Travel Award Winners
The following students are the recipients of the 2010 Wisconsin Symposium on Emotion Travel Awards:
Melisa Carrasco
PhD/MD student, University of Michigan, Neuroscience Graduate Program
Aberrant Functional Plasticity in the Default Network of Adolescents with Autism Spectrum Disorder
Authors: M. Carrasco, J. L. Wiggins, S. J. Peltier, S. Risi, C. Lord and C. S. Monk
Background: Functional magnetic resonance imaging (fMRI) studies in adults have shown plastic changes in brain connectivity in response to treatment. Weaker connectivity within the default network is associated with specific impairments in Autism Spectrum Disorders (ASD). ASD is a condition that may be, in part, a disorder of atypical brain plasticity involving the default network. ASD is characterized by disturbances in social function and communication, and the presence of repetitive behaviors. As part of an ongoing study, we will be examining the effects of different therapeutic practices on default network plasticity in ASD. A first step towards completion of this study will involve characterizing default network connectivity in a sample of adolescents with ASD; pertinent findings will be included as part of this poster presentation.
Methods: 25 ASD children (ages 10-18) and 25 controls matched for age, gender and IQ took part in this functional MRI (fMRI) study. The Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule were used to assist in the ASD diagnosis. During fMRI acquisition, participants were instructed to “let your mind wander freely” while looking at a fixation cross displayed in the middle of the screen for 10 minutes during fMRI acquisition. A seed region was placed in the PCC and functional connectivity was examined by obtaining the correlational activity between the posterior cingulate cortex (PCC) and other areas of the default network. We will use self-organizing maps and other resting fMRI techniques to identify differences in posterior to anterior connections in the default network between ASD’s and typical controls. In addition, we will determine whether strength of posterior-anterior connectivity between foci of the default network is related to repetitive symptoms in ASD.
Conclusions: Preliminary results will show whether there are group differences in default network functional connectivity between adolescents with ASD and typical individuals. Findings will aid in the development of treatment aimed to strengthen default network connectivity in ASD’s.
Disclosure: Melisa Carrasco and the other co-authors have no financial
relationships to disclose.
Keywords: fMRI, plasticity, default network, autism, treatment response.
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Tracy Doty
PhD student
NIH Graduate Partnership Program with Karolinska Institutet, Stockholm, Sweden
Hypersensitivity to Fearful Faces in Healthy Adults Correlates with Harm Avoidance and Activity in the Medial Prefrontal Cortex
Doty TJ, Japee S, Ingvar M, Ungerleider LG
Previous studies investigating the behavioral and neural mechanisms of emotion processing have reported inter-subject variability in healthy adults associated with sub-clinical levels of anxiety. However, in these experiments threat was not related to the task. But in the natural environment threat is generally encountered directly, therefore we aimed to explore inter-subject variability in visual threat processing when threat was directly related to the task. Our functional magnetic resonance imaging (fMRI) study manipulated the expectation of fearful and neutral faces during an emotion categorization task and correlated the reaction time results with personality measures and hemodynamic brain activity in healthy human adults. We parametrically altered valence expectation by presenting face images within 50-trial blocks containing three different proportions of fearful:neutral faces: 80:20, 20:80, and 50:50. Before each block, subjects were explicitly told the ratio of fearful to neutral faces, and subjects were instructed to categorize each face as fearful or neutral on each trial. Overall subjects (N=24) responded significantly faster to the face type that was expected. However, individual subjects represented a continuum of responses. By taking the difference in reaction time between fearful and neutral faces in all three expectation blocks, we quantified fear reaction time biases for all subjects. These reaction time biases significantly correlated with harm avoidance scores (r=0.76, p=0.003), such that subjects who responded faster to fearful than to neutral faces in all expectation blocks had higher harm avoidance scores. The fear reaction time bias also positively correlated with fMRI activity in the medial prefrontal and subgenual cingulate cortices to unexpected fearful faces (i.e. fearful faces in 20:80 trials), such that subjects responding faster to fearful faces had more activity in these regulatory regions of the brain. These results indicate that, even in a healthy population, harm avoidant individuals are hypersensitive to potential threat; they are able to classify fearful faces faster than individuals who are more willing to take risks. The susceptibility of the medial prefrontal and subgenual cingulate cortices to this inter-subject variability makes these brain areas important targets for future mood disorder research, even in a sub-clinical population.
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Nicole R. Giuliani
PhD student
Stanford University Psychophysiology Laboratory
Is bigger better? The relation between anterior cingulate cortex volume and emotional reactivity and regulation
Nicole R. Giuliani, Emily M. Drabant, James Gross
The ability to flexibly regulate emotion is a hallmark of successful psychological functioning. One particularly important type of emotion regulation is cognitive reappraisal, which refers to the reinterpretation of emotional stimuli or events with the goal of changing their emotional meaning. Previous research suggests that: 1) reappraisal consistently activates brain regions known to be involved in cognitive control, including the anterior cingulate cortex (ACC), 2) the ACC contains a dorsal/cognitive and ventral/affective division, and 3) the volume of this region is reduced in clinical populations that have dysregulated emotions (e.g. Post-Traumatic Stress Disorder, aggression, bipolar disorder). However, it is not known whether the volume of the ACC is correlated with emotional reactivity and/or regulation in healthy individuals. In this study we analyzed high-resolution anatomical MRI images from 52 female subjects using the region of interest (ROI) method, which is considered to be the “gold standard” in the field of volumetry research. We also gathered individual-difference measures of emotional reactivity, emotion regulation success, and emotion regulation frequency. Consistent with previous research on clinical populations, we hypothesized that there would be (1) a negative correlation between the volume of the ventral (affective) ACC and emotional reactivity, and (2) a positive correlation between the volume of the dorsal (cognitive) ACC and cognitive reappraisal success, frequency and capability in our healthy subjects. We found a negative correlation between right ventral ACC volume and emotional reactivity (r = -0.349, p = 0.011). For regulation, the correlation between
dorsal ACC volume and reappraisal success was not significant. However, the positive correlation between dorsal ACC volume and reappraisal frequency was significant (r = 0.375, p = 0.006), as was the relationship between dorsal ACC volume and reappraisal capability (r = 0.43, p = 0.001).
No disclosures.
