Research Statement
Greg Siegle, Ph.D.
The state of the art in
mental health care involves subjective diagnosis, prescribing based on clinical
insight, and treatments that do not target specific disease mechanisms,
yielding notoriously poor recovery and remission rates. My research is devoted
to formulating, validating, and disseminating a next generation of tools for
better understanding and treating mental disorder. Using neuroimaging, psychophysiology,
behavioral assessment, and computational modeling, my lab works to understand
neural mechanisms of disruptions in cognition and emotion in psychopathology, and
to translate our observations into practical algorithms and tools for case conceptualization,
treatment referral, mechanistically targeted interventions, and biological
measures of treatment response. This research program necessitates building
bridges between often disparate literatures from basic cognitive / physiological
processes to clinical phenomena, and units of analysis from neural activity to
symptoms. My vision is that such integrations will soon become the norm in
mental health research and treatment yielding increased precision in diagnosis
and treatment, decreased stigma as mental health conditions achieve parity with
other biologically specified disease, and lower costs as treatment efficiency
improves.
I specifically concentrate on processes common to emotional
disorders, such as depression and anxiety. Some of the most clinically salient
aspects of these conditions involve disruptions in how people process emotional
information, i.e., how they attend to, remember, and interpret emotional
stimuli. For example, I have argued that sustained processing of emotional
stimuli, in particular, is key to phenomena demonstrated to increase severity
and interfere with treatment such as rumination1,
2. Thus, my research program
has three themes including 1) understanding basic mechanisms of disease such as
processes underlying rumination, 2) quantifying how conventional treatments
from psychotherapy to medications to Yoga affect, and are impacted by these
mechanisms, and 3) developing novel treatments targeted at specific
mechanisms underlying individual differences in symptom expression. I have
authored or co-authored over 80 peer-reviewed original research publications, 14
invited articles, 15 book chapters, and over 200 presentations, and have had
multiple K, R01- and center-project level grants in this area.
Basic Science: Mechanisms
of Sustained Emotional Information Processing in Psychopathology.
My work has focused on brain
mechanisms underlying sustained emotional reactions and associated
abnormalities of adaptive emotion regulatory control in adult affective
disorders, particularly unipolar depression. This research has used computational
modeling3-11
and brain imaging assessments of patients and healthy adults to validate the
models7, 12-15. A representative result,
replicated using different methodologies and populations, is that depressed
individuals display sustained amygdala activity and decreased prefrontal
control in response to briefly presented emotional stimuli e.g., 7, 16.
Working to assess
the robustness and generalizability of these results has lead my colleagues and
I to further examine whether the information processing abnormalities we have examined
are present throughout the lifespan in unipolar depression 14,
17-21
and its precoursor, childhood anxiety 22,
23.
Similarly, I have examined ways in which disruptions of cognitive and emotional
information processing in depression are similar to or different from
disruptions observed in other psychopathologies also characterized by
abnormalities in prefrontal and limbic activity 9,
24-29.
Understanding disruptions of emotional
information processing in psychopathology requires building on, and extending
understanding of emotional functioning in healthy individuals. As such, my
group has also worked on the basic mechanisms of emotional information
processing in healthy individuals 30-33.
We have also needed to develop necessary statistical technologies for assessing
relevant aspects of neural phenomena 34,
35
and to formulate stronger assessment standards 36.
Current directions in this work include
examining sustained processing of negative information in the context of 1) a continuum
with blunted, shut-down, or avoidant affective information processing on the
other side e.g., 37,
38,
for which we have recently funded (R01 MH096334; Siegle, D'Andrea PI's), 2) in
relation to sustained and blunted processing of positive information and
reward, e.g., 39-42.
Specific ongoing projects, with Nicole Prause and
Dana McMakin, involve understanding whether
sustained negative information processing interferes with secondary and primary
reward processing.
Translational
Goal 1. Predicting Treatment Response.
My
computational models led to specific predictions for which individuals should
recover in cognitive behavioral therapy, and how to modify behavioral
interventions based on basic neuroscience. Building on a history in treatment
outcome research dating back to graduate school 43, my group has explored
brain imaging as a method of treatment prediction and treatment development 12, 15, 44, 45. A representative result is that 93% of the variance in recovery from
depression in Cognitive Therapy can be explained by increased amygdala and
decreased regulatory subgenual cingulate activity
observed on a pre-treatment scan12. To support the
generalizability of this algorithm, we have replicated it in expert and
non-expert therapists 45
and have, in collaborations, used the same tasks to predict outcome with
medication 46.
