Bradley S' Peterson, M'D'

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BRAIN IMAGING STUDIES OF DEVELOPMENTALLY BASED
PSYCHOPATHOLOGIES
Bradley S. Peterson, M.D. Columbia College of
Physicians Surgeons New York State Psychiatric
Institute
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Outline

• Design Challenges When Studying Developmentally
  Based Psychopathologies
• Some Possible Solutions
• Examples in ADHD Other Conditions

Peterson BS, Development Psychopathology
15811-832, 2003
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Design Challenges

• 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

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Design Challenges (contd)

• 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

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Design Challenges (contd)

• 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)

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Design Challenges (contd)

• 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

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Some Possible Solutions

• 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

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Possible Solutions (Contd)

• 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 subjects unique
  anatomy

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Possible Solutions (Contd)

• 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

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Information Processing
Motor Response
Motor Planning
Working Memory
Response Monitoring
Error Detection
Long-Term Memory
Affect
Higher Order Sensory Association (Heteromodal)
Cortices
Lower Order Sensory Association Cortices
Primary Sensory Cortices
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Example of Yoking to a Clinical Trial Stimulant
Medications in Children Adolescents with ADHD
Potenza et al., Submitted
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Stroop Word-Color Interference

• 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

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Stroop Word-Color Interference
Congruent RED BLUE YELLOW GREEN
Incongruent RED BLUE YELLOW GREEN
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Stroop Activation
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SURFACE MORPHOLOGY ADHD VS CONTROLS
Frontal
Temporal
Frontal
Temporal
LEFT
TOP
RIGHT
Sowell et al., Lancet, 2003
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Subjects
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The Neural Circuitry of Self-Regulation
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Ongoing Projects in Unique Clinical Samples

• 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)

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Ongoing 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