Bradley S. Peterson, M.D.

Columbia College of Physicians & SurgeonsNew York State Psychiatric Institute

BRAIN IMAGING STUDIES OF BRAIN IMAGING STUDIES OF DEVELOPMENTALLY BASED DEVELOPMENTALLY BASED

PSYCHOPATHOLOGIESPSYCHOPATHOLOGIES

• Design Challenges When Studying Developmentally Based Psychopathologies

• Some Possible Solutions

• Examples in ADHD & Other Conditions

OutlineOutline

Peterson BS, Development & Psychopathology 15:811-832, 2003

1. Distinguishing findings of core pathological processes from epiphenomena or compensatory responses

• Why? Because in vivo imaging data are inherently correlational, both in cross-sectional and longitudinal studies

Design ChallengesDesign Challenges

2. Delineation of the natural history and developmental correlates of an illness, particularly in cross-sectional studies

• Common assumption in cross-sectional studies is that members of differing age cohorts who have the same diagnosis belong to the same larger population of subjects with the same biological illness

• Corollary is that younger subjects will, with time, resemble their older counterparts

• Untrue in most cases

• Most childhood-onset illnesses differ from their adult-onset counterparts in phenomenology, familial risk, comorbidities, and natural history

Design Challenges (cont’d)Design Challenges (cont’d)

3. Interpreting differences in brain activation in fMRI studies across differing ages or diagnostic groups

• may represent differences across groups or ages in:

• task processing strategies

• degrees of effort, frustration, or confusion while performing the task

• epiphenomenal features associated with differing performance levels on the task across groups (e.g. emotional and cognitive reactions to recognition of performing poorly)

Design Challenges (cont’d)Design Challenges (cont’d)

4. Differences in underlying anatomy across diagnostic groups

• commonly reported in most childhood disorders in which it has been examined systematically

• may confound interpretation of functional differences

• may impair attempts at spatial normalization

Design Challenges (cont’d)Design Challenges (cont’d)

Next generation of imaging studies should examine more representative samples using more novel and informative experimental designs

1. Extend studies to progressively younger age groups and to high-risk cohorts prior to illness onset

• identify trait rather than state markers of CNS functioning that predispose individuals to particular illnesses

2. Yoke imaging studies to randomized, controlled clinical trials

• a putative, causally relevant variable is experimentally controlled and manipulated

Some Possible SolutionsSome Possible Solutions

3. Study samples that are epidemiologically ascertained in both cross-sectional and longitudinal frameworks

• will provide data more valid for inferences about natural history and developmental correlates than will data acquired in samples that are affected by ascertainment biases

4. Consider ROI over voxel-based comparisons of activity across diagnostic groups

• ROIs defined according to each subject’s unique anatomy

Possible Solutions (Cont’d)Possible Solutions (Cont’d)

5. Include elementary and simple tasks that are likely to minimize differences across groups in effort, performance, and task processing strategies

• demonstrating similar activations across age or diagnostic groups using even the most elementary of tasks will help to constrain interpretation of where in the information processing stream differences in activation across ages or diagnoses first arise

Possible Solutions (Cont’d)Possible Solutions (Cont’d)

Primary Sensory Cortices

Lower Order Sensory Association Cortices

Higher Order Sensory Association (Heteromodal) Cortices

Working Memory

Response Monitoring

Error Detection

Long-Term Memory

Affect

Motor Planning

Motor Response

Information Processing

Example of Yoking to a Clinical Trial:Example of Yoking to a Clinical Trial:Stimulant MedicationsStimulant Medications

in Children & Adolescents with ADHDin Children & Adolescents with ADHD

Potenza et al., Submitted

• Requires inhibiting the performance of the more automatic task (word reading) to perform the less automatic task (color naming)

• Is therefore a model for self-regulation

• Thesis: Distractibility, hyperactivity, and impulsivity may be a consequence of disturbances in self-regulatory control in children with ADHD

•Therefore, the Stroop is an appropriate cognitive and behavioral probe of the efficacy of stimulant medications in treating AHD

Stroop Word-Color InterferenceStroop Word-Color Interference

Stroop Word-Color Interference

Congruent

RED

BLUE

YELLOW

GREEN

Incongruent

RED

BLUE

YELLOW

GREEN

Stroop Activation

R LR L

RIGHT LEFTTOP

SURFACE MORPHOLOGY

ADHD VS CONTROLS

TemporalFrontal

TemporalFrontal

Sowell et al., Lancet, 2003

SubjectsSubjects

ADHD Normal Controls

N=16 N=20

7-18 years

mean 14 ± 2.4 years

7-18 years

mean 13.4 ± 3.1 years

The Neural Circuitry of Self-The Neural Circuitry of Self-RegulationRegulation

Yoking of MRI studies to clinical trials research:

•Stimulants for ADHD

•Antidepressants (John Stewart)

•Use of naltrexone for smoking cessation (Lirio Covey)

•Prevention of neonatal intraventricular hemorrhage (Laura Ment)

•Trichotillomania, chronic depression (David Hellerstein)

•Longitudinal study of the effects of psychoanalysis on brain structure and function in analytic candidates and matched control subjects (Columbia Psychoanalytic Center)

Ongoing Projects in Unique Clinical SamplesOngoing Projects in Unique Clinical Samples

MRI of conditions that confer risk for disturbances in CNS development, in representative samples:

• Premature birth (Laura Ment)

• Prenatal exposure to drugs of abuse (Tove Rosen)

• Environmental teratogens (Frederica Perera)

• 3-Generation sample of children at risk for major depression (Myrna Weissman)

• Trauma-exposed families of WTC disaster (Christina Hoven)

• A longitudinal study of Autistic 3-4 year-olds and unaffected controls ascertained in an epidemiological birth cohort in Norway

Ongoing Projects in Unique Clinical SamplesOngoing Projects in Unique Clinical Samples