Medical Student Research Fellowship for Summer 2007

Mentor: Uma Rao
Department: Psychiatry
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Project Summary
Neuronal Risk Markers for Nicotine Dependence in Youth
PURPOSE: To relate the responsiveness of the orbitofrontal cortex (OFC) and associated brain regions (henceforth referred to as OFC network) to the risk for nicotine dependence (ND) during prospective follow-up in depressed adolescents and controls.
BACKGROUND: Cigarette smoking begins often during adolescence and is associated with significant socioeconomic burden. The presence of depression may be associated with more severe ND symptoms and adversely affects an individual's attempts to quit smoking. Studies in animals and humans suggest that the mesostriatal-mesocorticolimbic dopamineric (DA) circuits may play an important role in the susceptibility to both of these disorders. In considering the functional neuroanatomical changes in the mesostriatal-mesocorticolimbic DA circuits associated with smoking behavior (or depressive illness), in humans, it is important to consider that the studies were performed in patients with long history of illness. Furthermore, recurrent depressive episodes and chronic nicotine use can induce changes in the common neurobiological substrate. Therefore, in order to delineate potential vulnerability markers from neurobiological adaptations resulting from an illness, it is ideal to recruit populations before the onset of the disorder and prospectively assess the neurobiological manifestations and course of illness. This proposal will attempt distinguish premorbid neuronal vulnerability markers from neuronal changes occurring as a consequence of ND. In a series of studies, we reported that certain neurobiological markers are evident prior to the onset of depression and substance use disorder (SUD). For instance, adolescents who manifested higher cortisol secretion had a greater frequency of initiating smoking during prospective follow-up compared with youngsters who had lower cortisol secretion. We propose to extend these findings to identify brain circuits associated with the characteristics of ND in adolescents with and without depression, by focusing on the OFC and related circuitry (namely the mesostriatal-mesocorticolimbic DA reward circuits).
CONCISE SUMMARY OF PROJECT: In total, 60 depressed (30 with no regular nicotine use and 30 with nicotine use) and 60 normal controls will be recruited over 4 years. The study will include baseline and follow-up phases. The baseline has three stages: 1) telephone screening, 2) clinical and laboratory measures, 3) neurocognitive tasks and fMRI study. The follow-up evaluations will be conducted at 6-month intervals after baseline.

Baseline Phase:
1) Telephone Screening: All potential subjects will be screened over the telephone to determine preliminary eligibility criteria, including the confirmation of depressive symptoms, nicotine, alcohol and other drug use, and medical and treatment history.

2) Clinical and Laboratory Measures: Following informed consent/assent, subjects will receive an extensive diagnostic evaluation, including verbal interviews, in which the clinician will ask questions about the child's general health, current and past childhood trauma, current and past psychiatric symptoms, family psychiatric and medical history, and nicotine use history. The subject/guardian will also complete written questionnaires about similar information. The interview will last 1-3 hours and will be audio taped with the subject's permission. The child will then undergo a brief physical examination and routine blood tests. In addition, a clear saliva sample (approximately 5 ml.) will be collected to measure cotinine levels.

3) Neurocognitive tasks and fMRI study:
Neurocognitive tasks: The subject will be asked to participate in two neurocognitive tasks. The first one is the Wheel of Fortune (WOF). The WOF is organized into separate subtasks, a losing and a winning subtask. In each subtask, the subjects view successively and in a random order one of three types of circles. Each circle is divided into two slices (blue and magenta) in proportions of 50/50, 30/70, or 10/90. The proportions of the slices reflect the probability of winning money in the winning subtask or losing money in the losing subtask condition. Each slice is paired with a dollar amount (magnitude of gain/loss) such that the smaller proportion is paired with the higher dollar amount ($0.5/$0.5 or $4/$4 for the 50/50 conditions; $1/$0.5 for the 30/70 condition; and $4/$0.5 for the 10/90 condition). The subjects are instructed to make a decision on which slice they think an imaginary pointer would land on if the circle would get spun. In the winning subtask, if the imaginary pointer lands on the slice chosen by the subject, the indicated dollar amount is added to a starting amount of $0. In the losing subtask, if the imaginary pointer lands on the slice chosen by the subject, the indicated dollar amount is subtracted from a starting amount of $75. Each subtask lasts about 20 minutes. After choosing a slice, subjects are presented with the result of their choice (won or not won, and lost or not lost); participants then are asked to rate how they feel on a 5-point scale (0 being the worst, and 5 best).
The second task is the Prisoner's Dilemma (PD). The PD is a task that measures social cooperativeness. In this game, the subject will independently choose to either cooperate with another "player" (the computer) or not, and is awarded a sum of money that depends upon the interaction of both players' choices in that round. There are 4 possible outcomes of a round: Player A (the subject) and Player B (the computer) cooperate (CC), Player A cooperates and Player B defects (CD), Player A defects and Player B cooperates (DC), or Player A and Player B defect (DD). The pay-offs for the outcomes are arranged such that DC > CC > DD > CD, and CC > (CD + DC) / 2. Each cell of the pay-off matrix corresponds to a different outcome of a social interaction:
Player A
Cooperate Defect
$5 ($5) $6 ($0)
$0 ($6) $1 ($1)

