Enhancing Efficacy of PTSD Treatment: Role of Circuits, Genetics, and Optimal Timing

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138439/1/cpsp12203_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138439/2/cpsp12203.pd

Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD

Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46359/1/213_2003_Article_1634.pd

DRD4 polymorphisms modulate reward positivity and P3a in a gambling task: Exploring a genetic basis for cultural learning

Prior work shows that people respond more plastically to environmental influences, including cultural influences, if they carry the 7 or 2‐repeat (7/2R) allelic variant of the dopamine D4 receptor gene (DRD4). The 7/2R carriers are thus more likely to endorse the norms and values of their culture. So far, however, mechanisms underlying this moderation of cultural acquisition by DRD4 are unclear. To address this gap in knowledge, we tested the hypothesis that DRD4 modulates the processing of reward cues existing in the environment. About 72 young adults, preselected for their DRD4 status, performed a gambling task, while the electroencephalogram was recorded. Principal components of event‐related potentials aligned to the Reward‐Positivity (associated with bottom‐up processing of reward prediction errors) and frontal‐P3 (associated with top‐down attention) were both significantly more positive following gains than following losses. As predicted, the gain‐loss differences were significantly larger for 7/2R carriers than for noncarriers. Also, as predicted, the cultural backgrounds of the participants (East Asian vs. European American) did not moderate the effects of DRD4. Our findings suggest that the 7/2R variant of DRD4 enhances (a) the detection of reward prediction errors and (b) controlled attention that updates the context for the reward, thereby suggesting one possible mechanism underlying the DRD4 × Culture interactions.Is there a genetic basis for cultural learning? Recent work suggests carriers of 7‐ or 2‐repeat allele of the dopamine DRD4 are more likely than non‐carriers to acquire their culture’s beliefs and practices. We show carriers are more closely attuned to reward signals compared to non‐carriers. This finding offers a possible missing link in the analysis of the co‐evolutionary dynamic between genes and culture.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162723/2/psyp13623_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162723/1/psyp13623.pd

The neural correlates of intertemporal decision‐making: Contributions of subjective value, stimulus type, and trait impulsivity

Making choices between payoffs available at different points in time reliably engages a decision‐making brain circuit that includes medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and ventral striatum (VS). Previous neuroimaging studies produced differing accounts of the functions of these regions, including that these regions: (1) are sensitive to the value of rewards discounted by a function of delay ('subjective value'); (2) are differentially sensitive to the availability of an immediate reward; and (3) are implicated in impulsive decision‐making. In this event‐related fMRI study of 20 volunteers, these hypotheses were investigated simultaneously using a delay discounting task in which magnitude of rewards and stimulus type, i.e., the presence or absence of an immediate option, were independently varied, and in which participants' trait impulsivity was assessed with the Barratt Impulsiveness Scale. Results showed that mPFC, PCC, and VS are sensitive to the subjective value of rewards, whereas mPFC and PCC, but not VS, are sensitive to the presence of an immediate reward in the choice option. Moderation by individual differences in trait impulsivity was specific to the mPFC. Conjunction analysis showed significant overlap in mPFC and PCC for the main effects of subjective value and stimulus type, indicating these regions may serve multiple distinct roles during intertemporal decision‐making. These findings significantly advance our understanding of the specificity and overlap of functions subserved by different regions involved in intertemporal decision‐making, and help to reconcile conflicting accounts in the literature. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86833/1/21136_ftp.pd

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression

Aberrant Reward Center Response To Partner Reputation During A Social Exchange Game In Generalized Social Phobia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97533/1/da22091.pd

Effects of Trauma in Adulthood and Adolescence on Fear Extinction and Extinction Retention: Advancing Animal Models of Posttraumatic Stress Disorder

Evidence for and against adolescent vulnerability to posttraumatic stress disorder (PTSD) is mounting, but this evidence is largely qualitative, retrospective, or complicated by variation in prior stress exposure and trauma context. Here, we examine the effects of development on trauma vulnerability using adult post-natal (PN) day 61, early adolescent (PN23) and mid adolescence (PN34) rats and two types of trauma: an established animal model of PTSD, single prolonged stress (SPS), and a novel composite model—SPS predation (SPSp) version. We demonstrate that early and mid adolescent rats are capable of fear conditioning and fear extinction, as well as extinction retention. Our results also demonstrate that both types of trauma induced a deficit in the retention of fear extinction in adulthood, a hallmark of PTSD, but not after early or mid adolescence trauma, suggesting that adolescence might convey resilience to SPS and SPSp traumas. Across all three life stages, the effects of SPS exposure and a novel predation trauma model, SPSp, had similar effects on behavior suggesting that trauma type did not affect the likelihood of developing PTSD-like symptoms, and that SPSp is a predation-based trauma model worth exploring

