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Behavioral/Systems/Cognitive

Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses

Fabrizio Benedetti, Antonella Pollo, Leonardo Lopiano, Michele Lanotte, Sergio Vighetti and Innocenzo Rainero
Journal of Neuroscience 15 May 2003, 23 (10) 4315-4323; https://doi.org/10.1523/JNEUROSCI.23-10-04315.2003
Fabrizio Benedetti
1Department of Neuroscience, University of Turin Medical School, Turin, Italy 10125
2Department of Clinical and Applied Physiology Program, University of Turin Medical School, Turin, Italy 10125
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Antonella Pollo
1Department of Neuroscience, University of Turin Medical School, Turin, Italy 10125
2Department of Clinical and Applied Physiology Program, University of Turin Medical School, Turin, Italy 10125
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Leonardo Lopiano
1Department of Neuroscience, University of Turin Medical School, Turin, Italy 10125
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Michele Lanotte
4Division of Neurosurgery, CTO Medical Center, Turin, Italy 10126
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Sergio Vighetti
1Department of Neuroscience, University of Turin Medical School, Turin, Italy 10125
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Innocenzo Rainero
1Department of Neuroscience, University of Turin Medical School, Turin, Italy 10125
3Department of Neurology III–Headache Center, University of Turin Medical School, Turin, Italy 10125
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  • Figure 1.
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    Figure 1.

    Experimental and control groups for each experimental paradigm (pain, Parkinson's disease, hormone secretion) used in the present study.

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    Figure 2.

    The effects of verbally induced expectations and pharmacological conditioning on pain tolerance. A, Natural history of tolerance to ischemic arm pain over 4 consecutive days. B, Verbal suggestion of analgesia (placebo) on day 2 induces an increase in tolerance. C, Suggestion of hyperalgesia (nocebo) on day 2 induces a decrease in tolerance. D, Suggestion of analgesia on day 4 after a 2 d preconditioning with ketorolac (ket) induces a larger increase in tolerance than verbal suggestion alone in B. E, The same ketorolac preconditioning is totally ineffective, however, if suggestion of hyperalgesia is given on day 4. Pla, Placebo; Noc, nocebo.

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    Figure 3.

    The effects of verbally induced expectations on motor performance in Parkinsonian patients with implanted stimulating electrodes in the subthalamic nuclei. After the stimulator (Stim) had been turned off several times, a sham turning off (nocebo) induces a velocity decrease (•). This decrease is completely blocked (○) by the opposite verbal instruction (placebo). The broken line represents the natural history.

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    Figure 4.

    Natural history of GH (A) and cortisol (B) plasma concentrations for 3 consecutive days. Note that the mean concentrations do not change either during an observation period of 90 min or over a period of 3 d.

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    Figure 5.

    Verbal suggestions of GH increase (A) and decrease (B) have no effect on GH plasma concentration. C, After 2 d of sumatriptan preconditioning, suggestion of GH increase (Placebo) mimics the effects of sumatriptan. D, This effect is not caused by the suggestion itself, however, because the same sumatriptan-like effect is present after the opposite verbal instruction. *p < 0.05; **p < 0.03; ***p < 0.01.

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    Figure 6.

    Verbal suggestions of cortisol decrease (A) and increase (B) have no effect on cortisol plasma concentration. C, After 2 d of sumatriptan preconditioning, suggestion of cortisol decrease (Placebo) mimics the effects of sumatriptan. D, This effect is not caused by the suggestion itself, however, because the same sumatriptan-like effect is present after the opposite verbal instruction. *p < 0.04; **p < 0.02; ***p < 0.01.

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    Figure 7.

    Model to explain the findings of the present study. During a placebo procedure, conscious physiological processes, such as pain and motor performance, are affected by verbally induced expectations, even though a conditioning procedure is performed. By contrast, unconscious physiological processes, such as hormone secretion, are totally unaffected by expectations, whereas they are influenced by placebos through unconscious conditioning mechanisms.

Tables

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    Table 1.

    Characteristics of the subjects who underwent experimental ischemic arm pain

    Group Sex (male/female) Age (years) Weight (kg)
    1 7/7 45.1 ± 7.5 58.9 ± 11.1
    2 6/6 46.9 ± 8.8 60.6 ± 10.5
    3 5/7 45.8 ± 9.4 62.5 ± 9.7
    4 5/6 44.1 ± 9.7 59.9 ± 10.3
    5 6/5 46.4 ± 7.5 60.5 ± 9.8
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    Table 2.

    Characteristics of the patients and stimulation parameters of the subthalamic nuclei for optimal therapeutic effect

    Left nucleus Right nucleus
    Patient Age (years) Sex History of Parkinson's disease (years) Time from surgery (months) Stage of disease before/after surgery Int (V) Freq (Hz) Width (μsec) Int (V) Freq (Hz) Width (μsec)
    1 51 female 25 19 4.5/3 3.6 130 60 3.6 135 60
    2 69 male 15 14 4/2 3.6 170 90 3.6 170 90
    3 57 female 13 20 4/2 3.6 160 60 3.6 135 60
    4 70 female 19 27 4/2.5 3.3 130 90 3.6 135 60
    5 62 male 12 7 3/0.5 3.5 135 60 3.3 130 60
    6 46 female 9 5 2.5/2 3.6 130 90 3.6 170 90
    7 61 male 12 20 4/0.5 3.5 135 90 3.5 130 90
    8 67 male 10 18 3/1.5 3.5 160 60 3.5 130 90
    9 57 male 8 9 4/3 3.4 135 90 3.6 130 90
    10 68 male 19 9 4.5/2.5 3.6 130 60 3.6 130 60
    • Intensity (Int) is expressed in volts (V), frequency (Freq) in Hertz, and pulse width in microseconds (μsec).

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    Table 3.

    Characteristics of the subjects who were tested for hormonal responses

    Group Sex (male/female) Age (years) Weight (kg)
    1 8/7 47.4 ± 10.5 64.7 ± 12.5
    2 5/4 49.3 ± 11.8 65.6 ± 11.7
    3 5/6 49.1 ± 10.4 64.4 ± 12.6
    4 5/4 50.1 ± 9.5 61.6 ± 12.9
    5 5/6 48.7 ± 10.1 65.5 ± 11.4
    6 4/5 47.0 ± 9.2 61.9 ± 12
    7 5/5 49.0 ± 11.2 63.4 ± 13.1
    8 5/5 50.8 ± 10.7 62.9 ± 12.4
    9 5/6 48.4 ± 9.9 63.8 ± 11.8
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The Journal of Neuroscience: 23 (10)
Journal of Neuroscience
Vol. 23, Issue 10
15 May 2003
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Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses
Fabrizio Benedetti, Antonella Pollo, Leonardo Lopiano, Michele Lanotte, Sergio Vighetti, Innocenzo Rainero
Journal of Neuroscience 15 May 2003, 23 (10) 4315-4323; DOI: 10.1523/JNEUROSCI.23-10-04315.2003

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Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses
Fabrizio Benedetti, Antonella Pollo, Leonardo Lopiano, Michele Lanotte, Sergio Vighetti, Innocenzo Rainero
Journal of Neuroscience 15 May 2003, 23 (10) 4315-4323; DOI: 10.1523/JNEUROSCI.23-10-04315.2003
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Keywords

  • expectation
  • conditioning
  • placebo
  • pain
  • Parkinson's disease
  • hormones

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