process that
requires the activities of the left frontal cortex. As a result of episodic memory one can travel
back to different epochs, in order to produce a coherent biographical narrative. This capacity
appears at about 24 months of age (Bauer 1996). and it is predominantly a function of the right
hippocampus and of the right orbitofrontal cortex, brain areas that are topographically related
to the limbic system (Nelson and Carver 1998). For this reason, episodic memory not only
includes the details of past experiences but it invariably includes elements of their original
emotional tone.
Implicit memory includes all of the experiences learned outside of consciousness, but it also
includes certain acquired procedural memories, e.g., how to ride a bicycle, drive a car, or play
a musical instrument, etc. Implicit memory does not require the hippocampus for either its
encoding or retrieval
The capacity for implicit memory is present at birth and it extends to a spectrum of autonomic
nervous system and sensorimotor activities. Implicit memories are encoded in utero and after
birth by the early interactions of the thalamus, the somatosensory cortices, the orbitofrontal
cortices, the amygdala, and anterior cingulate gyrus with the environment. Implicit memories
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form the basis for multimodal schemata that determine how the infant evaluates change in its
environment (Stern 1985).
Autonomic nervous system and sensorimotor background levels or tones, as well as
sensorimotor maps of the body, are also stored as implicit memories. These memories form our
ground of being, and contribute to the perception of self-constancy. Thankfully none of us need
be aware of the innumerable sensations that contribute to our experience, as they would
undoubtedly flood consciousness. The design of the nervous system appears to purposefully
limit what may be consciously attended to.
Feelings and Evaluation
Discomfort is negative feeling. But in reference to what are feelings evaluated? Let’s assume
for now that there is a core mind/body construct that can be termed self, and that feelings are
evaluated with reference to it. Later I will provide a clearer understanding of what I mean by
the self.
There is evidence based on functional magnetic resonance imaging (fMRI) that the amygdala
nuclei, located deep within in the brain, play a critical role in generating feelings (Damasio
1994). The amygdala is extensively connected to the sensory nuclei of the thalamus and to both
cortical and subcortical neural systems. It is also well integrated with the activities of the
hippocampus, which as will be recalled contributes to the registration and recall of explicit
memories. Logically, feelings should be recognizable by the responses that they engender, i.e.,
attractive, aversive, or neutral. However, feelings and responses may not always be congruent.
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At the level of subliminal (unconscious) neural processing, the boundaries between
neurological and psychological activities blur. Research demonstrates that feelings do not
depend on consciousness (McNally, Amir et al. 1994). Furthermore, with respect to feelings,
the self that is referenced in the determination of feelings may not be the same as the self that is
consciously perceived. In other words, the construct of self can be split between a self that we
know and a self that we do not. Psychoanalysts have long been aware of this paradox.
Why is this important with respect to the placebo response? Most experimental approaches to
the placebo response are based on patient self-reporting and do not address subliminal
evaluations. But reliance on conscious reporting may not reflect what is actually felt. An
important experimental piece of evidence that supports the role of implicit processes in the
evaluation of feeling comes from a psychological test referred to as the emotional Stroop
paradigm (McNally, Amir et al. 1994). In this test, stimuli predicted to evoke strong feelings
are presented as words with letters represented in different colors. The subject is required to
read the word and then rapidly to identify its color by pressing a button that accurately times
the delay in response. Strong feeling tones can disturb the processing of semantic memory
thereby increasing the time elapsed from the initial stimulus to the response, i.e., the latency of
response. This delay is attributed to a defect in "filtering", which means that the task is
disturbed by an extraneous internal stimulus.
In the subliminal Stroop test paradigm, the disturbing word is presented on a screen for a
period of 200 milliseconds, just long enough for the subject to read it but too brief a time for it
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to be registered within consciousness. Subsequently, a second neutral word is immediately
projected on the screen that in effect "masks" the prior word. Nevertheless, the processing of
the emotionally charged word at subliminal levels still causes the subject's response to the
“neutral” word to be delayed.