Keywords: ACC, ROI, emotion regulation, reappraisal
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Gretchen Hermes, MD, PhD
Adult Psychiatry Resident
Yale University, Department of Psychiatry
Neurosciences Research Training Program
The sectored foraging field: A novel design to quantify spatial strategies, learning, memory, and emotion
Gretchen L. Hermes and Martha K. McClintock
Although Norway rats are naturally gregarious, males typically live alone at some point during adulthood. Different social ecologies often require different learning strategies and also modulate response to stressors and gonadal development. To measure effects of the social environment on the interaction between cognition and emotion during aging, we focused on a natural learning context and devised the sectored foraging field, a progressively difficult spatial navigation task. Here, we describe how this apparatus and protocol permits multiple learning strategies in a minimally stressful environment, enabling finely graded analyses of cognition and emotionality. Male Sprague–Dawley rats living alone throughout adulthood adopted a sex‐typic discernible spatial strategy. In contrast, males housed in group contexts utilized an algorithmic kinesthetic strategy, repeating the same motor action until they found food. Removal of food and distal cues, but not local cues, elicited anxious alertness, particularly in group‐housed males. Cognitive performance of grouphoused rats subsequent to food and cue removal was significantly impaired, yet enhanced in isolates. Presentation will include spatial strategies of group housed and isolated females.
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Julia M. Hormes MA
PhD student
Department of Psychology, University of Pennsylvania
Department of Psychiatry and Human Behavior
University of Mississippi Medical Center
The temporal dynamics of ambivalence: Changes in positive and negative affect in response to consumption of an “emotionally charged” food
Julia M. Hormes, M.A. & Paul Rozin, Ph.D.
Introduction: Ambivalence is the “degree to which an attitude object is evaluated positively and negatively at the same time.” Individuals who experience cravings for highly appealing substances, such as chocolate, are believed to be ambivalent as they are simultaneously drawn toward and repelled from consumption. Not much is known about the temporal dynamics of ambivalence, especially as it may vary in relationship to consumption.
Methods: Participants (n=482, 56.8% female) were given a single-serving bar of chocolate and five minutes to eat as much as they wished. Positive and negative affect was assessed prior to, immediately after, and 30 minutes following consumption using the Positive and Negative Affect Schedule. Ambivalence was calculated using the formula [Amb=(Ap + An) - |(Ap – An)|], where Ap/An represent ratings of positive/negative affect.
Results: Mixed between-within subjects analyses of variance (ANOVA) were conducted to explore the impact of time, gender and chocolate consumption on levels of affective ambivalence. There was a significant main effect of time, with ambivalence decreasing over time. There were also significant main effects of time and consumption on ratings of positive affect, with positivity decreasing over time, and more rapidly in those who consumed chocolate. There were no significant effects on negative affect ratings.
Conclusions: Levels of ambivalence fluctuate significantly with changing interactions with a target stimulus. Ambivalence peaked prior to a decision about consumption, and declined with increasing temporal distance from the point of decision-making, whether or not that decision was in favor of consumption. The decrease in ambivalence was driven by decreasing positive affect. Ambivalence appears to be related to a conflict between approach and avoidance tendencies towards a particular stimulus, and relatively independent of actual consumption. Results are consistent with hypotheses about ambivalence playing a role in cravings for ingested substances. There were also significant main effects of time and consumption on ratings and rates of change of positive affect, with positivity decreasing over time, and more rapidly in those who consumed chocolate.
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Brent L. Hughes
Graduate Student
Self Regulation Lab
Department of Psychology
University of Texas at Austin
Not So Fast: Social Accountability Reduces Evaluative Bias by Increasing Cognitive Control
Brent L. Hughes, Jennifer S. Beer
The motivation to view one’s self positively (i.e., self-enhance) has a powerful impact on behavior. For example, people often try to bolster their self-views by over-claiming scholarly knowledge. Over-claiming is the tendency to claim familiarity with fake knowledge items and inflate familiarity with real knowledge items (Paulhus et al., 2003). Increasing social accountability curtails over-claiming. Currently it is unclear whether social accountability reduces over-claiming because it destroys cognitive control efforts to substantiate over-claiming or whether impression management concerns engender more careful processing for familiarity claims. These two perspectives suggest that social accountability should either reduce or increase the engagement of neural regions associated with cognitive control, respectively. In an fMRI study, participants evaluated their familiarity with real and fake knowledge items. Social accountability was manipulated by the presence or absence of cues that warned participants that lists might include fake items. This study found evidence that social accountability reduces over-claiming by increasing neural activation associated with cognitive control. When participants were warned that some items might be fake, they reduced their familiarity ratings and engaged neural regions associated with cognitive control (i.e., ACC, OFC, MPFC). These findings are consistent with the engagement of self-control regions in response to concerns about social acceptance (Amodio et al., 2008; Eisenberger et al., 2003; Klucharev et al., 2009). Furthermore, findings are discussed in relation to individual differences in concerns about social acceptance (i.e., narcissism).
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Nanxin (Nick) Li
Department of Psychology
Laboratory of Molecular Psychiatry
Yale University School of Medicine
Rapid antidepressant actions of ketamine: role of NR2B and vascular endothelial growth factor
Nanxin Li, Boyoung Lee, Mounira Banasr, Ronald Duman
Clinical studies demonstrate that a single injection of ketamine, an NMDA channel blocker, produces a rapid antidepressant response (within 24 hours) in patients resistant to typical antidepressant treatments, and that this effect lasts for up to a week. Preclinical studies have shown that ketamine is active in behavioral models (e.g., forced swim test) that are responsive to acute antidepressant treatment and therefore are not predictive of rapid acting agents. To address this issue and to investigate the molecular mechanisms underlying the actions of ketamine, we have tested ketamine in the chronic unpredictable stress (CUS) model of depression. CUS is considered one of the most relevant and valid models of depression because it measures anhedonia (sucrose preference) and because chronic administration (3 weeks) of a typical antidepressant is required to reverse the CUS-anhedonia. We show that a single dose of ketamine (10mg/kg) produces a rapid antidepressant effect in the sucrose preference test within 24 hours, and that this effect is sustained for up to 10 days. Ketamine also decreases the latency to feed in the novelty suppressed feeding (NSF) test, another model that typically requires chronic (3 weeks) of antidepressant treatment. We also demonstrate that a single dose of Ro-25 6981 (10mg/kg), an NR2B selective antagonist, produces similar, rapid antidepressant actions in the CUS/anhedonia and NSF tests. Finally, we demonstrate that ketamine up-regulates hippocampal expression of vascular endothelial growth factors (VEGF) mRNA and protein in stressed animals. Taken together, these studies validate the rapid antidepressant effects of ketamine in the CUS and NSF models and highlight possible involvement of NR2B and VEGF signaling pathways.