As brain imaging may not be adopted quickly
for use in the clinic due to its expense and inconvenience we have also
examined behavioral and psychophysiological proxies, which we have shown to
reflect function and dysfunction in relevant brain circuits. This work began
with psychophysiological characterization of the same tasks we have examined in
the scanner 28,
47-51
and with pharmacological probes 52 as well as
contrasts of healthy and depressed individuals using behavioral and peripheral
psychophysiological measures 8,
27, 28, 53-57.
A representative result, is that sustained pupil dilation in response to
emotional information before treatment, together with initial severity, is strongly
prognostic for response to Cognitive Therapy 58. Current
directions in this work include 1) developing lowest-cost algorithms to allow
confident response prediction with iterative, individually tailored assessment
plans, 2) using newly available low-cost physiological assessment technologies
(e.g., web-cams for pupil dilation and consumer grade EEG) to translate this
work to the clinic, and 3) using pre/post treatment assessment to understand
therapeutic change processes allowing for assessment-based mid-course
corrections and outcome evaluation; trials in medications, psychotherapy, and
yoga are ongoing or have recently finished.
Translational Goal 2:
Developing Targeted Treatments.
Current treatments for depression are
not generally targeted at specific brain mechanisms but rather reflect broad
psychological constructs or neurochemical systems, leading to lengthy, often
expensive treatments or unwanted side-effects. Initial work on developing more
targeted treatments based on basic brain imaging research led my group to
develop a novel computer-based intervention for depression that targets
specific aspects of prefrontal regulatory function. Initial data suggests this
intervention targets relevant brain regions 59, is effective
above and beyond medications and dialectical behavior therapy for severe,
complex depressions 44,
60, has lasting impact on health
system visits over a subsequent year 60, requires more
than one session, attesting to its likely response to true training effects 61, and compares
favorably to placebo 62. Uniting my
research program, we find that response to this intervention can be predicted
by pupillary responses pre-intervention60. Understanding
whether this intervention generalizes clinically to other populations and
disorders is being evaluated in ongoing collaborations around the world,
including augmentation with D-Cycloserine (PI, Otto),
TMS (PI's DeRaedt & Segrave).
Other behavioral interventions similarly targeted at specific brain mechanisms
of unipolar depression are also being explored in this context in my lab
including savoring of positive information 39, and a novel
intervention for sustained affective information processing involving
involuntary attention to physical uncomfortable stimuli.
The near future
I intend to continue to
examine the neural substrates of disruptions of emotional information
processing, and their translation to treatment for the foreseeable future. My work
is increasingly moving towards considerations of practically implemental neuroscience-based
assessments and mechanistically targeted treatments.
References
1. Jones NP, Siegle GJ, Thase
ME. Effects of rumination and initial severity on response to Cognitive Therapy
for depression. Cognitive Therapy and
Research. 2008;32:591-604.
2. Siegle
GJ, Thayer JT. Physiological aspects of depressive rumination. In: Papageorgiou
C, ed. Depressive Rumination Nature
Theory and Treatment. New York: Wiley; 2004:79-104.
3. Elliot
C, Siegle GJ. Emotion intensity factors in simulated believable agents WAUME 93 Workshop on Architectures
Underlying Motivation and Emotion Birmingham UK The University of Birmingham
1993.
4. Siegle
GJ. Why I make models or what I learned in graduate school about validating
clinical causal theories with computational models. The Behavior Therapist. 1997;20:179-184.
5. Siegle
GJ. A neural network model of attention biases in depression. Progress in Brain Research. 1999;121:415-441.
6. Siegle
GJ, Hasselmo ME. Using connectionist models to guide assessment of
psychological disorder Psychological
Assessment. 2002;14 263-278.
7. Siegle
GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Can't shake that feeling:
fMRI assessment of sustained amygdala activity in response to emotional
information in depressed individuals. Biological
Psychiatry. 2002;51:693-707.
8. Siegle
GJ, Steinhauer SR, Thase ME. Pupillary assessment and computational modeling of
the Stroop task in depression. International
Journal Psychophysiology. Mar 2004;52(1):63-76.