Experiments in my laboratory have demonstrated that when patients are challenged with lists
of words that include medical references, such as illness, disease, hospital, doctor, etc., patients
who exhibit either conscious (supraliminal Stroop) and unconscious (subliminal Stroop)
abnormalities subsequently demonstrate increased placebo responses compared to subjects who
do not exhibit Stroop disturbances. This suggests that semantic associations to health-related
terms are emotionally charged for some patients, and that subliminal feelings may be
associated with placebo reactivity. Recall that Shapiro also found that anxiety was a good
predictor of placebo response. However, these results should not be interpreted to suggest that
certain types of patients are susceptible to placebos. Instead, they appear to indicate that
emotional evaluations, i.e., feelings occurring both in and outside of consciousness can
influence placebo reactivity.
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Well-being
I feel happy-deep down. All is well. Katherine Mansfield (last journal entry)
If discomfort motivates people to seek medical attention, the underlying motivation is to avoid
discomfort and to restore well-being. Like discomfort, well-being is also a feeling, but it is a
positive evaluation of sensation with respect to the self. But whereas discomfort generally
triggers concern, well-being is often taken for granted, because it represents a normal
background state for most people.
When observing a newborn infant, its life appears to be uncomfortable a good percentage of
the time. When it is not sleeping, it is often either fitfully crying or writhing in discomfort. The
caregiver has a variety of potential strategies to alleviate the infant's discomfort. These are
initially implemented on a trial and error basis, in an effort to soothe the infant. Common
strategies include picking up the infant, rocking it, warming it, singing to it, changing its
diaper, feeding it, etc.
How do behavioral interventions both soothe the infant and reinforce positive feeling? In the
1950s, animal researchers noted that rats responded to electrical stimulation of certain areas of
the brain by returning over and over to the place in the cage where the stimulation had taken
place. They were eventually able to localize the site in the brain that yielded this result to a
large bundle of axons, called the median forebrain bundle (MFB), that pass close to the
hypothalamus at the base of the brain. The axons in the MFB synapse primarily on dopamine
producing neurons in the brainstem.
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For some time, researchers were convinced that these dopaminergic neurons were responsible
for pleasure seeking behaviors. Animal models showed a striking correspondence between
brain-stimulation reward paradigms and the dopaminergic system (Bergman, Madars et al.
1989). Ablating dopaminergic areas in the brain, or blocking the effects of dopamine, both
obliterated the repetitive pleasure-seeking responses. In addition, addictive drugs, including
cocaine, were subsequently demonstrated to act via stimulating dopamine receptors. The brain
regions involved were putatively termed the brain’s reward system and includes pathways
linking the MFB, nucleus accumbens and ventral tegmental regions of the brainstem. In
addition to dopamine, neurons in this pathway were also demonstrated to produce, serotonin,
enkephalins, and opioids, neurotransmitters that are recognized to participate in the generation
of positive feeling, or so called hedonic tone.
Parkinson's disease is a degenerative idiopathic neurological disorder. Behaviorally, these
patients develop characteristic tremors, gait disorders, and anhedonia. The brains in Parkinson's
disease are deficient in dopamine, due to a marked diminution in dopaminergic neurons within
the pontine substantia nigra and locus ceruleus. De la Fuente-Fernandez (de la FuenteFernandez, Ruth et al. 2001) and colleagues examined the positron-emission tomography scans
of patients with Parkinson's disease who had been told that they would be receiving a drug to
help their Parkinson's disease but instead received a placebo. The patients who received
placebo then underwent positron emission tomography (PET) scanning of the brain with [11C]
raclopride, a radiolabeled molecule that binds to specific dopamine receptors. The patients
who developed placebo responses showed reduced raclopride binding in the striatal regions of
the brain, a finding that is explained by an increase in brain dopamine levels. This was one of
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the first studies to demonstrate that a placebo intervention could lead to actual changes in brain
chemistry and that it may specifically increase levels of dopamine, which is associated with
feelings of well-being. .
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Learning Placebo
The more intensively the family has stamped its character upon the child, the more it will tend to see its early
miniature world again in the bigger world of adult life-Carl Jung
Donald Smith has proposed that a set of brain activities contribute to what he termed functional
salutogenesis (Smith 2002). He suggests that the brain has evolved a set of pathways aimed
specifically at promoting well-being. As man is a social animal it might be expected that at
least some of these endowed compensatory strategies might involve human interaction. The
placebo response is the case in point.
The placebo response is almost certainly innate, but it is not purely instinctual. Instead, its
features are critically dependent on what is learned early in development within relationships
with caretakers.
