, Volume 218, Issue 3, pp 503–512

Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

  • Daniel H. Wolf
  • Theodore D. Satterthwaite
  • James Loughead
  • Amy Pinkham
  • Eve Overton
  • Mark A. Elliott
  • Gersham W. Dent
  • Mark A. Smith
  • Ruben C. Gur
  • Raquel E. Gur
Original Investigation



Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation.


We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis.


An oral 1 mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3 T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory.


Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task.


GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia.


Pharmacological fMRI Benzodiazepine Endophenotype Amygdala Facial emotion GABA Schizophrenia 

Supplementary material

213_2011_2348_MOESM1_ESM.doc (982 kb)
(DOC 982 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Daniel H. Wolf
    • 1
  • Theodore D. Satterthwaite
    • 1
  • James Loughead
    • 1
  • Amy Pinkham
    • 5
  • Eve Overton
    • 1
  • Mark A. Elliott
    • 2
  • Gersham W. Dent
    • 4
  • Mark A. Smith
    • 4
  • Ruben C. Gur
    • 1
    • 2
    • 3
  • Raquel E. Gur
    • 1
    • 2
  1. 1.Department of PsychiatryUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of RadiologyUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Philadelphia Veterans Administration Medical CenterPhiladelphiaUSA
  4. 4.AstraZeneca Pharmaceuticals LPWilmingtonUSA
  5. 5.Department of PsychologySouthern Methodist UniversityDallasUSA

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