Effects of social exclusion on brain metabolism: a possible pathway for increased risk of schizophrenia in the hard of hearing.

Background:

According to the social defeat hypothesis the long-term experience of social exclusion or social defeat leads to enhanced baseline activity and/or sensitization of the mesolimbic dopamine (DA) system and puts the individual at increased risk for psychotic disorder and/or schizophrenia. This pilot study tests the hypothesis by comparing DAergic function in two groups who are expected to differ greatly: (1) socially excluded young adults acquired deafness; (2) hearing peers.



Subjects and methods:

15 subjects with acquired deafness and 15 healthy subjects, recruited through patient organizations, treatment facilities and websites in the Netherlands, will be examined using SPECT-imaging with the D2 tracer [123I]iodobenzamide. In one session, baseline D2 receptor binding and endogenous DA release after stimulation with D-amphetamine sulphate (0.3 mg/kg iv) will be assessed (bolus/constant infusion technique). SAHI and healthy subjects will be matched for age, sex and smoking status.



Main hypotheses:

1. The baseline [123I]IBZM binding potential ([123I]IBZM-BP) in the ventral striatum is smaller in participants with acquired deafness than in hearing subjects, due to increased baseline activity of the mesolimbic dopamine system;

2. The decrease in [123I]IBZM-BP after amphetamine challenge is significantly greater in participants with acquired deafness than in hearing subjects;

3. There is a greater psychological/behavioural response to amphetamine (happiness, restlessness, increased level of energy) in subjects with acquired deafness than in hearing subjects.



Power:

Animal experiments have demonstrated large effects of humiliation on DA function (Cohen’s d > 1), but there has not been any study in humans. It is proposed to compare 15 deaf subjects and 15 healthy subjects using a t-test for independent samples. Thus, the study has 85% power (α = 0.05; one-tailed) to demonstrate a large effect size (Cohen’s d = 1.0). The results will be examined for confounding and effect modification by socio-economic status, salivary cortisol, serum testosterone and polymorphisms of genes coding for COMT, DA transporter and D2-receptor.



Scientific and social relevance:

1. The social defeat hypothesis may explain the higher risk of major psychiatric disorder for people who rank low in societal hierarchy;

2. Understanding the biological mechanisms underlying the unequal risk is a first step towards prevention.

1. The baseline [123I]IBZM binding potential in the ventral striatum is higher among healthy subjects than among participants with acquired deafness (due to increased baseline activity of the mesolimbic dopamine system among participants with acquired deafness);

2. The decrease in [123I]IBZM binding potential after amphetamine challenge (representing endogenous DA release) is significantly greater in participants with acquired deafness than in healthy subjects;

3. The [123I]IBZM binding potentials before and after amphetamine challenge are correlated with scores on scales related to social exclusion and self esteem (UCLS, Social Defeat Scale, Social Comparison Scale, BCSS, RSES);

4. There is a greater psychological/behavioral response to amphetamine (happiness, restlessness, increased level of energy) in participants with acquired deafness than in hearing control subjects;

5. The [123I]IBZM binding potentials before and after stimulation with amphetamine are correlated with scores for non-clinical psychotic or psychosis-like symptoms.

Testing day 1:

1. Edinburgh Handedness Inventory;

2. Number of addresses in range of postal code, for three different time frames, current residence / longest residence age 0-10 yrs / longest residence age 10-20 yrs;

3. Parental Education levels;

5. Deaf participants: Audiogram. Control participants: Automated (Békésy) audiogram.

For deaf participants only:

4. Question about deafness in medical interview;

6. Speech audiometry.



Testing day 2 (preferably within 1 month of testing day 1):

7. UCLA Loneliness Scale (v3);

8. Social Defeat Scale;

9. Rosenberg Self Esteem Scale;

10. Beck Depression Inventory (II);

11. Social Comparison Scale;

12. Childhood Trauma Questionnaire;

13. Community Assessment of Psychic Experiences;

14. Visual Analogue Scale, t(amphetamine) -5, 5, 15, 25, 35, 45, 55, 120 minutes;

15. Community assessment of Psychic Experiences - state version. 2x. Assessing the 120 minutes before and 120 minutes after amphetamine administration;

16. Brief Core Schema Scales;

17. Cortisol from saliva, 2x. Directly before each SPECT scan;

18. Blood sample before start of IBZM infusion;

19. Blood sample before start of IBZM infusion;

20. Either 3t scan acquired locally, or for CI users scan acquired at institution where Cochlear Implant was placed;

21. SPECT Scan, 2x. 120 minutes after start of IBZM infusion and 240 minutes after start of IBZM infusion (60 minutes after D-amphetamine infusion);

22. Blood sample, 4x (directly before and after each SPECT scan);

23. Cognitive Emotion Regulation Questionnaire (CERQ);

24. Penn Emotion Recognition Task (PERT);

25. Hinting task;

26. Blood pressure measurements t(amphetamine) -5, 0, 5, 10, 15, 20, 25, 30 minutes.

The procedure for deaf (n=15) and control (n=15) participants is the same. Participants with acquired deafness are assumed to have experienced extreme social exclusion due to their loss of hearing. Control participants will be matched to deaf participants on age (+/- 1 yr), sex, and smoking habits.



D-amphetamine sulphate iv (0.3 mg/kg body weight).