NITSCHKE, JACK B.
Assistant Professor
Departments of Psychiatry and Psychology
-on faculty for Clinical Internship Program in Department of Psychiatry
-on faculty for Clinical Area in Department of Psychology
Ph.D. 1998, University of Illinois at Urbana-Champaign
My research career centers on the neuroscience of human emotion and affective disorders. One of
my research goals is to determine the neurobiological substrates of heterogeneity in anxiety and
depression. My studies use clinical and nonclinical samples and employ an array of methodologies
including fMRI, EEG, eye-blink startle, neuropsychological tasks, cortisol, and autonomic
psychophysiology.
My early research examined patterns of brain activity associated with anxiety and depression and
their co-occurrence using electroencephalography (EEG) and the Chimeric Faces Task, a behavioral
neuropsychology measure (Heller et al., 1997a, 1997b; Keller et al., 2000; Nitschke et al., 1999). A major
emphasis of this work was disentangling the neural circuitry associated with different forms of anxiety. In
two separate studies, we found that anxious apprehension (i.e., worry) resulted in activation of lefthemisphere structures, whereas anxious arousal (i.e., panic) implicated right-hemisphere structures
(Heller et al., 1997a; Nitschke, 1998; Nitschke et al., 1999; see also Nitschke & Heller, 2002; Nitschke et
al., 2000). We also conducted a large psychometric study demonstrating the separability of those two
forms of anxiety (Nitschke et al., 2001a). Based on the above empirical studies, we wrote four theoretical
pieces (Heller & Nitschke, 1997, 1998; Heller et al., 1998; Nitschke et al., 2000; see also Davidson et al.,
1999).
In an attempt to further inform distinctions between different types of anxiety and depression, I
turned to a different methodology – the eye-blink startle reflex. We found differences between anxious
apprehension, anxious arousal, and anhedonic depression in startle responses to unpleasant and pleasant
pictures (Nitschke et al., 2001b). An unexpected finding was that the symptomatic and control groups all
showed a robust potentiation in anticipation of aversive pictures (Nitschke et al., 2002), indicating the
potency of this paradigm for eliciting aversive anticipation that is likely linked to anticipatory anxiety. I
then moved to bring that paradigm into the magnet to interrogate the neural circuitry associated with such
aversive anticipation. Using event-related fMRI, we were successfully able to identify distinct circuits
modulating anticipatory and response processes in viewing aversive pictures. Although several structures
were implicated both in the anticipatory and in the response systems, a number of regions were uniquely
activated for each (Nitschke et al., 2004a). In an ongoing replication study of these fMRI data, we will
examine relations of this circuitry with memory performance and with on-line eye movement and skin
conductance measurements collected during the scan. We are currently employing the same fMRI
paradigm with generalized anxiety disorder patients, with the hypothesis that they will exhibit functional
abnormalities in the anticipation circuit that will resolve following successful pharmacological treatment.
Building further on this laboratory-based model we developed examining anticipatory and reactivity
processes elicited by emotional stimuli, we are currently analyzing the fMRI data for a similar paradigm
using flavors instead of pictures that examines the placebo effect as a function of expectancy.
This strategy of parsing symptomatology and of isolating constituent components and processes
has also proven fruitful in my research on depression. Using a new EEG source localization method, we
found melancholic features, depression severity, and anxiety to modulate patterns of brain activity in the
prefrontal cortex of people with major depressive disorder (Pizzagalli et al., 2002). In that same sample,
we replicated previous reports (e.g., Mayberg et al., 1997) that more pre-treatment rostral anterior
cingulate activity in depressed patients predicts better clinical outcome (Pizzagalli et al., 2001). The
parsing of depression in terms of the neural substrates affected has been further elaborated in three recent
review chapters we wrote (Davidson et al., 2002a, 2002b, 2003).
A long-term career goal of mine is to reframe our conceptualization of psychopathology as it
relates to anxiety, fear, and depression. I am convinced that our current view as embodied in the DSM-IV
has room for improvement. Neuroscience research on emotion and affective disorders is the path I am
intent on pursuing because it has tremendous potential for contributing to our understanding of
psychopathology, in part due to the recent advances made in this area both in terms of the technology
available for studying the brain and in terms of our knowledge about functions served by different brain
territories that are of relevance to anxiety and depression. Neurobiological evidence can be garnered to
inform diagnosis as well as treatment. Specific subtypes, features, or symptoms of anxiety and depression
are characterized by abnormalities in certain brain regions, which in turn may affect projections to other
areas. We can then target those symptoms and the corresponding brain structures via biological or
psychological interventions.