Supported by MH45481.
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Pawel Licznerski, PhD
Department of Psychiatry
Yale University School of Medicine
Role of Serum- and Glucocorticoid- Induced Kinase 1 (SGK1) in the Rat Learned Helplessness Model
P. Licznerski, V. Duric, M. Banasr, R.S. Duman
Post-traumatic stress disorder (PTSD) is associated with improper functioning of amygdala and prefrontal cortex, however little is known about the molecular mechanisms underlying the pathophysiology of PTSD. In order to identify genes abnormally regulated, we examined gene expression profiles in postmortem brains of patients diagnosed with PTSD. Our microarray-based study showed SGK1 expression to be specifically down-regulated in the prefrontal cortex of a small cohort of patients with PTSD. SGK1 is a serine/threonine protein kinase involved in cellular stress responses and in modulating the expression of different ion channels and transporters. To further characterize the regulation and function of SGK1 we are using a learned helplessness (LH) paradigm as an animal model of PTSD. The LH paradigm has several characteristics that make it a relevant model of PTSD, including exposure to uncontrollable or inescapable stress/trauma, and resulting behaviors including despair, altered endocrine function, and disrupted sleep cycles. We found that rats exposed to inescapable stress, which results in helplessness (i.e., decreased escapes), decreased the expression levels of SGK1 mRNA in the medial prefrontal cortex of rats. We are currently investigating the functional role of SGK1 in this behavioral paradigm by using an adeno-associated virus (AAV) –based in vivo delivery approach to express a dominant negative mutant of SGK1. Our study will contribute to a better understanding of the function of SGK1 and to the molecular mechanisms underlying behavior in the LH model as well as in PTSD.
Supported by MH45481 and a VA PTSD fellowship.
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Darcy Mandell
PhD Program in Clinical Psychology
Center for the Neural Basis of Cognition
University of Pittsburgh
Somatic Awareness in Anxious Youth: Relating self-reported symptoms to neural mechanisms of vigilance-avoidance
Darcy Mandell, Greg Siegle, Naho Ichikawa, Cecile Ladoucer, Jennifer Silk, Ronald Dahl, Neal Ryan
Over half of anxious youth report “clinically significant” somatic symptomatology, and anxious youth are often considered to be hyper-aware of somatic sensations. However, the same youths have shown deficits in emotional self-awareness, a skill that—according to biological theories of emotion—requires an awareness of physical sensations. Recent fMRI studies have provided additional evidence that somatic and emotional awareness are associated with activity in the same brain regions, including insula anterior cingulate cortex (ACC). How can these discrepant findings be combined to create a coherent picture of somatic awareness in anxious youth? Functional neuroimaging studies of pediatric anxiety have described neural substrates of a “vigilance-avoidance” pattern of attention allocation that takes into account the time-course of neural responses to threat. If avoidant responses to external threat co-occur with an attentional neglect of bodily sensations during acute threat, anxious children may not develop an appropriate awareness of their emotional reactions, giving rise to emotion regulation difficulties and chronic anxiety symptoms. The current study examined the relationship between individual differences in self-reported state somatic symptomatology and neurocognitive patterns of vigilance-avoidance previously found in anxious youth.
Preliminary analyses on amygdala function indicate a negative correlation between somatic symptom scores and amygdala activity peaking at scan 4 (left: r=-.28, p=.1; right: r=-.34, p=.05). This pattern is consistent with sustained attentional avoidance of external threat stimuli. Hypotheses for subsequent analyses include negative associations between somatic symptom scores and activity in both the anterior insula and the rACC (consistent with a lack of bodily awareness), and a positive association between somatic symptom scores and caudal ACC activity (consistent with attentional avoidance of threat through downstream activation of regulatory structures). Together, these findings will help determine whether an awareness (or lack of awareness) of physical symptoms is related to classic threat-related processing biases central to pediatric anxiety disorders. To the extent that these phenomena are causally related, interventions that increase early awareness of somatic phenomena during stress could encourage the development of more flexible regulatory responses.
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Emilie R. Muelly
MD/PhD Student
College of Medicine
Pennsylvania State University
Neural Sequelae of Maple Syrup Urine Disease
Emilie R. Muelly, Don C. Bigler, Kevin A. Strauss, D. Holmes Morton, Gregory J. Moore.
Maple Syrup Urine Disease (MSUD) is a rare genetic error of metabolism with high prevalence in the Old Order Mennonite population in central Pennsylvania. Deficiency in the enzyme branched-chain alpha-ketoacid dehydrogenase (BCKD) causes an inability to metabolize branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Buildup of these amino acids and their respective keto-acids can damage the brain and cause death. Patients with lifelong dietary treatment are still at risk for acute metabolic crises and encephalopathy in times of even minor illness, and may also suffer from chronic neuropsychiatric sequelae. Anxiety, depression, and attention deficit symptoms are especially common in these patients. Biochemical pathways predict that increased leucine levels results in neurotransmitter depletion by blocking entry of precursors into the brain and by consumption of glutamate in a reversed transamination reaction. Recently, some MSUD patients have undergone successful liver transplant therapy. This treatment option eliminates the risk of acute crises in patients with MSUD, but its effects on neurochemistry and neuropsychiatric sequelae is uncertain. Magnetic Resonance Spectroscopy in patients during acute illness has shown neurochemical abnormalities including a decrease in N-acetyl-aspartate, a marker for neuronal health and viability. Follow-up neurochemical analysis just after treatment reveals a return to normal neurochemistry, indicating plasticity of these alterations. Some patients in the chronic state have leucine levels that rise slowly to very high levels, which may cause subacute neurochemical changes in the brain. In this study, we use magnetic resonance spectrosopy (MRS) to compare the neurochemical sequelae of MSUD patients, patients who have undergone liver transplantation, and unaffected sibling controls. Using MRS it is possible to quantify neurochemical markers of neuronal health and viability (N-acetyl-aspartate) and membrane turnover or breakdown (choline compounds), as well as to look directly at specific neurotransmitter (Glutamate, GABA) levels. Future studies are planned to evaluate the relationship between these findings and neuropsychiatric outcomes, which could not only provide valuable information to MSUD patients considering liver transplantation, but may also provide insight into the neurochemistry of common neuropsychiatric conditions. This research was financed by internal funds from the Department of Psychiatry and Center for Emerging Neurotechnology and Imaging at Penn State University, College of Medicine.
