Translational Research Updates: Tools, toys, theories, and

trying to get funded

Greg Siegle

University of Pittsburgh School of Medicine

Supported by MH082998Greg Siegle is an unpaid consultant for Trial IQ and Neural Impact

Topics

• RDoC

• Ambulatory EEG

• One super-cool upcoming article

• Automating fMRI meta-analyses

• Getting translational research funded

The NIMH Research Domain Criteria

(RDoC)

mentalhealth.gov/research-funding/rdoc

Please do:-Look at dimensions that span disorders – this means recruiting across traditional disorder boundaries-Consider psychopathology as extremes of normal dimensions-Integrate genetic, neurobiological, behavioral, environmental, and experiential components -Translate RDoC domains to interventions

RDoC example: Negative Valence Systems

• Responses to acute threat (Fear).• Responses to potential harm (Anxiety) • Responses to sustained threat• Frustrative non-reward• Loss

• http://mentalhealth.gov/research-funding/rdoc/negative-valence-systems-workshop-proceedings.shtml

Why care? Targeting brain

Mechanisms

Measuring Brain-Behavior Target

Altering Brain-Behavior

Target: Neurofeedback

Ambulatory EEG is here!

e.g., Alpha EEG (8-13Hz) activity represents inactivity. Increased LEFT frontal alpha in depression assymetry

Davidson (2000) American Psychologist

Bargain: $299! • 1) Train on brain target directly. Several case series: reduced asymmetry & lasting reductions in depression and anxiety in treatment-refractory MDD and dysthymia patients (up to 5-year follow-up; e.g., Baehr, 1997)– Difficult to replicate– Training on failure

feedback is difficult to tolerate

• Train on emotion template and maintain or avoid that

• Train on an emotion & situation, test without emotion

Must read article: Forgeard, M. J. C., Haigh, E. A. P., Beck, A. T., Davidson, R. J., Henn,

F. A., Maier, S. F., Mayberg, H. S., Seligman, M. E. P. (in press). Beyond depression: Towards a process-based approach to research, diagnosis, and treatment. Clinical Psychology: Science & Practice,

18(4).

– Learned Helplessness is not dead – it’s in the lateral habenula…

– Biological taxonomies are essential– Convergence among psychological and neurobiological

processes– Implications for diagnosis and treatment

• Neurobehavioral interventions• Go to the “prefrontal doctor” or “cingulate doctor” – not a

psychiatrist or psychologist

Finding your brain targets – automated meta-analyses at

neurosynth.org

Interpreting your brain data: The fMRI Individual Differences

Database!

http://www.tinyurl.com/BrainIndivDbase

Everything old is new again

Hekmat H, Vanian D (1971): Behavior modification through covert semantic desensitization. J Consult Clin Psychol. 36:248-251.

Me PowerfulMyself strong….

Funding: NIMH mechanisms• Basic mechanistic research

– RDoC: RFA-MH-12-100 – Dimensional Approaches to Research Classification in Psychiatric Disorders (R01)

– RFA-HL-12-037. Mechanistic Pathways Linking Psychosocial Stress and Behavior (R01)

• Interventions– PAR-11-177. Translational Research for the Development of Novel

Interventions for Mental Disorders (R21/R33)• applications to speed the translation of emerging findings on the neuroscience of

mental disorders into novel intervention approaches • A range of non-pharmacologic treatment approaches will be accepted, including

those based on neurophysiological, cognitive, affective, and/or social neuroscience models, basic behavioral science, and neurodevelopmental models

– PAR-09-173, Pilot Intervention and Services Research Grants (R34)• Includes “rehabilitative efforts to reduce residual symptoms and/or enhance

functioning.”– PA-09-075, Collaborative R34s for Pilot Studies of Innovative Treatments

in Mental Disorders (Collaborative R34)• This FOA should be used when at least two but no more than three sites are needed to

complete the study.– PAR-12-007. Innovative Pilot Studies of Novel Mechanism of Action

Compounds for Treating Psychiatric Disorders (U01)

Funding: Outside NIMH• There are mechanisms– PA-04-109, Cross-Disciplinary Translational Research

at NIH (R01)• Institutes: NIDA (Drug Abuse), NCI (Cancer)• Extend basic or clinical research findings to yield a

knowledge base for the development of novel, efficacious drug abuse prevention or treatment interventions.

– PA-11-123, Translational Research to Help Older Adults Maintain their Health and Independence in the Community (R01)• Institutes: NIA (Aging)

– PA-09-075, Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders (Collaborative R34)• Institutes: NIMH, NCCAM (Complementary)

Funding: Strategies for getting past review

• Tell your reviewers that your agency wants it– Quote the PA– Quote the Institute Strategic plan e.g., NIMH

• Opportunities to Develop New Psychosocial and Behavioral Therapies ■ Determine the basic mechanisms by which psychosocial interventions operate to produce therapeutic change to increase opportunities for innovative developments.

– Quote the branch, e.g., NIMH Division of Adult Translational Research and Treatment Development (DATR) mission• Define predictors and understand the mechanism of treatment

response.• Create and refine biomarkers, behavioral assessments, and

phenotypic characterizations of disease.• Evaluate existing therapeutics for new indications, and, in

collaboration with academic, industry, and regulatory agencies, hasten the development of more effective new treatments for mental illness.

Funding: Strategies for getting past review

• Rumors: ITV doesn’t like mechanism.– Strategy: “If we don’t measure mechanism we could miss

our effects”

– Note: Program is speaking regularly to ITV reviewers

Change in Symptoms

Observed Not Observed

Change in physiological or neuroimaging data duringthe intervention

Observed Intervention could be working by predicted mechanism.

Intervention targeting the mechanism but mechanism isn’t (immediately) key to symptom change for this person

NotObserved

Mechanism isn’t targeted, but that doesn’t matter –mechanism isn’t key to symptom change.

Intervention not working, possibly because it’s not targeting the mechanism. Must revise the intervention OR the assessment

Siegle et al (2007) Cognitive Therapy and Research

Funding: Strategies for getting past review

• Rumor: APDA doesn’t like intervention– Strategy: Discuss short-term interventions as a

probe of causal relationships between brain and symptoms

– Emphasize public health relevance of developing the intervention

– Consider R21 mechanisms. They may indulge cheap over expensive.

– Pilot data helps even if the app says you don’t need pilot data

Funding: Strategies for getting past review

• Rumor: NCCAM wants us….– “studies focusing on CAM interventions used frequently by

the American public, and on the conditions for which they are most frequently used are particularly encouraged.”• If we can show we’re a viable mainstream (i.e., app-downloadable)

but unconventional treatment source, we have a shot…. Talk to program!

– Basic and Translational ResearchNCCAM's support of basic research emphasizes and encourages in vitro and in vivo studies of the biological effects and mechanisms of action underlying complementary and alternative medicine (CAM) approaches, as well as studies characterizing the active elements of an intervention,