Attachment is an innate drive in man. Attachment strategies are critical for mind/body
development because the earliest proto-schemas, i.e. organized memories, of attachment
become the templates for subsequent mental representations and bodily function.
There are many good reasons to suggest that the placebo response is rooted in early attachment
dynamics. The newborn infant is ill prepared to fend for itself. It is neurologically grossly
immature, and unable to ambulate, or feed independently. The period of human physical and
mental development is long, extending into the teenage years, or beyond, in complex societies.
Effective attachment reduces the likelihood of starvation, exposure to the elements, physical
attack, and separation from the group. In the absence of attachment figures, the life expectancy
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of the human infant is limited. Bowlby speculated that “a succession of increasingly
sophisticated systems” that include structures that modulate arousal and emotion mediate
attachment processes. The goal of attachment from a neurobiological perspective is a change in
the infant's behavioral organization (Main 1995). Systems are linked and, in large measure,
motivated by affect centers within the brain.
The amygdala, the area of the brain that plays a critical role in evaluation and feeling is mature
at birth. It assists in the discrimination of olfactory cues (sense of smell) and allow the
newborn infant to discern the maternal breast from that of another woman (Schore 2003). At
eight weeks of life, the infant's visual system becomes salient. With its maturation,
organizational control shifts from primarily subcortical to cortical regulation. The
synchronization of affects between mother and infant is largely coordinated via visual cues
and gaze-related attunement. Limbic system circuits are specialized for assessing social
intention. These circuits show reciprocal connections with the dopamine system that contribute
with the opioid and serotonin pathways in establishing background levels of positive feeling.
Connections to the limbic system are specifically activated by social transactions and they
contribute to the development of implicit episodic memories of mind/body states during social
transactions.
One of the first developmental tasks for the infant is to learn how to regulate its somatic
activities. These include regulation of sleep-wake cycles and autonomic nervous system tone.
These are also strongly influenced by attachment. The psychologist Myron Hofer has proposed
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that the early caregiver acts as a "hidden regulator" for these activities (Hofer 1984), providing
physiological feedback that modulates the autonomic nervous system activities of the infant.
The influence of the right hemisphere dominates in the regulation of these activities.
Parasympathetic nervous or vagal tone evolves in an experience-dependent manner over the
first two years of life. Over time, the repeated activation of pathways that regulate autonomic
tone, sensorimotor maps, and background emotional tone, become strongly coordinately
encoded as implicit procedural memory. The result is mind/body states that are both coconstructed and re-created from moment to moment. These states yield the strong mental
representation of a both cohesive and constant self. At the same time that these developmental
tasks are being tackled, mental representations of the social attachment in which they were
learned are also integrated as episodic memory.
Placebo as Protosymbol
Donald Winnicott, British psychoanalyst and pediatrician, addressed how the infants capacity
to self-soothe is promoted via the adoption of transitional objects(Winnicott 1959). When the
infant's early caregivers are not available, transitional objects, e.g., baby’s blanket or Teddy
bear, are adopted as surrogate sources of comfort. These transitional objects, Winnicott argued,
are mental amalgam of objective reality and infantile fantasy. The transitional object is a
template for mental symbol formation and contributes to how the infant and over tinme, the
adult construe meaning.
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These protosymbols serve to mediate the psychophysical effects of self-soothing. With respect
to the placebo response, it has been posited that placebo medications and other placebo
interventions assume the role of transitional objects that evoke remembered states of wellbeing. Indeed, as the psychologist Donald Balak suggests, for some patients, separating them
from their placebos evokes the same discomfort that taking away a blanket or Teddy bear does
for the infant.
The psychoanalyst Joseph Sandler examined psychological motivations from the perspective of
object-relations theory (Sandler and Sandler 1998). In contrast to classical drive theory, he
speculated that positive affects contribute to the development of a benign super-ego, whose
primary role is to maintain a background experience of well-being as well as to motivate the
distressed ego to seek external objects (people or transitional objects) that can re-establish
these states. According to Sandler:
Initially this (positive) affective state, which normally forms a background to
everyday experience, must be the state of bodily well-being…This affective state
later becomes localized in the self…. The maintenance of this central affective
state is perhaps the most powerful motive for ego development.
