Neuroscience

This procedure does not involve classical conditioning per se (because there is no active unconditioned stimulus), which has been associated with non-opioid-mediated analgesic mechanisms (Amanzio and Benedetti, 1999Go).

After correction for multiple comparisons, statistically significant effects of placebo on µ-opioid system activation were obtained in the left (ipsilateral to pain) dorsolateral prefrontal cortex (DLPFC) [at Brodmann areas (BA) 8 and 9], pregenual rostral right (contralateral) anterior cingulate (BA 24 and 25), right (contralateral) anterior insular cortex, and left (ipsilateral) nucleus accumbens (Fig. 3).

PAG neurons project upwards to the telencephalon as well as downwards to the spinal cord, and it may well be that PAG modulates the central representation of pain through the activation of opioid release in cortical and limbic regions (Zubieta et al., 2005aGo).

Evidence for decreases during pain would suggest that placebo treatment alters nociceptive sensory and/or affective processing, not just retrospective judgments about pain (Kienle and Kiene, 1997Go; Hrobjartsson and Gotzsche, 2001Go, 2004Go).

The pharmacological approach The neurobiology of the placebo effect was born in 1978, when it was shown that placebo analgesia could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978Go).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department ...

The left side of the axial and coronal images corresponds to the right side of the body (contralateral to pain) (radiological convention).

Changes in regional glucose metabolism (FDG PET) in fluoxetine (top), placebo (middle), and cognitive (bottom) therapy responders measured before and after a standard course of each respective treatment.

In addition, it has been found that expectations of poor versus good motor performance modulate the therapeutic effect of subthalamic nucleus stimulation in parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation (DBS).

After correction for multiple comparisons, statistically significant effects of placebo on µ-opioid system activation were obtained in the left (ipsilateral to pain) dorsolateral prefrontal cortex (DLPFC) [at Brodmann areas (BA) 8 and 9], pregenual rostral right (contralateral) anterior cingulate (BA 24 and 25), right (contralateral) anterior insular cortex, and left (ipsilateral) nucleus accumbens (Fig. 3).

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

The PAG receives projections from insula, anterior cingulate, nucleus accumbens, amygdala, and frontal cortex (Bragin et al., 1984Go; Ma and Han, 1991Go; Rizvi et al., 1992Go).

The {beta}-adrenergic sympathetic system of the heart may also be inhibited during placebo analgesia, although the mechanism is not known (reduction of the pain itself and/or direct action of endogenous opioids).

Under these conditions, activation of this neurotransmitter system is evidenced by reductions in the in vivo availability of synaptic µ-opioid receptors to bind the radiolabeled tracer (Zubieta et al., 2001Go, 2002Go, 2003bGo; Bencherif et al., 2002Go).

However, if a preconditioning was performed with sumatriptan, a 5-HT1B/1D agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given (Fig. 1).

Although the methodology used does not examine the neurochemical mechanisms inducing the placebo analgesic effect, the regions implicated do present high concentrations of µ-opioid receptors and demonstrate increases in regional blood flow after the exogenous administration of µ-opioid receptor agonists (Firestone et al., 1996Go; Adler et al., 1997Go; Schlaepfer et al., 1998Go; Casey et al., 2000Go; Wagner et al., 2001Go).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psyc...

Paradoxically, placebo-induced increases in activity were found in secondary somatosensory cortex.

Indeed, a recent study examining placebo-induced anxiolytic effects shares several key regions in common with Wager et al. (2004bGo), including rostral anterior cingulate cortex and OFC (Petrovic et al., 2005Go) (see Fig. 8).

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

This study found that placebo-induced expectation of motor improvement activates endogenous dopamine in the striatum of parkinsonian patients.

Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004Go) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia.

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psyc...

Extrapolating liberally from these many preclinical experiments, metabolic changes occurring at 1 week of fluoxetine (or sham) treatment relative to baseline were assessed as a function of eventual 6 week response outcome, during what one might consider a period of ongoing expectation for clinical benefit (i.e., delivery of reward).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psyc...

In contrast, it was found that expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones.

ACing, Subgenual cingulate BA 25; PCing, posterior cingulate; P, pons; Hc, hippocampus; PFC, prefrontal cortex BA 9; Ins, anterior insula; Cau, caudate; OFC, orbital frontal cortex BA 11; MFC, medial frontal cortex BA 9.

Lateral and medial frontal increases with placebo continued through the pain period (results for experiment 2 shown in Fig. 5).

On the basis of the anti-opioid action of cholecystokinin (CCK) (Benedetti, 1997Go), the CCK antagonist proglumide was found to enhance placebo analgesia through the potentiation of the placebo-activated opioid systems (Benedetti et al., 1995Go).