Keywords: Neuroimaging, Magnetic Resonance Spectroscopy, Genetic Metabolic Disorders,
Neuropsychiatric Disorders.
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Nancy Padilla-Coreano
Department of Psychiatry
University of Puerto Rico School of Medicine
Dissociable roles of prelimbic and infralimbic cortices in fear expression and extinction, pespectively
Padilla-Coreano N, Sierra-Mercado D, Quirk GJ
Previous studies using lesion, local infusion, and recording techniques have implicated the ventral medial prefrontal cortex (vmPFC) in fear expression and extinction. The vmPFC consists of two main regions: the prelimbic (PL) and infralimbic (IL) cortices. For technical reasons, prior work has not sufficiently distinguished the roles of PL and IL in fear expression and extinction. To address this issue, we reversible inactivated either the PL or IL in an auditory fear conditioning task. The percent time freezing to the tone was measured to indicate fear levels. On Day 1, rats were conditioned to fear a tone paired with a foot shock. On Day 2, prior to extinction training, rats were microinfused with muscimol or saline. PL inactivation reduced the expression of conditioned freezing, but did not interfere with extinction learning, as evidenced by normal retrieval of extinction on Day 3. IL inactivation, on the other hand, had no effect on the expression of conditioned freezing, but impaired the retrieval of extinction on Day 3. Thus, the roles of PL and IL could be doubly dissociated for fear expression and extinction, respectively. In humans, the inability to extinguish fear responses is correlated with increased activity of the dorsal anterior cingulate cortex (homologous to rodent PL) and reduced activity in the vmPFC (homologous to rodent IL). Thus, our rodent findings agree with human findings suggesting distinct functions of prefrontal subregions in fear expression and extinction. Understanding the neurobiology of fear expression and extinction will help in the design of better treatments for anxiety disorders.
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Rebecca D. Ray, PhD
Post-Doctoral Researcher, Affective Neuroscience Lab, Vanderbilt University, Nashville, Tennessee
Ruminators Can Reappraise: Short and long term benefits of reappraisal for ruminators
Ray, R. D., Tamir, M., & Gross, J. J.
The tendency to ruminate on negative thoughts and feelings has been associated with depression onset and the severity of depression symptoms. Reappraisal provides a way to think about upsetting events and/or feelings that decreases negative feelings. While reappraisal is effective in the main for reducing negative feelings, can those who regularly employ rumination effective deploy it? In a study of 114 females who had recently experienced an intense angry interpersonal event, individual differences in anger rumination were measured. After random assignment to a rumination or reappraisal group, each woman followed instructions to ruminate or reappraise on the angry event for three 90 second sessions. During the instruction periods there were no differences between high and low trait ruminators in their reappraisal success. Furthermore, one week later, those high trait ruminators who had been assigned to reappraise were less likely to ruminate about the angry event and discuss it with friends than those high trait ruminators who had been assigned to the rumination condition. This study demonstrates that even high trait ruminators experience short and long term benefits from reappraisal.
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Ulrike Rimmele PhD
Dept. of Psychology, New York University
The heightened subjective sense of remembering emotional stimuli is coupled to memory for intrinsic, but not extrinsic stimuli features.
Ulrike Rimmele, Lila Davachi, Elizabeth A. Phelps
Department of Psychology, New York University
Emotion strengthens the subjective experience of recollection. For neutral stimuli, the subjective sense of recollection is associated with memory accuracy for a variety of contextual details (Perfect et al., 1996). However, for emotional events it has been suggested that the subjective judgments of recollection do not reflect accurate memory for details (Talarico & Rubin, 2003). It has been suggested that emotion benefits memory for intrinsic item details, but not for extrinsic contextual details (see Kensinger, 2009; Mather, 2007 for review). Given this, we propose that the subjective judgment of recollection for emotional stimuli is associated with memory for intrinsic, but not extrinsic details. Using the remember/ know paradigm, we find that the heightened subjective sense of recollection for emotional stimuli converges with enhanced memory accuracy for intrinsic details, such as location of the emotional stimuli, but worse memory for extrinsic contextual details. In contrast, neutral pictures given a “remember” response were associated with better recollection of extrinsic contextual details and equally well recollection of an intrinsic contextual detail. These findings suggest that for emotional stimuli the quality and strength of memory for a few core details may mediate subjective judgments of recollection, whereas for neutral stimuli the quantity of contextual details may be more important. The authors report no financial interests or potential conflicts of interest.
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Moacyr A. Rosa MD, PhD
Division of Brain Stimulation and Therapeutic Modulation
Department of Psychiatry
Columbia University
Novel paradigms for optimizing magnetic seizure therapy: Theta Burst Stimulation
Moacyr A. Rosa, M.D., PhD; Angel Peterchev, PhD, Sarah H. Lisanby, M.D.
Objective: This study analyzed, for the first time, the value of theta burst stimulation (TBS) as a novel paradigm for therapeutic seizure induction in a pre-clinical model. Feasibility, neurophysiology patterns and safety issues were addressed. These initial results will inform the optimization of magnetic seizure therapy (MST) paradigms for human use, and will also inform safety guidelines for the use of TBS at subconvulsive levels.
Background: Repetitive transcranial magnetic stimulation (rTMS) is already an approved clinical tool for the treatment of major depression. It uses subconvulsive magnetic pulses that induce electric current in the brain in order to modulate its excitability. The use of rTMS as a means of deliberately inducing therapeutic seizures (magnetic seizure therapy) is now being tested in controlled trials with the goal of bringing the therapeutic power of electroconvulsive therapy (ECT) to severely depressed patients who need it, while sparing them the cognitive side effects. One main advantage of the MST approach is the more focal stimulation that passes unimpeded through the scalp, allowing more control over current paths, density and distribution within cortical tissue. On the other hand, engineering constraints limit output of MST devices, making the identification of more efficient stimulation paradigms important. An innovative way of improving the efficiency of rTMS is called TBS, which uses a combination of frequencies (bursts of high frequency – 50 Hz – delivered in a theta rhythm, i.e. 4-7 Hz). Conventional rTMS devices can deliver it and this pattern has shown to induce longer lasting and more robust changes in cortical excitability than those seen with conventional TMS. TBS is based on protocols optimized for inducing long-term potentiation (LTP) and long-term depression (LTD) with direct electrical stimulation, which were developed to resemble the normal patterns of neural firing occurring in the hippocampus of rats during exploratory behavior. TBS can be delivered in a continuous fashion (cTBS) or in an intermittent fashion (with variable intervals between the trains; iTBS) and has never before been used as a means of inducing seizures.
