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

Design Challenges When Studying Developmentally Based Psychopathologies Some Possible Solutions Examples in ADHD & Other Conditions Outline Peterson BS, Development & Psychopathology 15: , 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 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)

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)

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)

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 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)

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)

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: Stimulant Medications in 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 Interference

Congruent RED BLUE YELLOW GREEN Incongruent RED BLUE YELLOW GREEN

Stroop Activation RL RL

RIGHT LEFT TOP SURFACE MORPHOLOGY ADHD VS CONTROLS Temporal Frontal Temporal Frontal Sowell et al., Lancet, 2003

Subjects ADHDNormal Controls N=16N= years mean 14 ± 2.4 years 7-18 years mean 13.4 ± 3.1 years

The Neural Circuitry of Self-Regulation

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 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 Samples