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Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response

Identifieur interne : 000583 ( Main/Exploration ); précédent : 000582; suivant : 000584

Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response

Auteurs : Johanna M. Jarcho [États-Unis] ; Natasha A. Feier [États-Unis, Canada] ; Jennifer S. Labus [États-Unis] ; Bruce Naliboff [États-Unis] ; Suzanne R. Smith [États-Unis] ; Jui-Yang Hong [États-Unis] ; Luana Colloca [États-Unis] ; Kirsten Tillisch [États-Unis] ; Mark A. Mandelkern [États-Unis] ; Emeran A. Mayer [États-Unis] ; Edythe D. London [États-Unis]

Source :

RBID : PMC:4683423

Abstract

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [18F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.


Url:
DOI: 10.1016/j.nicl.2015.11.009
PubMed: 26759785
PubMed Central: 4683423


Affiliations:


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<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Naliboff, Bruce" sort="Naliboff, Bruce" uniqKey="Naliboff B" first="Bruce" last="Naliboff">Bruce Naliboff</name>
<affiliation wicri:level="1">
<nlm:aff id="af0005">Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0020">Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Smith, Suzanne R" sort="Smith, Suzanne R" uniqKey="Smith S" first="Suzanne R." last="Smith">Suzanne R. Smith</name>
<affiliation wicri:level="1">
<nlm:aff id="af0005">Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0020">Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Hong, Jui Yang" sort="Hong, Jui Yang" uniqKey="Hong J" first="Jui-Yang" last="Hong">Jui-Yang Hong</name>
<affiliation wicri:level="1">
<nlm:aff id="af0005">Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0020">Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Colloca, Luana" sort="Colloca, Luana" uniqKey="Colloca L" first="Luana" last="Colloca">Luana Colloca</name>
<affiliation wicri:level="4">
<nlm:aff id="af0040">School of Nursing, University of Maryland, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Nursing, University of Maryland, Baltimore, MD</wicri:regionArea>
<orgName type="university">Université du Maryland</orgName>
<placeName>
<settlement type="city">College Park (Maryland)</settlement>
<region type="state">Maryland</region>
</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="af0045">School of Medicine, University of Maryland, Baltimore, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Medicine, University of Maryland, Baltimore, MD</wicri:regionArea>
<orgName type="university">Université du Maryland</orgName>
<placeName>
<settlement type="city">College Park (Maryland)</settlement>
<region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Tillisch, Kirsten" sort="Tillisch, Kirsten" uniqKey="Tillisch K" first="Kirsten" last="Tillisch">Kirsten Tillisch</name>
<affiliation wicri:level="1">
<nlm:aff id="af0005">Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0020">Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0050">VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>VA Greater Los Angeles Healthcare System, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Mandelkern, Mark A" sort="Mandelkern, Mark A" uniqKey="Mandelkern M" first="Mark A." last="Mandelkern">Mark A. Mandelkern</name>
<affiliation wicri:level="1">
<nlm:aff id="af0050">VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>VA Greater Los Angeles Healthcare System, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Mayer, Emeran A" sort="Mayer, Emeran A" uniqKey="Mayer E" first="Emeran A." last="Mayer">Emeran A. Mayer</name>
<affiliation wicri:level="1">
<nlm:aff id="af0005">Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0020">Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0025">Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation>
<nlm:aff id="af0035">Pain and Interoception Network (PAIN), UCLA, Los Angeles, CA, Unit</nlm:aff>
<wicri:noCountry code="subfield">Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="London, Edythe D" sort="London, Edythe D" uniqKey="London E" first="Edythe D." last="London">Edythe D. London</name>
<affiliation wicri:level="1">
<nlm:aff id="af0030">Department of Physiology, UCLA, Los Angeles, CA, United States</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Physiology, UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0050">VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>VA Greater Los Angeles Healthcare System, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af0055">Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA</wicri:regionArea>
<wicri:noRegion>CA</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series>
<title level="j">NeuroImage : Clinical</title>
<idno type="eISSN">2213-1582</idno>
<imprint>
<date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [
<sup>18</sup>
F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in
<italic>Control</italic>
and
<italic>Placebo</italic>
conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the
<italic>Placebo</italic>
PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the
<italic>Placebo</italic>
condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (ρ = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo.</p>
</div>
</front>
<back>
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<author>
<name sortKey="Ko, J H" uniqKey="Ko J">J.H. Ko</name>
</author>
<author>
<name sortKey="Monchi, O" uniqKey="Monchi O">O. Monchi</name>
</author>
</analytic>
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<analytic>
<author>
<name sortKey="Turk, D C" uniqKey="Turk D">D.C. Turk</name>
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<author>
<name sortKey="Rudy, T E" uniqKey="Rudy T">T.E. Rudy</name>
</author>
<author>
<name sortKey="Sorkin, B A" uniqKey="Sorkin B">B.A. Sorkin</name>
</author>
</analytic>
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<analytic>
<author>
<name sortKey="Von Korff, M" uniqKey="Von Korff M">M. Von Korff</name>
</author>
<author>
<name sortKey="Wagner, E H" uniqKey="Wagner E">E.H. Wagner</name>
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</author>
<author>
<name sortKey="Saunders, K W" uniqKey="Saunders K">K.W. Saunders</name>
</author>
</analytic>
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<analytic>
<author>
<name sortKey="Von Korff, M" uniqKey="Von Korff M">M. Von Korff</name>
</author>
<author>
<name sortKey="Ormel, J" uniqKey="Ormel J">J. Ormel</name>
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<author>
<name sortKey="Dworkin, S F" uniqKey="Dworkin S">S.F. Dworkin</name>
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</analytic>
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<author>
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<name sortKey="Sokolik, A" uniqKey="Sokolik A">A. Sokolik</name>
</author>
<author>
<name sortKey="Casey, K L" uniqKey="Casey K">K.L. Casey</name>
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<name sortKey="Davidson, R J" uniqKey="Davidson R">R.J. Davidson</name>
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<name sortKey="Kosslyn, S M" uniqKey="Kosslyn S">S.M. Kosslyn</name>
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<name sortKey="Rose, R M" uniqKey="Rose R">R.M. Rose</name>
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<author>
<name sortKey="Cohen, J D" uniqKey="Cohen J">J.D. Cohen</name>
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<author>
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<name sortKey="Zubieta, J K" uniqKey="Zubieta J">J.K. Zubieta</name>
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<author>
<name sortKey="Wager, T D" uniqKey="Wager T">T.D. Wager</name>
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<author>
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<name sortKey="Rilling, J K" uniqKey="Rilling J">J.K. Rilling</name>
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<author>
<name sortKey="Watson, A" uniqKey="Watson A">A. Watson</name>
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</author>
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<name sortKey="Vogt, B A" uniqKey="Vogt B">B.A. Vogt</name>
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<name sortKey="Jones, A K" uniqKey="Jones A">A.K. Jones</name>
</author>
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<author>
<name sortKey="Wise, R A" uniqKey="Wise R">R.A. Wise</name>
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<biblStruct>
<analytic>
<author>
<name sortKey="Wu, Y" uniqKey="Wu Y">Y. Wu</name>
</author>
<author>
<name sortKey="Carson, R E" uniqKey="Carson R">R.E. Carson</name>
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<analytic>
<author>
<name sortKey="Zald, D H" uniqKey="Zald D">D.H. Zald</name>
</author>
<author>
<name sortKey="Woodward, N D" uniqKey="Woodward N">N.D. Woodward</name>
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<author>
<name sortKey="Cowan, R L" uniqKey="Cowan R">R.L. Cowan</name>
</author>
<author>
<name sortKey="Riccardi, P" uniqKey="Riccardi P">P. Riccardi</name>
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<author>
<name sortKey="Ansari, M S" uniqKey="Ansari M">M.S. Ansari</name>
</author>
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<name sortKey="Baldwin, R M" uniqKey="Baldwin R">R.M. Baldwin</name>
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<name sortKey="Bueller, J A" uniqKey="Bueller J">J.A. Bueller</name>
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<name sortKey="Jackson, L R" uniqKey="Jackson L">L.R. Jackson</name>
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<name sortKey="Nichols, T E" uniqKey="Nichols T">T.E. Nichols</name>
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<name sortKey="Yau, W Y" uniqKey="Yau W">W.Y. Yau</name>
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<name sortKey="Scott, D J" uniqKey="Scott D">D.J. Scott</name>
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<name sortKey="Stohler, C S" uniqKey="Stohler C">C.S. Stohler</name>
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<li>Maryland</li>
<li>Québec</li>
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<li>Université du Maryland</li>
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