Design/Methods: Four macaca mulatta were tested, on separate days one week apart, and received two forms of conventional MST (50 Hz and 18 Hz) and two forms of TBS (continuous or intermittent). The efficiency to induce a generalized seizure was defined as the lowest number of pulses needed to observe motor (controlled with a cuffed upper limb) and electroencephalographic (controlled with two fronto-mastoid EEG leads) generalization. Subjects were anesthetized during the procedures (methohexital 0.5 mg/Kg IV) and received muscle relaxant (succinylcholing 2.4 mg/Kg IV), in a similar fashion as that used for clinical ECT and MST. Seizure threshold titration was performed for each modality of treatment.
Results: Both forms of MST nd the continuous form of TBS were efficient in inducing generalized seizures in all subjects. MST delivered at 50 Hz frequency needed the highest number of pulses (100 for 3 subjects and 150 for one), while MST 18 Hz and cTBS showed a similar seizure threshold (48 to 108 pulses). Intermittent TBS was the less efficient of all, unable to induce a seizure in two of the animals and needing a high number of pulses in another (480 pulses). No complications were observed during the experiments.
Conclusions: Continuous TBS has shown to be as effective as conventional MST for inducing seizures in this pre-clinical model. There were no apparent differences in seizure quality or duration between both modalities. Results open up the possibility of translating the findings to the use of theta-burst paradigms for therapeutic seizure induction in humans.
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Paula L. Ruttle
Ph.D. Candidate (Psychology)
Center for Research in Human Development
Concordia University
Disentangling psychobiological mechanisms underlying children’s mental health symptoms: Longitudinal and concurrent associations with diurnal cortisol
Paula L. Ruttle, M.A., Elizabeth A. Shirtcliff, Ph.D., Lisa A. Serbin, Ph.D., Dahlia Ben-Dat Fisher, Ph.D., Dale M. Stack, Ph.D., & Alex E. Schwartzman, Ph.D
Cortisol is associated with mental health symptoms; however, research on this topic is seemingly contradictory with studies showing that both internalizing and externalizing symptoms are related to high and low cortisol. One extant theory to explain divergent findings in the stress literature is that both hypo- and hyper-arousal may be present depending on time since onset of the stressor. This theory may extend to mental health symptom onset. To examine this possibility, salivary cortisol samples were repeatedly collected over two waking days in 96 adolescents participating in an intergenerational, longitudinal project. Composite measures of internalizing and externalizing symptoms were formed using mother and teacher reports. When examined collectively, mental health symptoms were associated with cortisol and its diurnal rhythm; as predicted, the direction of the association was dependent on whether symptoms were measured recently or if substantial time had elapsed since symptom onset. More precise analyses showed that, when examined longitudinally, youth with more internalizing symptoms in childhood had low basal cortisol levels as adolescents; however, there was a positive association between basal cortisol levels and internalizing symptoms when symptoms were examined concurrently in adolescence. Youth with more externalizing symptoms in childhood had flattened diurnal cortisol rhythms as adolescents, and this association persisted when concurrent externalizing symptoms were examined in adolescence. The present study extends an extant theory to mental health symptoms in youth and helps clarify the divergent literature by simultaneously examining concurrent and longitudinal associations of cortisol and its diurnal rhythm with internalizing and externalizing symptoms. Findings support the theoretical model of blunting of the hypothalamic-pituitary-adrenal (HPA) axis over time. While initially, the HPA axis may show hyper-arousal when youth first display symptoms, long-term exposure may lead to a hypo-arousal of the HPA axis which culminates in a dysregulated diurnal rhythm.
Key words: diurnal cortisol, blunting, internalizing symptoms, externalizing symptoms
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Lisa Talbot
University of California, Berkeley
Doctoral candidate in Clinical Science
The Bidirectional Association between Sleep and Mood in Bipolar Disorder and Insomnia
Lisa S. Talbot, Ilana S. Hairston, Polina Eidelman, June Gruber, and Allison G. Harvey
University of California, Berkeley
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Sleep and mood are important across psychiatric disorders (e.g., Benca, et al., 1997). A bidirectional relationship has been proposed whereby disruptions in nighttime sleep and daytime mood may be mutually reinforcing across a number of psychiatric disorders. This current research examines this relationship in bipolar disorder and insomnia. Aims were to: 1) examine differences in nighttime sleep parameters and daytime mood parameters across interepisode bipolar, insomnia, and healthy control groups, and 2) examine the sleep and mood relationships across the three group using experience sampling methodology. Individuals with bipolar disorder in the inter-episode period (n = 49), individuals with insomnia (n = 34), and individuals with no history of any psychiatric or sleep disorder (n = 52) completed seven days of sleep diaries and mood measures at home. The Profile of Mood States—Short Form (POMS-SF; Shacham, 1983) was used to assess mood. Each morning on waking participants completed the sleep diary and POMS-SF and each evening participants again completed the POMS-SF. Results indicate that the bipolar and insomnia groups differed from the healthy control groups on the following sleep variables over the course of the week: sleep onset latency, number of awakenings, wake after sleep onset, sleep efficiency, and total wake time. Interestingly, the bipolar and insomnia groups did not differ from each other. The bipolar and insomnia groups also exhibited greater morning and evening mood disturbance than the healthy control group. Again, the bipolar and insomnia groups did not differ from each other on mood disturbance. Multilevel analyses were used to examine possible time effects prior to conducting the analyses of the sleep and mood relationships. There were no differences between groups in time trajectories of sleep or mood. Regression analyses were then conducted to examine the sleep and mood relationships using the same database structure as for the HLM analyses in order to include all daily data points in the analysis. Total wake time was associated with subsequent morning total mood disturbance, and bipolar diagnostic status moderated this effect. Examining POMS mood subscales, total wake time was specifically associated with morning anxiety and depression in the bipolar group. Evening total mood disturbance was associated with the subsequent night’s total wake time, and both bipolar and insomnia diagnostic status moderated this relationship. POMS mood subscales indicated specific associations between evening anxiety and total wake time in both the bipolar and insomnia groups, as well as associations between depression and anger and total wake time in the bipolar group only. These findings suggest that sleep disturbance is associated with subsequent morning mood disturbance for the bipolar group and evening mood disturbance is associated with subsequent sleep disturbance for the bipolar and insomnia groups. Potential implications include the development of sleep and time-targeted mood interventions for bipolar disorder and insomnia to improve the course of the disorders.