Evidence for prefrontal cortex increases during expectation of pain would suggest that placebo expectancies are active neurobiological processes that involve the frontal lobes.

These results indicated that placebo treatment engaged active prefrontal processing mechanisms, and their colocalization with activations from studies of working memory and cognitive control suggest that these regions may play a general role in representing expectancies and other elements of situational context across both cognitive and affective domains.

Neural responses to placebo in clinical trials of antidepressants Major depression is another useful model to examine neurobiological mechanisms of the placebo effect, because placebo responses are common in antidepressant trials of many interventions, including medication, psychotherapy, and somatic treatments (DeRubeis et al., 1999Go, 2005Go; Kirsch and Sapirstein, 1998Go; Enserink, 1999Go; Khan et al., 2000Go; Quitkin and Klein, 2000Go; Quitkin et al., 2000Go; Walsh et al., 2002Go;...

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

This hypothesis, however, would appear to be contradicted by findings of consistently low placebo rates with somatic treatments such as electroconconvulsive therapy (ECT), although the typical patient has generally already failed multiple previous interventions (Pagnin et al., 2004Go).

The respiratory centers may also be inhibited by endogenous opioids.

A recent study used positron emission tomography (PET) to assess the competition between endogenous dopamine and [11C]raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release (de la Fuente-Fernandez et al., 2001Go).

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

On the basis of the anti-opioid action of cholecystokinin (CCK) (Benedetti, 1997Go), the CCK antagonist proglumide was found to enhance placebo analgesia through the potentiation of the placebo-activated opioid systems (Benedetti et al., 1995Go).

The pharmacological approach The neurobiology of the placebo effect was born in 1978, when it was shown that placebo analgesia could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978Go).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psyc...

To first test this hypothesis, cerebral glucose metabolism was measured using FDG PET in a group of depressed men participating in an inpatient, randomized, placebo-controlled study of the approved antidepressant fluoxetine (Mayberg et al., 2000Go, 2002Go).

Under these conditions, activation of this neurotransmitter system is evidenced by reductions in the in vivo availability of synaptic µ-opioid receptors to bind the radiolabeled tracer (Zubieta et al., 2001Go, 2002Go, 2003bGo; Bencherif et al., 2002Go).

In particular, the possibility of recording from single neurons offers us the chance to identify the neuronal changes that take place in the basal ganglia circuitry during the placebo response.

A recent study used positron emission tomography (PET) to assess the competition between endogenous dopamine and [11C]raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release (de la Fuente-Fernandez et al., 2001Go).

This procedure was performed intraoperatively after preoperative pharmacological conditioning with apomorphine, a powerful antiparkinsonian drug.

The pharmacological approach The neurobiology of the placebo effect was born in 1978, when it was shown that placebo analgesia could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978Go).

Dorsal and ventral PFC are activated by a large class of cognitively demanding conditions.

This procedure was performed intraoperatively after preoperative pharmacological conditioning with apomorphine, a powerful antiparkinsonian drug.

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

However, they may be functionally separable; the issue at stake is the level of the CNS at which nociceptive signals are modulated by placebo.

The placebo effect in motor control: studies in Parkinson's disease Recently, Parkinson's disease has emerged as an interesting model to understand the neurobiological mechanisms of the placebo response.

The regions in which placebo administration increased the endogenous opioid neurotransmission primarily coincided with that observed by Wager et al. (2004Go) as reductions in pain-induced metabolic demands as measured by fMRI during placebo administration (i.e., prefrontal cortex, pregenual anterior cingulate, and insular cortex).

The functions of descending and ascending opioid projections may be closely coupled; indeed, given the recurrent connectivity that is a hallmark of brain circuitry, it would be surprising if they were not.

Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004Go) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia.

The study of the placebo effect also has immediate clinical and ethical implications, because the use of inactive (placebo) conditions in clinical trials when effective treatments are available has created an ethical controversy.

This study supports a conditioning mechanism in immunosuppressive placebo responses and is in keeping with the effects of sumatriptan conditioning on GH and cortisol secretion (Benedetti et al., 2003Go).

These responder-nonresponder differences are also consistent with the time course and location of changes identified in animal studies of selective serotonin reuptake inhibitors antidepressants that emphasize early brainstem and hippocampal changes and late cortical effects (Duman et al., 1999Go; Freo et al., 2000Go; Blier, 2001Go; Vaidya and Duman, 2001Go).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department ...

The posterior right insula achieved subthreshold levels of significance (44, -15, 4; cluster size, 732 mm3; z score, 3.81; p < 0.0001 uncorrected for multiple comparisons). z scores of statistical significance are represented by the pseudocolor scale on the right side of the image and are superimposed over an anatomically standardized MRI image in coronal views.