Sandler recognized that background affects of well-being were critical to normal development
and that could be re-established by fantasies and memories. He suggested that the loss of these
states motivates a dynamic that promotes affiliation with outer world caregivers who can
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provide this crucial self-object function. It is clear that the conditions described by Sandler
parallel the conditions that evoke placebo effects
A Novel Hypothesis
I frame no hypotheses; for whatever is not deduced from the phenomena is to be called an hypothesis, and
hypotheses, whether metaphysical or mechanical, have no place in experimental philosophy- Isaac Newton
Up until this point, we have examined how developmental pathways are critical in how
mind/body well-being develops and I have suggested strong parallels between early
development and the situations and feelings that characterize the placebo response. But many
basic questions remain unanswered. For instance, how many placebo responses are there? As
placebo effects have been reported in virtually all areas of medicine, and range from
experimental placebo analgesia to near miraculous cancer cures, what if anything do these all
have in common? This is a critical question because if each placebo response is different from
every other, then the concept of a monolithic unitary placebo response must be incorrect. So
the question is how might a multiplicity of placebo effects be explained by a single
mechanism? I will confess at the beginning that I am not certain of the answer. But what
follows is my attempt at developing a model for how mind/body placebo effects develop.
Like many biological responses, the placebo response can be conceptually divided into input,
processing, and output limbs, i.e., the basic servo-motor response. There is a set of events that
evoke the response and another set that mediate its effects. Up until now, we have
predominantly focused on how the placebo response might be evoked. The more complex
question is how does a multiplicity of effects develop out of the response?
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To begin with let’s imagine that placebo effects are subdivided into two subsets. The first may
be termed a shared, or public effect. What do all placebo effects share in common? As patients
who develop placebo responses invariably report "feeling better." the answer is a renewed state
of positive feeling and well-being ( or its opposite in the nocebo response).
The second set of effects may be referred to as ideographic or private effects. In other words,
these target the specific symptoms and signs associated with discomfort. In practice, they may
range from an improvement in minor functional discomforts, such as headache or
gastrointestinal upset, to substantial objective effects, e.g., a reduction in tumor burden or
blood pressure. The observed placebo response is the combination of its public and private
effects.
Placebo Complex
Carl Jung, a Swiss psychiatrist, working at the Burgholzli Hospital in Zurich in the early
1900's, noted when patients were asked to give their immediate associations to a series of
stimulus words that certain words consistently led to delayed responses. These indicator
words also yielded autonomic arousal, as evidenced by increases in heart rate, respiratory rate,
and changes in galvanic skin responses, all markers of sympathetic nervous system arousal.
Jung concluded that this response was due to a complex, i.e. a disturbance in patients' mental
associations.
Based on our current understanding of neurobiology, a complex can be defined as a constellation of
neural pathways linking semantic associations to feeling-toned implicit memories that are capable of
modifying somatic physiology. An important feature of the complex is its automaticity, i.e., its ability to
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spontaneously activate changes in mind-body states without conscious volition. Jung referred to
complexes in later writings as "splinter personalities," and suggested that when they were extensive and
sufficiently emotionally charged that they could actually replace normal consciousness, with
uncharacteristic thoughts, feelings, and behaviors (Jacobi 1959). This phenomenon is observed in
"multiple personality disorder" in which. complexes dissociated from consciousness can emerge as
distinct personalities or alter egos. What is of interest is that fact that complexes can yield profound
changes in somatic physiology. In one documented case, the alter ego of a patient with DID was
demonstrated to be an insulin-dependent diabetic.
J
Jung's concept of the complex captures elements of the critical mind-body connections that
characterize placebo responses (Kradin 2004). Whereas Jung never specifically referred to the
placebo response, he was certainly aware of how complexes might contribute to psychosomatic
disorders (Jung 1967). Jung suggested that the complex was mediated via an internal image.
\
Self and Image
Edelman and Tononi (Edelman and Tononi 2000) have suggested that the uniqueness of the
acquired neural repertoire of the nervous system gives rise to a psychophysical neurosignature.
This neurosignature is the neural matrix that of self. In their model, self-experience reflects the
moment-to-moment stereotypic self-organization of the individual's somatosensory map. The
apparent "solidity" of consecutive emergent self-states is a function of implicit procedural
somatic memories dependent on the established strong synaptic strengths of the neural
pathways. These pathways are in turn linked to modular domains, e.g., the amygdala pathways
and the dopamine reward-reinforcement pathways, that monitor the activities of the core self
and modify the background affect state accordingly.
