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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.