Together, these synergistic effects have been interpreted by some as evidence that the active intervention actually contributes a relatively small percentage to the observed efficacy rates of published antidepressant drug trials (Kirsch and Sapirstein, 1998Go).

Evidence for prefrontal cortex increases during expectation of pain would suggest that placebo expectancies are active neurobiological processes that involve the frontal lobes.

ACing, Subgenual cingulate BA 25; PCing, posterior cingulate; P, pons; Hc, hippocampus; PFC, prefrontal cortex BA 9; Ins, anterior insula; Cau, caudate; OFC, orbital frontal cortex BA 11; MFC, medial frontal cortex BA 9.

Axial (left), sagittal (middle), and coronal (right) views; increases are in red, and decreases are in blue.

On the lateral surface, these regions include the DLPFC, VLPFC, and possibly a third cluster of activations around the rostral PFC. On the medial surface, two clusters appear around the midrostral dorsal anterior cingulate and neighboring superior medial PFC. On the orbital surface, many peaks are grouped around the medial orbital sulcus bilaterally.

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

A recent study, in which the sympathetic control of the heart was analyzed during placebo analgesia, found that placebo analgesia was accompanied by a reduced heart rate and a decreased {beta}-adrenergic response, an effect that was reversed by naloxone, which indicates that opioid-mediated placebo analgesia also affects the cardiovascular system (Pollo et al., 2003Go) (Fig. 1).

Under these conditions, activation of this neurotransmitter system is evidenced by reductions in the in vivo availability of synaptic µ-opioid receptors to bind the radiolabeled tracer (Zubieta et al., 2001Go, 2002Go, 2003bGo; Bencherif et al., 2002Go).

These findings suggest that expectations have no effect on hormonal secretion, although they affect pain and motor performance.

Slice location is in millimeters relative to anterior commissure.

Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004Go) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia.

A recent study used positron emission tomography (PET) to assess the competition between endogenous dopamine and [11C]raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release (de la Fuente-Fernandez et al., 2001Go).

The left side of the axial and coronal images corresponds to the right side of the body (contralateral to pain) (radiological convention).

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004Go) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia.

These data are additionally consistent with the notion that placebo-responding regions and neurochemical systems (e.g., the endogenous opioid system and µ-opioid receptors) are an intrinsic part of neuronal processes that mediate the interaction between positive environmental conditions (in the present case the suggestion of analgesia) and the corresponding physical and emotional responses of the individual.

In one additional study in chronic pain patients, it was found that placebo responders showed higher concentration of endorphins in the CSF than placebo nonresponders (Lipman et al., 1990Go).

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

During both clinical and experimentally induced pain, placebo administration with expectation of analgesia has been associated with reductions in pain ratings that were reversed by either the open or hidden administration of naloxone (i.e., they were mediated by the activation of pain-suppressive endogenous opioid neurotransmission) (Gracely et al., 1983Go; Grevert et al., 1983Go; Levine and Gordon, 1984Go; Benedetti, 1996Go; Amanzio and Benedetti, 1999Go).

Unique to fluoxetine were additional increases in pons and decreases in caudate, insula, and hippocampus, regions with known efferent connections to both subgenual cingulate and prefrontal cortex, in which changes were seen in both groups.

However, if a preconditioning was performed with sumatriptan, a 5-HT1B/1D agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given (Fig. 1).

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

The superposition of peak coordinates of increased activation in each of these conditions reveals a set of frontal regions that appear to be consistently increased during diverse tasks in which negative affect must be suppressed.

The role of conditioning in the placebo effect is also shown by studies on the immune responses (Ader, 2003Go).

Additional multivariate analyses, examining the interaction of these ventral striatal changes with the rest of the brain over time, further identified an ongoing correlation between ventral striatal activity and lateral prefrontal and subgenual cingulate changes at both the early and late time points, which was predictive of clinical outcome with both active drug and placebo (data not shown).

From this perspective, one might presume that the identification of pure placebo-mediated response changes would reveal a "final common pathway" for depression remission because the placebo group would be unaffected by nonspecific drug, cognitive, or lesion effects evoked by the medication, psychotherapy, or surgical procedure under investigation.

In fact, after repeated administrations of the opioid buprenorphine in the postoperative phase, which induces mild respiratory depression, a placebo is able to mimic the same respiratory depressant response, an effect that can be totally blocked by naloxone (Benedetti et al., 1999aGo).

Anatomically concordant metabolic changes were seen with both active fluoxetine and placebo response: increases in prefrontal (at BA 9/46), parietal (BA 40), and posterior cingulate (BA31), and decreases in subgenual cingulate (BA 25) (Fig. 6, rows 1, 2).