Single prolonged stress: toward an animal model of posttraumatic stress disorder

Although selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in decreasing posttraumatic stress disorder (PTSD) symptoms, a subgroup of PTSD patients remain chronically symptomatic and maintain conditioned fear responses to traumatic stimuli. In this context, the establishment of an appropriate animal model of PTSD is necessary to promote better understanding of the mechanisms of the disorder and to facilitate the development of more effective therapeutic alternatives to SSRIs. Although no single widely accepted animal model of PTSD has been established to date, the single prolonged stress (SPS) animal model has been partially validated as a model for PTSD. SPS rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety-like behavior and glucocorticoid negative feedback, and they exhibit the expected therapeutic response to paroxetine on enhanced fear memory. In addition, SPS rats exhibit enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which is alleviated by D -cycloserine. The enhanced consolidation and impaired extinction of fear memory found in SPS rats suggests that this model has additional value because recent studies of PTSD indicate that memory abnormalities are a central feature. In this study, we summarize the behavioral and pathophysiological PTSD-like symptoms in SPS, focusing on memory abnormalities, and evaluate the validity of SPS as an animal model of PTSD. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64546/1/20629_ftp.pd

Psychophysiologic responses to the Rorschach in PTSD patients, noncombat and combat controls

While psychophysiologic studies of posttraumatic stress disorder (PTSD) have investigated the effects of trauma-related stimuli on arousal, none have explored the development of intrusive imagery and affect states in the absence of such specific cues. The present study compares autonomic arousal during PTSD-related Rorschach responses in PTSD veterans vs. combat controls and noncombat controls. It was found that Rorschach responses containing traumatic content were found only in the PTSD group, and that these responses showed elevations in skin conductance (SC) and heart rate (HR). Our data also suggest that PTSD patients are more easily hyperaroused, especially under conditions of experienced stress and helplessness. Finally, combat control subjects exhibited lower baseline SC and HR than their counterparts, as well as decelerated HR during trauma- and stress-related Rorschach responses, suggesting a physiologic resilience in this group. Depression and Anxiety 8:112–120, 1998. © 1998 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35216/1/3_ftp.pd

Cognitive Flexibility Training Improves Extinction Retention Memory and Enhances Cortical Dopamine With and Without Traumatic Stress Exposure

Stress exposure can cause lasting changes in cognition, but certain individual traits, such as cognitive flexibility, have been shown to reduce the degree, duration, or severity of cognitive changes following stress. Both stress and cognitive flexibility training affect decision making by modulating monoamine signaling. Here, we test the role cognitive flexibility training, and high vs. low cognitive flexibility at the individual level, in attenuating stress-induced changes in memory and monoamine levels using the single prolonged stress (SPS) rodent model of traumatic stress in male Sprague-Dawley rats. Exposure to SPS can heighten fear responses to conditioned cues (i.e., freezing) after a fear association has been extinguished, referred to as a deficit in extinction retention. This deficit is thought to reflect an impairment in context processing that is characteristic of posttraumatic stress disorder (PTSD). During a cognitive flexibility training we assessed individual variability in cognitive skills and conditioned rats to discriminately use cues in their environment. We found that cognitive flexibility training, alone or followed by SPS exposure, accelerated extinction learning and decreased fear responses over time during extinction retention testing, compared with rats not given cognitive flexibility training. These findings suggest that cognitive flexibility training may improve context processing in individuals with and without traumatic stress exposure. Individual performance during the reversal phase of the cognitive flexibility training predicted subsequent context processing; individuals with high reversal performance exhibited a faster decrease in freezing responses during extinction retention testing. Thus, high reversal performance predicted enhanced retention of extinction learning over time and suggests that cognitive flexibility training may be a strategy to promote context processing. In a brain region vital for maintaining cognitive flexibility and fear suppression, the prelimbic cortex (PLC), cognitive flexibility training also lastingly enhanced dopamine (DA) and norepinephrine (NE) levels, in animals with and without traumatic stress exposure. In contrast, cognitive flexibility training prior to traumatic stress exposure decreased levels of DA and its metabolites in the striatum, a region mediating reflexive decision making. Overall, our results suggest that cognitive flexibility training can provide lasting benefits by enhancing extinction retention, a hallmark cognitive effect of trauma, and prelimbic DA, which can maintain flexibility across changing contexts