Keywords: Sleep, Bipolar Disorder, Insomnia, Profile of Mood States
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Kristina Thurin
NIMH, Genes, Cognition and Psychosis Program, Neuroimaging Core, Bethesda, MD
Abnormal cognitive control processing in unaffected siblings of patients with schizophrenia: an fMRI
intermediate phenotype for schizophrenia?
Kristina Thurin, Fabio Sambataro, Martin Safrin, Giuseppe Blasi, Ashley Wabnitz, Brad Zoltick, Joseph
Callicott, Venkata S. Mattay, Daniel R. Weinberger
Background: Aberrant activity in regions underlying cognitive control has been shown in patients with schizophrenia (SCZ). However, it is unclear whether this represents a ‘state’ or ‘trait’ effect. To this end, we compared fMRI BOLD activity in normal controls (NCs), SCZs, and unaffected siblings (SIB) of SCZs while they performed a cognitive control task.
Methods: 70 SCZs, 65 SIBs, and 235 NCs performed a modified flanker task, which included a conflict monitoring and interference suppression condition (INCON) and a response inhibition condition (NoGo). BOLD fMRI data for correct trials was analyzed using ANCOVAs with covariates for gender, age, WRAT, and reaction time (RT) with diagnostic group as predictor (p<0.05 corrected for multiple comparisons). Functional connectivity of brain regions involved in executive function was analyzed using Psychophysiologic Interaction (PPI). Correlations of activity in the clusters of interest with performance and PANSS were performed. Results: During the INCON condition, SCZs showed lower accuracy (M=95.8%, SD= ±8.34, p=0.026) than NCs (M=97.6%, SD= ±4.99) and SIBs (M=98.2%, SD= ±2.67, p=0.025). Also in the INCON condition, SCZs showed longer reaction time (M= 818 ms, SD= ±174, p=3.77X10‐4) than NCs (M=747 ms, SD= ±132) and were not different than SIBs (M=782 ms, SD= ±128, p=0.186). During the NoGo condition, both SCZs (M=86.2%, SD= ±16.8) and SIBs (M=91.3, SD=7.96) had lower accuracy than NCs (M=94.2, SD= ±6.73). SIBs showed intermediate accuracy. (NC>SCZ p=9.40×10‐9; NC>SIB p= 0.004; SIBs>SCZs, p=0.025). At the imaging level, an ANCOVA revealed significant group differences in the anterior cingulate (aCC). Post hoc t‐tests showed that SCZs had less activation in the anterior cingulate cortex (aCC) than NCs during the INCON condition(p=0.001). SIBs did not have significantly different activation than NCs (p=0.306) or SCZs (p=0.085) during INCON. However, during the NoGo condition both SIBs (p=0.014) and SCZs (p=0.004) showed decreased activation in the aCC as compared to NCs. There was no significant difference in activation between SCZs and SIBs (p=.767). NoGO>Con PPI results revealed greater connectivity between the aCC and the left DLPFC in SCZs (p=0.002) and SIBs (p=0.041) when compared to NCs, with SIBs showing similar connectivity to SCZs (p=0.388). There were no significant correlations between activation in the aCC during the INCON or NoGo conditions and performance or PANSS.
Conclusions: Our results show that not only SCZs but also their SIBs show decreased capacity for cognitive control as well as decreased activity and connectivity of the aCC during response inhibition. This aberrant activity and connectivity of aCC during response inhibition may represent a potential intermediate phenotype for genetic studies of schizophrenia.
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Sunali Wadehra
Wayne State University School of Medicine
Disordered fronto-limbic interactions during emotion processing in the vulnerable brain: fMRI and Dynamic Causal Modeling applied to the study of adolescents
Sunali Wadehra, Simon B. Eickhoff, Patrick Pruitt , M. S. Keshavan , Eric Murphy, Vaibhav A. Diwadkar
Abstract
Background: Disordered organization of cortico-limbic circuits in the brain may underlie documented social impairments in schizophrenic offspring (SCZ-Off; Philips and Seidman, 2008). Advanced techniques such as Dynamic Causal Modeling (DCM; Stephan et al., 2007) are ideally suited to understand network interactions in the brain, yet have never been applied to this important developmental question. Here we use a combination of DCM and fMRI to investigate cortico-limbic network interactions during affective appraisal in a group of adolescent (10 ≤ age ≤ 20 yrs) SCZ-Off (n=19) and controls (n=24).
Methods: All subjects provided consent or assent before performing an event-related affective appraisal task (continuously presented faces; Ekman & Oster, 1979). DCM was conducted (SPM8) on fMRI data (4.0T) using time series (p<.05, effects of interest) from five cortico-limbic regions (V1, FG, Amyg, DPFC, VPFC). To comprehensively address model fit, we employed 100 models per subject to explore a combination of intrinsic and modulatory interactions between regions. Finally, Bayesian model selection (Stephan et al., 2009) identified the appropriate models within and across groups.
Results: Results of a conjunction analysis (activation to faces) in Controls and SCZ-Off are depicted in Figure 1 and show activation in both groups in our network of interest. Significant clusters (p<.05) are depicted on dorsal (a; bilateral DPFC), ventral (b; visual, fusiform, amygdala, and VPFC) and medial (c; amygdala, fusiform, and visual) views of the brain. Figure 2 shows, (a) Reduced intrinsic DPFC → Amygdala and VPFC → Amygdala connectivity/coupling (in 1/s) in SCZ-Off, relative to HC and (b) in SCZ-Off, markedly increased modulatory inhibition of activity in these pathways by the valence of the face.
Conclusions: Aberrant cortico-limbic responses appear to characterize the impaired affective response in adolescent SCZ-Off and may reflect a substantive disordering of this important pathway.
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Sara Walker, Ph.D.