Cooperate
Player B
Defect

DC represents the situation where player A opts for noncooperation and Player B cooperates so that Player A benefits at Player B's expense (CD is the converse). CC involves mutual cooperation and DD involves mutual noncooperation.

fMRI study: The WOF will be performed again in an fMRI scanner. Participants will view the task through adjustable goggles in the scanner. The experimental designs are all based on rapid event related models. Behavioral/cognitive performance (as described above) will be recorded. Prior to the fMRI procedure, each participant will have a training session in the MRI scanner in order to become familiar with the fMRI environment and experimental procedures. Simultaneously subjects will be trained on the reward-processing task that they will perform in the fMRI environment. The order of subtask presentation will be counterbalanced between participants. During periods when the participant does not perform the task, a DVD of the subject's choice will be presented.

Follow-up Phase: Follow-up evaluations will be conducted at 6-month intervals. Information on quantitative measures of nicotine, alcohol and other drug use, as well as depressive symptoms, will be obtained every 6 months. More comprehensive evaluations will be performed annually. A clear saliva sample (approximately 5ml.) will be collected at each follow-up visit to measure cotinine levels.

CRITERIA FOR INCLUSION OF SUBJECTS: Subjects will be between 12 years and 21 years, inclusive. Because the proposed instruments have not been translated into other languages and tested for their validity, every adolescent subject must speak and read English to be included in the study. Subjects must be at least at the 6th grade reading level as determined by the Slosson test, and they must have a general IQ score above 80. They will be medication free (except acetaminophen) for at least two weeks (6 weeks for fluoxetine) prior to the fMRI studies. Only youth who are not on psychotropic medication at the time of initial screening will be recruited into the study.

Specific Inclusion Criteria for
Depressed Adolescents: Subjects will meet DSM-IV criteria for current MDD, and a score ?15 on the first 17-items of the Hamilton Depression Rating Scale (HDRS). Associated functional impairment will be required (a score of ?60 on the Children's Global Assessment Scale).
Controls: Subjects should have no evidence of any psychiatric disorder currently or in the past. Also, there should be no history of psychiatric disorder in any first-degree relative.
High Risk Adolescents: Subjects should have no evidence of any psychiatric disorder currently or in the past, and must have one or more parent(s) who meet criteria for MDD and/or Dysthymia.
Non-smokers: Lifetime tobacco use should be >3 times and <5 cigarettes (minimal experimentation). There should be no tobacco use in the previous month. Urine cotinine levels should be below 50 g/L.
Smokers: Cigarette smoking should occur in the past month with a frequency of at least 4 days/week. However, subjects should not meet DSM-IV criteria for ND either currently or in the past. Subjects with other forms of nicotine use will be excluded.

CRITERIA FOR EXCLUSION OF SUBJECTS: Any adolescent having one or more DSM-IV symptoms of non-nicotine substance use disorder (SUD) currently or in the past, will be excluded. Other criteria include substance use in the past two weeks (confirmed by a urine drug screen), significant medical illness as determined by physical examination and routine laboratory tests, and pregnancy or suspected pregnancy. Subjects with metallic devices or objects (e.g. pacemakers, artificial heart valves, implanted infusion pumps, cochlear implants, etc.), or those having symptoms of claustrophobia (discomfort in enclosed spaces, such as an MRI scanner) or color blindness, will be excluded.

Specific Exclusion Criteria for Depressed Adolescents: Adolescents with a diagnosis of schizophrenia, schizo-affective disorder or autism will be excluded. Subjects with other comorbid conditions will not be excluded. In exploratory analyses, the influence of comorbidity on task performance and OFC responsivity and on the risk for ND, will be evaluated in this study.

