A Longitudinal Investigation of the Endocrine and Neurobiologic Events Accompanying Puberty

Despite the clear importance of adolescence in the emergence of a number of disease states
and processes, there is surprisingly little known about how the endocrine and metabolic
events accompanying puberty in humans impact normal developmental neurobiology. Epidemiologic
studies have identified sexual dimorphisms in the prevalence of several neuropsychiatric
disorders, including depression, schizophrenia, and substance abuse. Many of these sex
differences emerge during or shortly after puberty and are maintained until the 5th-6th
decade of life. For example, the two-fold greater risk of unipolar depression in women
compared with men does not appear until adolescence, and prior to puberty girls are not at
increased risk relative to boys. Puberty is a structured, transitional process that can be
influenced by both nutritional factors and environmental stressors; nonetheless, the
variability in the timing and duration of puberty is largely determined by oligogenic
inheritance. Basic neuroscience research has demonstrated that hormonal events accompanying
puberty impact on many of the physiologic systems involved in the regulation of brain
function (e.g., the appearance of new neurons in a brain-region specific pattern, neuronal
remodeling, and the pruning of cortical connectivity). Additionally, not only does stress
during puberty increase the risk of disturbances in affective adaptation during adulthood,
but the events accompanying puberty modify stress responsivity (e.g., alterations in the
duration and peak response of hypothalamic-pituitary-adrenal [HPA] axis hormones to
stressors). Moreover, animal work has demonstrated that neural connectivity differs in a
brain regional specific manner according to the stage of puberty (i.e., early versus late).
In humans, puberty also occurs in stages, and although the endocrinology of puberty,
surprisingly, has not been fully characterized with longitudinal data, studies have
documented that the physical changes measured by Tanner stages I to V are accompanied by
progressive increases in the secretions of both gonadal and adrenal steroids. Nonetheless,
there remains considerable variability in the timing and duration of this otherwise highly
structured reproductive transition.

We propose to perform a longitudinal, naturalistic study examining changes in brain structure
and function, behavior, and stress responsivity in boys and girls across the pubertal
transition. Because the pubertal transition is defined by a complex series of physiologic
events that emerge sequentially over several years and involve changes in multiple endocrine
and growth systems, and because there is also considerable variability in the timing of these
events reflecting the influence of both genetic and environmental factors, puberty cannot by
delineated by age of the participants as has been done in most imaging and other
neurobiological studies of adolescence. The present study will formally bridge this gap by
defining pubertal events per se in participants.

Participants will include healthy boys and girls whose pubertal status will be assessed, and
in whom endocrine, metabolic, and brain imaging measures will be evaluated at eight - ten
month intervals from age eight years (pre-puberty) until age 17 years (post-puberty).
Reproductive endocrine, metabolic, and physical measures will be employed to characterize the
stage and duration of pubertal development. Outcome measures will be derived via multimodal
neuroimaging techniques, cognitive/behavioral assessments, metabolic measurements, and
evaluations of HPA axis function. Additionally, the impact of genetic variation on the
developmental trajectory of these parameters (both reproductive and CNS) will be determined.

This cross-institute proposal will employ a multidisciplinary approach to evaluating the
effects on CNS function of the process of puberty in both boys and girls. This work will not
only serve to inform research on the mechanisms by which sexual dimorphisms in
neuropsychiatric disorders develop, it will also have important implications for the
prevention and treatment of these disorders.

- INCLUSION CRITERIA - SAMPLE 1:

Child volunteers will qualify for inclusion if they meet the following criteria:

- Good general health and normal IQ; A normal IQ will be determined by the scores on
Test of Irregular Word Reading Efficiency (TIWRE)

- Age 8 years;

- Body Mass Index (kg/m^2) between the 15th and 85th percentiles for age and sex
according to the US Centers for Disease Control and Prevention 2000 growth charts;

- A normal tempo of growth as determined by skeletal age within +/- 1.64 standard
deviations of chronologic age according to the Greulich and Pyle radiographic atlas
(i.e., no evidence for precocious puberty or abnormal delay of maturation); Research
criteria for determining bone age will be performed by the collaborating pediatric
endocrinologist. This criterion is required only for the initial entry into this study
and is not one of the inclusion criteria for subsequent visits;

- No history of significant neurologic or cognitive disorders. Examples include neonatal
anoxic encephalopathy, seizure disorders, autism, and most learning disorders
including attention deficit hyperactivity disorder;

- Able to provide assent. Parents will provide consent.

EXCLUSION CRITERIA - SAMPLE 1:

Child volunteers will be excluded for the following reasons:

- Presence of any medical condition that increases risk for MRI (e.g., pacemaker,
metallic foreign body in eye or other body part, dental braces);

- Presence or history of medical conditions known to affect cerebral anatomy;

- Children who are not pre-pubertal as indicated by the presence of Tanner stage 2
development (i.e., areolar development in girls and testicular volume > 3 cc in boys);

- Individuals who have, or whose parent or guardians have, current substance abuse or a
psychiatric disorder or any other condition which, in the opinion of the
investigators, would impede the ability to give informed consent or possibly hinder
completion of the study; presence of any psychiatric disorder in the subject, sibling,
or other first-degree relative;

- Subjects who regularly use prescription medications (the use of over-the-counter
medications will be reviewed on a case-by-case basis.);

- For females who have reached menarche: Pregnancy, lactation, or inability or
unwillingness to undergo pregnancy testing (a urine pregnancy test will be performed
prior to all MRI and X-ray procedures for girls who have had the onset of menses);

- Current or past use of psychiatric medication;

- I.Q. < 70.