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What is critical is that the core repertoire of self modulates not only the explicit psychological
activities that we attribute to consciousness but is primarily responsible for the features that
regulate metabolism, autonomic tone, musculoskeletal posture, etc. There is empirical
evidence, in part provided by placebo effects and the conditioning of immune activities, that
mind-body integration is more extensive than currently realized.
How might a neural image of self emerge? One can imagine the core neural pathways of self as
an attractor represent its most stable state. Imagine that the activated neurons of the core self
were illuminated so that we could identify them. If one were to capture the illuminated nervous
system with time-lapse photography, what would emerge would be the image or "structure"
corresponding to the system's most stable configuration, i.e. the self.
Attractors, Catastrophe and Placebo
Medical science has described many homeostatic systems. The most popular regulatory motif
includes receptors that are up and down-regulated by specific ligands, e.g. insulin receptors on
fat cells in the presence or absence of insulin molecules. However, no overarching model of
homeostatic regulation has ever been seriously entertained. However, the idea of a
supraordinate attractor of self carries the potential possibility of total mind/body self-regulation
that naturally resists overwhelming changes while allowing for functional elasticity.
From this perspective and adopting tenets of catastrophe theory, disease or dysfunction
represents the replacement of one attractor, i.e., the attractor of self with another attractor.
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Consider the following analogy. A smoothly flowing river can be described mathematically
and an attractor could be derived. If a modest amount of change is introduced either by, e.g. the
presence of a sandbar or in the increasing turbulence that occurs in the approach to waterfall,
then these changes would be governed by new attractors that would better predict the behavior
of flow. But if the perturbations were to be removed, the river would naturally revert to its
previous attractor. Might these shifts in attractors explain differences of health and disease at
the organismic level?. If so then it might be posited that the placebo response is a shift from an
attractor of discomfort and disease back to the pre-disease one of health and well-being. The
attractive aspect of such a mechanism is that it does not require innumerable private mind/body
responses but instead relies on re-establishing a remembered global mind/body state.
The placebo response represents a shift from one attractor that governs mind/body dysfunction
to the previously established attractor of self. . If mind/body states are remembered then they
can also under appropriate conditions self-organize. By evoking subliminal procedural
memories of mind/body states of well-being it is possible to reduce the perturbational stress
that promotes a shift to a new attractor back to one of well-being.
The foregoing model furthermore predicts parameters and limits to the placebo response, most
of which are supported by phenomenological observation. First, the placebo (or nocebo)
response is almost certainly a universal human capacity that is both innate and acquired. The
potential to mount the response is inherited but its execution depends on early attachment and
learned meanings that can be attributed to the therapeutic situation.
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Second, there must be limits to the capacities of the placebo response. It stands to reason that
profound disruptions in the neural pathways that mediate and evaluate mind/body pathways
have to limit the potency of the placebo response. Whereas profound physical changes have
been attributed to the placebo response, these are more the exception than the rule.
Third, the predictability of placebo responses must be difficult to determine. Due to the
sensitivity to initial conditions that is seen in non-linear systems, a placebo responder on
Monday may be a non-responder on Tuesday, even under apparently similar circumstances.
This hypothesis departs from the usual way of thinking about the placebo response and it is
highly speculative. It is also undoubtedly in some respects naïve, nevertheless intuition
suggests that it contains a large kernel of truth. But whereas the heuristic value of a theory is
important, only careful testing will establish its accuracy. One reason that linear approaches
have retained their importance in biomedical science is because most medical experiments
yield relatively few data points for analysis and these are inadequate for establishing nonlinearity. However, continuous physiological traces, e.g. the electrocardiogram,
electroencephalogram, and computer modeling of neural nets, are exceptions and not
surprisingly it has been from data generated from these sources that most advances have been
made in the application of non-linear approaches to biomedical activities (Goldberger and
West 1987). But what can safely be concluded with is that the complexity of mind/body
interactions will not yield to traditional linear analyses.
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The placebo response is about to enter yet another phase in its labyrinthine history. Instead of
being considered as imaginary or as a confounder of clinical trials, it will next be recognized as
a scientifically definable endogenous mode of healing rooted in mind/body psychophysiology
and complexity.
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