SOURCES OF RESEARCH MATERIAL: The source of research material will include clinical interviews, self-report forms, audio tapes of interviews, blood and urine samples, cognitive function measures, and brain scans. The materials used will be marked with a research code number and the patient's initials. All information will be obtained specifically for research purposes. All the clinical information collected will be stored in a computer, and will be password protected. All paper records will be double-locked in a file cabinet. There will also be no intent to publish any subject's personal information that would link the subject to the study.
RECRUITMENT OF SUBJECTS: Prospective subjects will not be patients of the investigator, however, prospective patients will at no time be contacted directly by the research team. Depressed adolescents will be directed to the study by the psychiatric and pediatric clinics at UTSWMC and affiliated institutions, and through community agencies, local schools and advertisements in newspapers. Similarly normal controls will be directed to the study by local medical clinics, community agencies, and by advertisement. Interested potential participants will be requested to directly contact the research team. Prior to conducting the initial evaluation, the coordinator of the study or the evaluator will inform the patient and guardian about the study and will obtain informed consent, as well as the HIPAA authorization form. The original consents will be maintained in the subject's research binder.
POSSIBLE RISK(S): Based on extensive prior experience with similar protocols and methodologies, no untoward effects are expected from the proposed psychiatric and physical evaluations, or laboratory investigations. There is a potential risk of distress when discussing emotional difficulties although the vast majority of people find the discussion of personal problems to be a positive experience.
There are no known risks associated with the general physical examination. Blood will be drawn for routine investigations. A total of approximately10 ml. of blood will be drawn during initial recruitment to the study, and approximately 10 ml. during each MRI study for ACTH and cortisol measures. The venipuncture may be accompanied by pain and/or bruising. There are no untoward effects from urine samples.
The neurocognitive tasks do not involve any known physical risks. Most youngsters find computerized games exciting. However, some subjects might feel anxious while making choices that involve risk assessment (e.g., gain vs. loss) and social cooperation. Also, some subjects might be bored with the tasks.
There are no known physical risks to the MR scanning procedure. Some subjects may experience claustrophobia and anxiety while in the MR scanner due to the enclosed and tight space. Also, the scanner will make a constant, noisy sound. Although there are no known risks associated with the MR scanning procedure, the magnetism of the machine does attract certain metals. Scanning a person whose body contains metal devices or objects could result in a serious health risk.
Since depressed subjects will be required to be off from medications that can affect the central nervous system until the initial fMRI scan is completed, there is a potential risk for worsening of depressive symptoms.

SPECIAL PRECAUTIONS: Some participants may not improve during the study. Symptoms and functioning will be closely monitored weekly or biweekly. Participants and their parents will be given phone numbers to call should they have any questions, or if significant adverse events occur, or if symptoms worsen. Subjects will be withdrawn from the study if the evaluating physician recommends immediate treatment.
PROCEDURES TO MAINTAIN CONFIDENTIALITY: All records relating to this project will be handled and safeguarded according to standard University policy for medical records. Any information obtained in connection with this study that can be identified with the subject will remain confidential, and will be disclosed with patient's permission. Information about the subjects will be stored in the investigator's research file and identified only by a code number. Only the research personnel will have access to information regarding patients' identity. All research files are stored in locked cabinets to ensure privacy. All subjects will sign the HIPAA authorization form.
In some cases, the IRB or sponsor may review the research information. In this event, these entities will have access to the research file, which will have no identifying information on the research documents. Original subject consent forms will be placed in the research chart; subjects will also receive a copy.
POTENTIAL BENEFITS: The subjects may not receive any benefit from participating in this study. However, potential depressed subjects will receive a free, comprehensive psychiatric evaluation and a referral for treatment. Oftentimes, such comprehensive evaluation is not provided as part of routine clinical care. If subject and parent(s) consent to the release of information, a written report of the evaluation can be provided to the primary clinician to help with diagnostic formulation and treatment-planning. Subjects also will receive a free psychoeducation manual and an individual session, providing pertinent information about depression. Similarly, psychoeducation materials will be provided on the effects of psychiatric evaluation and psychoeducation sessions and materials are available to patients through routine clinical treatment, without having to participate in the study.
There is a potential benefit of the study to society. This study may enhance knowledge regarding the risk factors associated with cigarette smoking in depressed and non-depressed adolescents, and its natural course and sequelae. Such knowledge potentially might have implications for the development of more effective treatment and preventive strategies for depression and for ND.
RISK/BENEFIT ASSESSMENT: Very minimal risks are involved in this study: possible discomfort in discussing personal information during the interview or possible anxiety associated with the cognitive and fMRI studies. The benefits greatly outweigh any risks, as subjects will receive systematic evaluation on an annual basis by experienced evaluators in child psychiatry. Any subjects with recurring or new difficulties will be provided with recommendations for treatment. The study may also benefit society through the development of treatment interventions for depressed adolescents at risk for substance problems.

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