The placebo consisted of a saline solution that was given to patients along with the suggestion that it was an antiparkinsonian drug.

A recent study used positron emission tomography (PET) to assess the competition between endogenous dopamine and [11C]raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release (de la Fuente-Fernandez et al., 2001Go).

In contrast, it was found that expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones.

In addition, it has been found that expectations of poor versus good motor performance modulate the therapeutic effect of subthalamic nucleus stimulation in parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation (DBS).

Placebos can also act on 5-HT-dependent hormone secretion, on both the pituitary and adrenal glands, thereby mimicking the effect of the analgesic drug sumatriptan.

It was hypothesized that placebo treatment would induce increases in DLPFC (BA 9 and 46) and ventrolateral prefrontal cortex (VLPFC) (BA 45 and 47) because of their roles in generating and maintaining cognitive expectancies that guide memory retrieval and attention.

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

Regarding the circuitry implicated in placebo analgesia (and as described in more detail below in Functional neuroanatomy of placebo analgesia), Wager et al. (2004Go) used functional magnetic resonance imaging (fMRI) to indirectly measure neuronal activity during the administration of a placebo with expectation of analgesia.

Placebos can also act on 5-HT-dependent hormone secretion, on both the pituitary and adrenal glands, thereby mimicking the effect of the analgesic drug sumatriptan.

The {beta}-adrenergic sympathetic system of the heart may also be inhibited during placebo analgesia, although the mechanism is not known (reduction of the pain itself and/or direct action of endogenous opioids).

A recent study, in which the sympathetic control of the heart was analyzed during placebo analgesia, found that placebo analgesia was accompanied by a reduced heart rate and a decreased {beta}-adrenergic response, an effect that was reversed by naloxone, which indicates that opioid-mediated placebo analgesia also affects the cardiovascular system (Pollo et al., 2003Go) (Fig. 1).

For example, repeated associations between cyclosporin A (unconditioned stimulus) and a flavored drink (conditioned stimulus) induced conditioned immunosuppression in humans, in which the flavored drink alone produced a suppression of the immune functions, as assessed by means of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}) mRNA expression, in vitro release of IL-2 and IFN-{gamma}, as well as lymphocyte proliferation (Goebel et al., 2002Go).

In addition, it has been found that expectations of poor versus good motor performance modulate the therapeutic effect of subthalamic nucleus stimulation in parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation (DBS).

These responder-nonresponder differences are also consistent with the time course and location of changes identified in animal studies of selective serotonin reuptake inhibitors antidepressants that emphasize early brainstem and hippocampal changes and late cortical effects (Duman et al., 1999Go; Freo et al., 2000Go; Blier, 2001Go; Vaidya and Duman, 2001Go).

Complicating the picture of determining the efficacy of a new treatment in light of significant placebo effects is the additional confound of improvement in depressive symptoms attributable to the natural history of the disorder.

Evidence for prefrontal cortex increases during expectation of pain would suggest that placebo expectancies are active neurobiological processes that involve the frontal lobes.

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department ...

The {beta}-adrenergic sympathetic system of the heart may also be inhibited during placebo analgesia, although the mechanism is not known (reduction of the pain itself and/or direct action of endogenous opioids).

Placebos can also act on 5-HT-dependent hormone secretion, on both the pituitary and adrenal glands, thereby mimicking the effect of the analgesic drug sumatriptan.

Micro-stimulation of ventrolateral OFC in rats transiently attenuates nociceptive reflex responses, and this effect is blocked by lesion of the PAG (Zhang et al., 1997Go, 1998Go).

Under these conditions, activation of this neurotransmitter system is evidenced by reductions in the in vivo availability of synaptic µ-opioid receptors to bind the radiolabeled tracer (Zubieta et al., 2001Go, 2002Go, 2003bGo; Bencherif et al., 2002Go).

The gate control theory posits and much subsequent work on central regulation of pain has shown that the periaqueductal gray (PAG) exerts central control over spinal pain pathways (Melzack and Wall, 1965Go; Fields, 2004Go).

Although normalization of frontal abnormalities is the best-replicated finding, other regional effects are commonly reported with variable patterns with different treatments.

Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003Go).

PAG neurons project upwards to the telencephalon as well as downwards to the spinal cord, and it may well be that PAG modulates the central representation of pain through the activation of opioid release in cortical and limbic regions (Zubieta et al., 2005aGo).

Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department ...

Remarkably, as shown in Figure 2 for two representative patients (a placebo responder and a nonresponder), there was a nice correlation between the subjective reports of the patients, the clinical assessment of the neurologist, and the electrical activity of single neurons.