INCLUSION CRITERIA - SAMPLE 2:

Child volunteers will qualify for inclusion if they meet the following criteria:

- Good general health and normal IQ;

- Ages 12-13 years;

- Body Mass Index (kg/m^2) between the 15th and 85th percentiles for age and sex
according to the US Centers for Disease Control and Prevention 2000 growth charts;

- A normal tempo of growth as determined by skeletal age within +/- 1.64 standard
deviations of chronologic age according to the Greulich and Pyle radiographic atlas
(i.e., no evidence for precocious puberty or abnormal delay of maturation); Research
criteria for determining bone age will be performed by the collaborating pediatric
endocrinologist. This criterion is required only for the initial entry into this study
and is not one of the inclusion criteria for subsequent visits.;

- No history of significant neurologic or cognitive disorders. Examples include neonatal
anoxic encephalopathy, seizure disorders, autism, and most learning disorders
including attention deficit hyperactivity disorder;

- Able to provide assent. Parents will provide consent.

EXCLUSION CRITERIA - SAMPLE 2:

Child volunteers will be excluded for the following reasons:

- Presence of any medical condition that increases risk for MRI (e.g., pacemaker,
metallic foreign body in eye or other body part, dental braces);

- Presence or history of medical conditions known to affect cerebral anatomy;

- Individuals who have, or whose parent or guardians have, current substance abuse or a
psychiatric disorder or any other condition which, in the opinion of the
investigators, would impede the ability to give informed consent or possibly hinder
completion of the study; presence of any psychiatric disorder in the subject, sibling,
or other first-degree relative;

- Subjects who regularly use prescription medications (the use of over-the-counter
medications will be reviewed on a case-by-case basis.);

- For females who have reached menarche: Pregnancy, lactation, or inability or
unwillingness to undergo pregnancy testing (a urine pregnancy test will be performed
prior to all MRI and X-ray procedures for girls who have had the onset of menses);

- Current or past use of psychiatric medication;

- I.Q. < 70.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 3:

Inclusion and exclusion criteria for sample 3 will be identical as those for sample 2 with
the exception that children between the ages of 8 and 17 will be included.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 4:

Sample 4 participants will also be volunteering in Protocol #95-M-0150 Neurobiological
Investigation of Patients with Schizophrenia Spectrum Disorders and Their Siblings, and/or
Protocol #81-M-0126, The Evaluation of Women with Menstrually-Regulated Mood and Behavioral
Disorders, in which they will also have signed consent and through which they will have
been screened.

INCLUSION CRITERIA - SAMPLE 4:

- Ages of 25 and 35 years at the time of enrollment.

- Each subject must have a level of understanding sufficient to agree to all required
tests and examinations and sign an informed consent document.

- No use of psychotropic substances in the last 3 months.

- No psychiatric or severe chronic medical illness at the time of the study, and by
history.

EXCLUSION CRITERIA - SAMPLE 4:

- Presence of impaired hearing.

- Pregnant or currently breast feeding. (a urine pregnancy test will be performed prior
to MRI procedures in women)

- Presence of a history head trauma with loss of consciousness in the last year or any
evidence of functional impairment due to and persisting after head trauma.

- Previous eye surgery with a prosthetic implant.

- Participants with tattoos will be excluded if the tattoos are in a location on the
body (eyes, lips, etc.) that could interfere with fMRI scans or contain a heavy metal
content.

- Presence of permanent tattooed makeup (eyeliner, lip, etc.) or general tattoos.
Participants with tattoos will be excluded if those are in a dangerous location in the
body or made with colors (e.g., dark blue and dark green) whose content in iron cannot
be definitely ruled out by the investigators.

- Presence of any non-organic implant or any other device such as: cardiac pacemaker,
insulin infusion pump, implanted drug infusion device, cochlear, otologic, or ear
implant, transdermal medication patch (Nitro), any metallic implants or objects, body
piercing(s), bone/joint pin, screw, nail, plate, wire sutures or surgical staples,
shunt.

- Presence of cerebral or other aneurysm clips.

- Presence of shrapnel or other metal imbedded in the body (such as from war wounds or
accidents).

- Previous employment in metal fields or with machines that may have left any metallic
fragments in or near the eyes.

- History of a severe accident in the past that may possibly have left metal in the
body.

- Psychological contraindications for MRI (e.g., suffer from claustrophobia);

- Less than an 8th grade education or an IQ below 70 as determined by the scores on Test
of Irregular Word Reading Efficiency [TIWRE] .

- NIMH employees and staff and their immediate family members will be excluded from the
study per NIMH policy.

INCLUSION/EXCLUSION CRITERIA - SAMPLE 5:

Inclusion and exclusion criteria for sample 5 will be identical as those for samples 1 and
2 (i.e., children will either be age 8-9 or between the ages of 12 and 13) with the
exception that children with a tempo of growth that is considered abnormal as demonstrated
by skeletal age greater than two standard deviations in advance of their chronologic age
according to the Greulich and Pyle Radiographic Atlas will be included. These children will
be matched for age, Tanner stage, race, ethnicity, and BMI with children currently enrolled
in the longitudinal study.