9. Larson
CL, Schaefer HS, Siegle GJ, Jackson CAB, Anderle MJ, Davidson RJ. Fear is fast
in phobics: Amygdala activation in response to fear-relevant stimuli. Biological Psychiatry. in press.
10. Thayer JF, Siegle GJ. Neurovisceral integration in cardiac and
emotional regulation. IEEE Eng Med Biol
Mag. Jul-Aug 2002;21(4):24-29.
11. Dombrovski AY, Clark L, Siegle GJ, Butters MA, Ichikawa N,
Sahakian BJ, Szanto K. Reward/Punishment reversal learning in older suicide
attempters. Am J Psychiatry. Jun
2010;167(6):699-707.
12. Siegle GJ, Carter CS, Thase ME. Use of fMRI to predict
recovery from unipolar depression with cognitive behavior therapy. American Journal of Psychiatry. 2006;163:735-738.
13. Siegle GJ, Konecky RO, Thase ME, Carter CS. Relationships
between amygdala volume and activity during emotional information processing
tasks in depressed and never-depressed individuals: an fMRI investigation. Annals of the New York Academy of Sciences. 2003;985:481-484.
14. Haggerty AE, Muelly ER, Konecky RO, Dahl RE, Thase ME,
Aizenstein HA, Drevets WC, Cho R, Siegle GJ. Amygdala volume in unipolar
depression through the lifespan. submitted.
15. DeRubeis RJ, Siegle GJ, Hollon SD. Cognitive therapy versus
medication for depression: treatment outcomes and neural mechanisms. Nat Rev Neurosci. Oct
2008;9(10):788-796.
16. Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME.
Increased amygdala and decreased dorsolateral prefrontal BOLD responses in
unipolar depression: Related and independent features. Biol Psychiatry. Oct 5 2007;61(2):198-209.
17. Ingram RE, Bailey K, Siegle GJ, Ingram RE. Emotional
Information Processing and Disrupted Parental Bonding: Cognitive Specificity
and Avoidance. Journal of Cognitive
Psychotherapy. Spr 2004;18(1):53-65.
18. Silk JS, Siegle GJ, Whalen DJ, Ostapenko LJ, Ladouceur CD,
Dahl RE. Pubertal changes in emotional information processing: pupillary,
behavioral, and subjective evidence during emotional word identification. Dev Psychopathol. Winter
2009;21(1):7-26.
19. Silk JS, Dahl RE, Ryan ND, Forbes EE, Axelson DA, Birmaher B,
Siegle GJ. Pupillary Reactivity to Emotional Information in Child and
Adolescent Depression: Links to Clinical and Ecological Measures. Am J Psychiatry. Dec
2007;164(12):1873-1880.
20. Gibbs LM, Dombrovski AY, Morse J, Siegle GJ, Houck PR, Szanto
K. When the solution is part of the problem: problem solving in elderly suicide
attempters. Int J Geriatr Psychiatry. Dec
2009;24(12):1396-1404.
21. Forbes EE, May JC, Siegle GJ, Ladouceur CD, Ryan ND, Carter
CS, Dahl RE. Reward-related decision-making in pediatric major depressive
disorder: An fMRI study. Journal of
Clinical Child and Adolescent Psychology. 2006;47(10):1031-1040.
22. Tan PZ, Forbes EE, Dahl RE, Ryan ND, Siegle GJ, Ladouceur CD,
Silk JS. Emotional reactivity and regulation in anxious and nonanxious youth: a
cell-phone ecological momentary assessment study. J Child Psychol Psychiatry. Feb 2012;53(2):197-206.
23. Price RB, Siegle GJ, Silk JS, Ladouceur C, McFarland A, Dahl
RE, Ryan ND. Sustained neural alterations in anxious youth performing an
attentional bias task: a pupilometry study. Depress
Anxiety. Jan 2013;30(1):22-30.
24. Hinkin CH, Castellon SA, Hardy DJ, Granholm E, Siegle G.
Computerized and traditional stroop task dysfunction in HIV-1 infection. Neuropsychology. Apr 1999;13(2):306-316.
25. Condray R, Siegle GJ, Cohen JD, van Kammen DP, Steinhauer SR.
Automatic activation of the semantic network in schizophrenia: evidence from
event-related brain potentials. Biological
Psychiatry. 2003;54(11):1134-1148.