Post-doctoral Fellow
University of Michigan
Neuropsychology Section
Department of Psychiatry
Auditory Learning and Memory Decrements in Symptomatic, but not Remitted Depression
Sara J. Walker, Sara L. Wright, Benjamin D. Long, Emily M. Briceno, Allison M. Kade, Jon-Kar Zubieta, Elizabeth A. Young, Linas A. Bieliauskas, Irma C. Smet, Saulo C.M. Ribeiro, Rudolph C. Hatfield, Juan F. Lopez, Melvin G. McInnis, Daniel F. Maixner, Huda Akil, Bruno Giordani, and Scott A. Langenecker
Background: Memory complaints are common in Major Depressive Disorder (MDD), although prior research has yielded conflicting results regarding the origin and extent of such difficulties. Among other research, the frontal and hippocampal theories each posit disrupted neural circuits potentially underlying memory decrements in depression. Memory organization and retrieval are dependent upon fronto-limbic functioning, whereas diminished hippocampal functioning should result in reduced learning curve and delayed recall.
Method: Learning and memory functioning in these domains, as measured by the California Verbal Learning Test-II (CVLT-II; Delis et al., 2000), were assessed in 220 participants (115 depressed patients, 95 healthy controls). The Hamilton Depression Rating Scale (HDRS) measured symptom severity, and between-group analyses were conducted among three groups: healthy control, symptomatic MDD, and remitted MDD.
Results: Those with symptomatic MDD, but not those with remitted MDD, exhibited decreased performance on tasks thought to rely on both frontal and hippocampal functioning. The healthy control group performed significantly better on several tasks (i.e., initial recall, recognition hits, recognition false positives), than did the symptomatic MDD group. The remitted group scored significantly better in terms of learning slope than did the healthy control group, with no other significant differences noted.
Conclusions: This study suggests difficulty in multiple aspects of learning and memory during active MDD. Learning and memory decrements in depression may be a state feature, reflecting temporary dysfunction in fronto-limbic systems, with more prominent hippocampal dysfunction.
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Diana Whalen
PhD candidate
Clinical-Developmental Psychology,
University of Pittsburgh
The Effect of Maternal Borderline Personality Disorder on Maternal Emotion Socialization and Adolescent Emotional Vulnerability
Whalen D, Silk JS, Dahl RE
Offspring of mothers with borderline personality disorder (BPD) are at an elevated risk for developing later psychopathology, however a better understanding of the mechanisms through which psychopathology is transmitted from mothers with BPD to their adolescents is needed. Invalidation in the home environment is one hypothesized mechanism of risk for BPD. More specifically, mothers with BPD may experience greater challenges in maintaining a stable and nurturing home environment than healthy mothers, which may lead to the development of emotional vulnerability in their adolescents. Pupillometry is one innovative methodology for investigating the temporal pattern of emotional vulnerability. Pupil dilation provides a peripheral index of brain activation in response to a specific stimulus. This study investigated pupil dilation as a physiological correlate of emotional vulnerability among the adolescents of mothers with BPD.
Participants included mothers between the ages 25 to 55 and their adolescents ages 9 to 14. Participants were divided into groups based on maternal psychiatric history: Control (n = 50), mothers with no psychiatric history; DEP (n= 20) mothers with a DSM-IV diagnosis of recurrent, chronic depression; and BPD (n= 18) mothers with a DSM-IV diagnosis of borderline personality disorder. Pupil dilation was measured during an emotional face processing task (Monk et al., 2003). The present report focuses on responses to a series of neutral faces, which were rated on a 1-5 scale based on one of three questions: “How afraid do you feel?” “How hostile is the face?” or “How wide is the nose?” Invalidation in the home environment was measured using the Emotions as a Child Scales (Klimes-Dougan, Brand, & Garside, 2001). These scales assess maternal responses to adolescent’s expressions of sadness, anger, and fear. Hypotheses were tested using separate ANOVAS for two specific regions of interest in the pupil dilation waveform: (1) a “peak” segment defines as the period 3-5 seconds following face presentation, and (2) a “late” segment defined as the latter seconds of the period during which the face was off-screen (6-8 secs).
Analyses compared groups on both pupil dilation in adolescents and invalidating emotion socialization strategies. Adolescents of BPD and DEP mothers significantly differed from CON adolescents on initial peak dilation during the how afraid, neutral faces condition (F= 4.97; p<.01). In addition, adolescents of BPD and DEP mothers significantly differed from CON adolescents on sustained late dilation during the how afraid, neutral faces (F= 3.42; p<.05). BPD mothers reported more invalidating emotion socialization when compared to the DEP and CON mothers (F=3.6; p<.05). More specifically, mothers with BPD reported more use of neglect (F= 4.9; p<.01) and override (F= 4.0; p<.05) as emotion socialization strategies.
Adolescents of mothers with DEP and BPD exhibited different pupil dilation patterns to neutral faces than adolescents of CON mothers: Adolescents of DEP mothers had the lowest pupil dilation, whereas adolescents of BPD mothers had the highest. Adolescents of mothers with BPD were also exposed to more invalidating emotion socialization than adolescents of mothers without BPD. Perhaps specific features associated with maternal BPD and DEP contributed to adolescent emotional vulnerability and invalidating emotion socialization strategies. Interventions aimed at teaching adolescents to experience and process facial information in a more adaptive ways and educating mothers in more supportive emotion socialization strategies may lessen the potential for the BPD-related risks found in this study.
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Sarah Whittle Ph.D.
Post Doctoral Research Fellow
Australian Research Council (ARC)
Orygen Youth Health Research Centre
Maternal responses to adolescent positive affect are associated with adolescents’ reward neuroanatomy
Sarah Whittle, Marie B. H. Yap, Murat Yücel, Lisa Sheeber, Julian G. Simmons,
Christos Pantelis, Nicholas B. Allen
The development of reward-based learning and decision-making, and the neural circuitry underlying these processes, appears to be influenced negatively by adverse child-rearing environments characterized by abuse and other forms of maltreatment. No research to-date has investigated whether normative variations in the child-rearing environment have effects on adolescent brain structure. We examined whether normative variations in maternal responses to adolescents’ positive affective behavior were associated with morphometric measures of the adolescents’ affective neural circuitry, namely the amygdala, orbitofrontal cortex (OFC), and anterior cingulated cortex (ACC). Healthy adolescents (N = 113) participated in laboratory-based interaction tasks with their mothers, and underwent high-resolution (3T) structural magnetic resonance imaging (MRI). The mother-adolescent interactions included a pleasant event-planning interaction (EPI) and a conflictual problem-solving interaction (PSI). Adolescents, whose mothers displayed more punishing responses to their positive affective behavior during both tasks, and only during the PSI, had larger left dorsal ACC and bilateral OFC volumes, respectively. In addition, boys whose mothers evidenced this pattern of behavior during the EPI had larger right amygdala volumes. These results suggest that normative variations in maternal responses to affective behavior are associated with the structural characteristics of adolescents’ affective neural circuitry, which may have implications for the development of their social, cognitive, and affective functioning.