Some of my research plans are spelled out in my NIMH K08 Career Research Award, with 4
studies designed with the specific objective of cleanly delineating anticipatory and reactivity processes in
anxiety and fear. Three of those studies also begin the search for abnormalities in the brain systems
governing anticipation of and reactivity to aversive events in generalized anxiety disorder and specific
phobia. One working hypothesis is that individuals with anxiety disorders who suffer from worry and
concern about the future will have higher levels of baseline activation or even morphometric differences
in those structures unique to the neural circuitry hypothesized for anticipation of aversive outcomes. Panic
attacks, on the other hand, may recruit the circuitry for responding to aversive or phobic events once they
have occurred. Another possibility is that the relevant circuitry looks completely normal until some
stimulus invokes exaggerated patterns of activation in a certain region of that circuitry. Alternatively, the
critical differences may be in the time course of the activation rather than the absolute magnitude. Perhaps
individuals with anxiety disorders that differ in their propensity to worry and panic show faster activation
of or a delayed return to baseline following the activation of the respective neural systems.
With regard to depression, I have two pending grant applications to fund research that will
systematically address different sources of heterogeneity in depression and the neurobiological
implications of such heterogeneity. In addition, the proposed research will employ an innovative eventrelated fMRI paradigm to tap specific symptoms of depression. Neuroimaging research to date has not
employed paradigms tailored to the symptomatology of depression, as has been done with anxiety
disorders via symptom provocation paradigms (Nitschke & Heller, 2002). The paradigm proposed targets
the rumination and compromised affective regulation central to depression and builds on our recent fMRI
work involving extensive development of a scenario-based paradigm. Given the frequently documented
limbic-hypothalamic-pituitary-adrenal (LHPA) axis irregularities in depression and its subtypes, this
planned research will be one of the first studies to assess fMRI and LHPA axis function in the same
sample of patients with major depressive disorder.
In another line of research that I have a long-standing interest in, my inaugural forays into the
neuroscience of positive emotion represent an important complement to my research program on
psychopathology. A diminished capacity to experience pleasant emotion has been observed in both
depressive and anxiety disorders and is the cardinal feature of melancholic depression. Such hedonic
deficits likely correspond to abnormalities in the circuitry governing positive emotion. Consequently,
conclusions derived solely from neurobiological studies investigating the unpleasant realm of emotional
life will be incomplete. A major obstacle for researchers in this area has been the challenge of eliciting
robust positive emotion reliably across subjects in a physiological laboratory setting. My first fMRI study
in this area imaged new mothers while they viewed photographs of their own infants (Nitschke et al.,
2004b). Photographs of mothers’ own infants resulted in bilateral activation of the OFC, which showed a
strong positive association with on-line pleasant mood ratings while viewing the infant pictures. We are
currently conducting a large project that serves as a replication study for the infant paradigm and includes
a scenario-based paradigm to examine the neural substrates of altruism related to the mother-infant bond.
One future direction is the isolation of circuitry devoted to the anticipation of strong positive emotion by
employing warning symbols that predict whether one’s own infant, another infant, or a non-infant
emotional picture will be presented. Another planned study will examine whether such positive,
interpersonal stimuli result in a diminution of amygdalar response commonly seen in response to aversive
stimuli. On a separate front using scalp EEG in a sample of middle-aged men and women, we found more
left than right frontal activity accompanying high levels of well-being (Urry et al., in press), consistent
with commonly cited neuropsychological models of emotion (e.g., Davidson, 1992; Heller, 1990).
Whether it is well-being, positive emotion, other constituents of anxiety and depression, or the placebo
effect, the promotion of health is a general theme that courses through all my research endeavors.
REPRESENTATIVE PUBLICATIONS
Nitschke, J.B., Nelson, E.E., Rusch, B.D., Fox, A.S., Oakes, T.R., & Davidson, R.J. (2004).
Orbitofrontal cortex tracks positive mood in mothers viewing pictures of their infants.
NeuroImage, 21, 583-592.
Nitschke, J.B., Heller, W., Etienne, M.A., & Miller, G.A. (2004). Prefrontal cortex activation
differentiates processes affecting memory in depression. Biological Psychology, 67, 125-143.
Nitschke, J.B., & Heller, W. (2002). The neuropsychology of anxiety disorders: Affect,
cognition, and neural circuitry. In H. D’Haenen, J.A. den Boer, & P. Willner (Eds.), Biological
psychiatry (pp. 975-988). Chichester, UK: John Wiley & Sons, Ltd.
Nitschke, J.B., Larson, C.L., Smoller, J.J., Navin, S. D., Pederson, A.J.C., Ruffalo, D.,
Mackiewicz, K.L., Gray, S.M., Victor, E., & Davidson, R.J. (2002). Startle potentiation in
aversive anticipation: Evidence for state but not trait effects. Psychophysiology, 39, 254-258.
Nitschke, J.B., Heller, W., Imig, J.C., McDonald, R.P., & Miller, G.A. (2001). Distinguishing
dimensions of anxiety and depression. Cognitive Therapy and Research, 25, 1-22.
Nitschke, J.B., Heller, W., Palmieri, P.A., & Miller, G.A. (1999). Contrasting patterns of brain
activity in anxious apprehension and anxious arousal. Psychophysiology, 36, 628-637.