26. Forman SD, Dougherty GG, Casey BJ, Siegle GJ, Braver TS, Barch
DM, Stenger VA, Wick-Hull C, Pisarov LA, Lorensen E. Opiate addicts lack
error-dependent activation of rostral anterior cingulate. Biol Psychiatry. Mar 1 2004;55(5):531-537.
27. Siegle GJ, Moore P, Thase ME. Rumination: One construct, many
features in healthy individuals, depressed individuals, and individuals with
Lupus. Cognitive Therapy & Research. 2004;28:645-668.
28. Siegle GJ, Condray R, Thase ME, Keshavan M, Steinhauer SR.
Sustained gamma-band EEG following negative words in depression and
schizophrenia. Int J Psychophysiol. Dec
11 2010;75(2):107-118.
29. Condray R, Siegle GJ, Keshavan MS, Steinhauer SR. Effects of
word frequency on semantic memory in schizophrenia: Electrophysiological
evidence for a deficit in linguistic access. Int J Psychophysiol. Nov 5 2009.
30. Lee KH, Siegle GJ. Different BOLD responses to emotional faces
and emotional faces augmented by contextual information. submitted.
31. Wheeler EZ, Siegle GJ. Ventromedial Prefrontal Cortex and
Affect: A Review of Neuroimaging studies of Primary and Secondary Inducers of
Emotion. submitted.
32. Franzen PL, Buysse DJ, Dahl RE, Thompson W, Siegle GJ. Sleep
deprivation alters pupillary reactivity to emotional stimuli in healthy young
adults. Biol Psychol. Mar
2009;80(3):300-305.
33. Lee KH, Siegle GJ. Common and distinct brain networks
underlying explicit emotional evaluation: a meta-analytic study. Soc Cogn Affect Neurosci. Mar 6 2009.
34. Thompson WK, Siegle G. A stimulus-locked vector autoregressive
model for slow event-related fMRI designs. Neuroimage.
Jul 1 2009;46(3):739-748.
35. Zhou D, Thompson WK, Siegle G. MATLAB toolbox for functional
connectivity. Neuroimage. Oct 1
2009;47(4):1590-1607.
36. Hansen N, Siegle GJ. Paving the road to the neurocognitive
clinic of tomorrow: Standards and milestones. In: Mohlman J, Deckersbach T,
Weissman AS, eds. Clinical psychology: A neurocognitive
perspective. New York: Routledge; in press.
37. Larson CL, Schaefer HS, Siegle GJ, Jackson CAB, Anderle MJ,
Davidson RJ. Fear is fast in phobic individuals: Amygdala activation in
response to fear-relevant stimuli. Biological
Psychiatry. Aug 15 2006;60(4):410-417.
38. Schlund MW, Siegle GJ, Ladouceur CD, Silk JS, Cataldo MF,
Forbes EE, Dahl RE, Ryan ND. Nothing to fear? Neural systems supporting
avoidance behavior in healthy youths. NeuroImage.
Aug 15 2010;52(2):710-719.
39. McMakin DL, Siegle GJ, Shirck SR. Positive Affect Stimulation
and Sustainment (PASS) module for depressed mood: A preliminary test of treatment-related
effects. Cognitive Therapy &
Research. in press.
40. Dombrovski AY, Szanto K, Clark L, Reynolds CF, Siegle GJ.
Reward Signals, Attempted Suicide, and Impulsivity in Late-Life Depression. JAMA Psychiatry. Aug 7 2013.
41. Dombrovski AY, Clark L, Siegle GJ, Butters MA, Ichikawa N,
Sahakian B, Szanto K. Reward/punishment reversal learning in older suicide
attempters. American Journal of
Psychiatry. in press.
42. Horner MS, Siegle GJ, Friedman ES. C'mon get happy! Decreased
affective reactivity to positive stimuli
in depression. submitted.
43. Shadish WR, Matt GE, Navarro AM, Siegle G, Crits-Christoph P,
Hazelrigg MD, Jorm AF, Lyons LC, Nietzel MT, Prout HT, Robinson L, Smith ML,
Svartberg M, Weiss B. Evidence that therapy works in clinically representative
conditions. J Consult Clin Psychol. Jun
1997;65(3):355-365.
44. Siegle GJ, Ghinassi F, Thase ME. Neurobehavioral therapies in
the 21st century: Summary of an emerging field and an extended example of
Cognitive Control Training for depression. Cognitive
Therapy & Research. 2007;31:235-262.