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Sara L. Wright, Ph.D.
Clinical Lecturer, University of Michigan, Department of Psychiatry
Staff Psychologist, VA Ann Arbor Healthcare System
Reward Anticipation Activation is Associated with Activation during Emotion Processing
Sara Wright, Brian Mickey, Tiffany Love, Heng Wang, Scott Langenecker, Jon-Kar Zubieta
Introduction: There has been increasing interest in the relationship between reward processing and response to emotional stimuli. Reciprocal projections between the striatum, known to be important for reward processing, and prefrontal and limbic regions, found to be associated with emotion processing, suggest shared functional pathways in emotion and reward processing. Indeed, attenuation of striatal activity during anticipation of reward has been observed during engagement in emotion regulation strategies (Delgado et al., 2008). Further, maintenance of positive affect has been associated with nucleus accumbens (NAcc) activation over time during a single study (Heller et al., 2009). The current study was designed to test the hypothesis that NAcc BOLD response during reward anticipation is related to activation during an emotion processing task.
Methods: Forty-nine healthy individuals (21 male, M age = 24.9O) completed reward (i.e., Monetary Incentive Delay- MID) and emotion (i.e., Emotion Words Task- EWT) processing tasks while undergoing functional MRI. Whole brain scans were performed using a 3.0 Tesla GE Signa scanner (Milwaukee, WI, USA) using a standard radio frequency coil. BOLD contrasts were acquired using a T2* weighted pulse sequence (repetition time, 2000 ms; echo time, 30 ms; 1 voxel, 3.75 x 3.75 x 4 mm), with single shot combined spiral in/out acquisition, which has been shown to reduce signal dropout near sinuses. The entire volume of brain (30 slices) was acquired at each repetition time. A high resolution T1 weighted pulse sequence was acquired to provide anatomical localization [three dimensional spoiled gradient recalled echo (3 DSPGR); repetition time, 24 ms; echo time, 5 ms; slice thickness, 1.5 mm]. The functional volumes were slice time corrected, realigned and then volumes were normalized with linear and non linear warping to standard space (Montreal Neurological Institute, Quebec, CA), and smoothed with a 6 x 6 x 6 (EWT) or 5 x 5 x 5 (MID) mm FWHM Gaussian filter to reduce residual interindividual anatomical variability, and analyzed with SPM2. BOLD Contrast t maps for each participant were derived using subtraction of negative word blocks minus neutral word blocks, positive word blocks minus neutral word blocks, and anticipation of rewarding stimuli minus anticipation of neutral stimuli in event-related designs. For the EWT task, ANOVAs, controlling for participant sex, were performed using SPM5. For the MID task, activation values were extracted from the NAcc and entered as a regressor in whole brain analysis of activation during the EWT, again controlling for participant sex (for all individual analyses, extent threshold = 15, p < .001, uncorrected).
Results: During viewing of positive words, significant activation was detected in the left superior frontal gyrus. During viewing of negative words, significant activation was detected in left superior and medial frontal gyri. NAcc activation during reward anticipation from the MID was significantly associated with activation in a number of limbic and posterior regions in the EWT. NAcc activation was negatively related to activation during viewing of positive words in bilateral posterior cingulate, left precuneus and cuneus, right middle occipital gyrus, right uncus, left insula, and right culmen. NAcc activation was negatively related to activation during viewing of negative words in left precuneus and left parahippocampal gyrus. There were no significant regions positively associated with NAcc activation.
Conclusions: Consistent with the hypothesis that networks involved in the processing of emotional stimuli are mutually regulated with those responding to reward, NAcc activation during reward anticipation was negatively related to emotion-related activation in a number of regions associated with complex visual processing (i.e., precuneus, cuneus, and middle occipital gyrus) and in areas associated with integration of emotion with learning and memory (i.e., parahippocampal gyrus, uncus, posterior cingulate). Together, these findings may suggest that activity of the NAcc during reward anticipation is modulated by the more integrated and complex processing of emotional stimuli. Functional connectivity analysis may augment these findings in further study.
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Ke Xu, M.D., Ph.D
Resident, Department of Psychiatry
Yale University
School of Medicine
Genetic Modulation of Plasma NPY Stress Response is Suppressed in Substance Abuse: Association with Clinical Outcomes
Ke Xu, Kwangik Adam Hong, Zhifeng Zhou, Richard L Hauger, David Goldman, Rajita Sinha
Background: Neuropeptide Y (NPY) is involved in stress regulation. Genetic variations predict plasma NPY and neural correlates of emotion and stress. We examined whether the functional NPY haplotype modulates stress-induced NPY and anxiety responses, and if plasma NPY stress responses are associated with substance dependence outcomes.
Methods: Thirty-seven treatment-engaged, abstinent alcohol/cocaine dependent patients (AC) and 28 controls (HC) characterized on NPY diplotypes (HH: high expression; HLLL: intermediate/low expression) were exposed to stress, alcohol/drug cues and neutral relaxing cues, using individualized guided imagery, in a 3-session laboratory experiment. Plasma NPY, heart rate and anxiety were assessed. Patients were prospectively followed for 90-days post-treatment to assess relapse.
Results: Diplotype and phenotypes modulated stress-induced NPY, heart rate and anxiety ratings. HH individuals showed significantly lower stress-induced NPY with greater heart rate and anxiety ratings, while the HLLL group showed the reverse pattern of NPY, anxiety and heart rate responses. This differential genetic modulation of NPY stress responses was suppressed in the AC group, who showed no increases in NPY and higher heart rate and greater anxiety, regardless of diplotype. Lower NPY predicted of higher number of days and greater amounts of post-treatment drug use.
Conclusion: Current findings are the first evidence of substance dependence influences on NPY diplotype expression where NPY diplotype modulation of stress-related plasma NPY, heart rate and anxiety responses was absent in addictive subjects. The finding that lower stress-related NPY is predictive of greater relapse severity provides support for therapeutic development of NPY targets in the treatment of substance dependence.