45. Siegle GJ, Thompson WK, Collier A, Berman SR, Feldmiller J,
Thase ME, Friedman ES. Toward clinically useful neuroimaging in depression
treatment: prognostic utility of subgenual cingulate activity for determining
depression outcome in cognitive therapy across studies, scanners, and patient
characteristics. Arch Gen Psychiatry. Sep
2012;69(9):913-924.
46. Miller JM, Schneck N, Siegle GJ, Chen Y, Ogden RT, Kikuchi T,
Oquendo MA, Mann JJ, Parsey RV. fMRI response to negative words and SSRI
treatment outcome in major depressive disorder: a preliminary study. Psychiatry Research: Neuroimaging. in
press.
47. Brown G, Kinderman S, Siegle GJ, Granholm E, Wong EC, Buxton
RB. Brain activation and pupil response during covert performance of the Stroop
color word task. Journal of the
International Neuropsychological Society. 1999;5(4):308-319.
48. Siegle GJ, Steinhauer SR, Stenger V, Konecky R, Carter CS. Use
of concurrent pupil dilation assessment to inform interpretation and analysis
of fMRI data. Neuroimage. 2003;20(1):114-124.
49. Gianaros PJ, Derbyshire SW, May JC, Siegle GJ, Gamalo MA,
Jennings JR. Anterior cingulate activity correlates with blood pressure during
stress. Psychophysiology. Nov
2005;42(6):627-635.
50. Gianaros PJ, May JC, Siegle GJ, Jennings JR. Is there a
functional neural correlate of individual differences in cardiovascular
reactivity? Psychosom Med. Jan-Feb
2005;67(1):31-39.
51. Papageorgiou C, Siegle GJ. Rumination and Depression: Advances
in Theory and Research. Cognitive Therapy
& Research. Jun 2003;27(3):243-245.
52. Steinhauer SR, Siegle GJ, Condray R, Pless M. Sympathetic and parasympathetic
innervation of pupillary dilation during sustained processing. Int J Psychophysiol. Mar
2004;52(1):77-86.
53. Siegle GJ, Granholm E, Ingram RE, Matt GE. Pupillary response
and reaction time measures of sustained processing of negative information in
depression. Biological Psychiatry. 2001;49:624-636.
54. Siegle GJ, Steinhauer SR, Carter CS, Ramel W, Thase ME. Do the
seconds turn into hours? Relationships between sustained pupil dilation in
response to emotional information and self reported rumination. Cognitive Therapy and Research. 2003;27(3):365-383.
55. Siegle GJ, Condray R, Thase ME, Keshavan M, Steinhauer SR.
Sustained gamma-band EEG during emotional information processing in depression
and schizophrenia. submitted.
56. Siegle GJ, Steinhauer SR, Carter CS, Thase ME. Is sustained
processing specific to emotional information in depression? Evidence from pupil
dilation. submitted.
57. Silk JS, Dahl RE, Ryan ND, Birmaher B, Axelson D, Siegle GJ.
Decreased late pupil dilation to emotional words in child and adolescent
depression. submitted.
58. Siegle GJ, Steinhauer SR, Friedman ES, Thompson WS, Thase ME.
Remission prognosis for cognitive therapy for recurrent depression using the
pupil: utility and neural correlates. Biol
Psychiatry. Apr 15 2011;69(8):726-733.
59. Price RB, Paul B, Schneider W, Siegle GJ. Neural correlates of
three neurocognitive intervention strategies: A preliminary step towards
personalized treatment for psychological disorders. First Posting Dec 14, 2012.
Cognitive Therapy and Research. Dec 2012,
pp. No Pagination Specified. 2012.
60. Siegle GJ, Price RB, Jones NP, Ghinassi F, Thase ME. You gotta
work at it: Pupillary indices of task focus are prognostic for response to a
neurocognitive intervention for depression. Clinical
Psychological Science. in press.
61. Calkins AW, Deveney CM, Weitzman ML, Hearon BA, Siegle GJ,
Otto MW. The effects of prior cognitive control task exposure on responses to
emotional tasks in healthy participants. Behav
Cogn Psychother. Mar 2011;39(2):205-220.
62. Calkins AW, McMorran KE, Siegle GJ, Otto MW. The effects of
computerized cognitive control training on community adults with depressed
mood. submitted.