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1.  A Selective Neurokinin-1 Receptor Antagonist in Chronic PTSD: a Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial 
The substance P-neurokinin-1 receptor (SP-NK1R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK1R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥ 50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8 weeks. The primary endpoint was mean change from baseline to endpoint in total CAPS score. Response rate (≥ 50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 vs. 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK1R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. ( Identifier: NCT 00211861, NCT 00383786)
PMCID: PMC3478767  PMID: 21194898
NK1; substance P; PTSD; clinical trial; randomized
2.  Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression 
Journal of affective disorders  2006;101(1-3):99-111.
Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression.
Subjects with (N =18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants.
Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory.
Limitations include a small sample size and variety of antidepressants used.
These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.
PMCID: PMC3233752  PMID: 17182108
PET; Memory; Depression; Cingulate; Frontal cortex
3.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder 
Psychological medicine  2005;35(6):791-806.
In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).
Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.
Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
PMCID: PMC3233760  PMID: 15997600
4.  Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder 
Biological psychiatry  2003;54(7):693-702.
Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD.
Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging.
Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume.
These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.
PMCID: PMC3233762  PMID: 14512209
Posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors
5.  Regional Brain Metabolic Correlates of α-Methylparatyrosine–Induced Depressive Symptoms 
We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion–induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using α-methylparatyrosine (AMPT).
To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.
Design, Setting, and Participants
Randomized, controlled, double-blind trial in which 18 patients recruited in 1997–2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.
After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.
Main Outcome Measures
Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.
AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P=.002) and dorsolateral prefrontal (P=.03) cortex and thalamus (P=.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.
Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.
PMCID: PMC3233764  PMID: 12813118
6.  Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression 
The American journal of psychiatry  2002;159(12):2072-2080.
Smaller hippocampal volume has been reported only in some but not all studies of unipolar major depressive disorder. Severe stress early in life has also been associated with smaller hippocampal volume and with persistent changes in the hypothalamic-pituitary-adrenal axis. However, prior hippocampal morphometric studies in depressed patients have neither reported nor controlled for a history of early childhood trauma. In this study, the volumes of the hippocampus and of control brain regions were measured in depressed women with and without childhood abuse and in healthy nonabused comparison subjects.
Study participants were 32 women with current unipolar major depressive disorder—21 with a history of prepubertal physical and/or sexual abuse and 11 without a history of prepubertal abuse—and 14 healthy nonabused female volunteers. The volumes of the whole hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans by a single rater who was blind to the subjects’ diagnoses.
The depressed subjects with childhood abuse had an 18% smaller mean left hippocampal volume than the nonabused depressed subjects and a 15% smaller mean left hippocampal volume than the healthy subjects. Right hippocampal volume was similar across the three groups. The right and left hippocampal volumes in the depressed women without abuse were similar to those in the healthy subjects.
A smaller hippocampal volume in adult women with major depressive disorder was observed exclusively in those who had a history of severe and prolonged physical and/or sexual abuse in childhood. An unreported history of childhood abuse in depressed subjects could in part explain the inconsistencies in hippocampal volume findings in prior studies in major depressive disorder.
PMCID: PMC3230324  PMID: 12450959
7.  Alterations in Stress Reactivity After Long-Term Treatment with Paroxetine in Women with Posttraumatic Stress Disorder 
Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis
8.  Habenula volume in post-traumatic stress disorder measured with high-resolution MRI 
The habenula plays an important role in regulating behavioral responses to stress and shows increased cerebral blood flow and decreased gray matter volume in patients with mood disorders. Here, we compare the volume of the habenula in unmedicated patients with post-traumatic stress disorder (PTSD) and healthy controls (HC) using MRI.
High-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume.
Our data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.
PMCID: PMC3384261  PMID: 22738208
9.  Acute Hydrocortisone Treatment Increases Anxiety but Not Fear in Healthy Volunteers: A Fear-Potentiated Startle Study 
Biological psychiatry  2011;69(6):549-555.
The debilitating effects of chronic glucocorticoids excess are well-known, but comparatively little is understood about the role of acute cortisol. Indirect evidence in rodents suggests that acute cortisone could selectively increase some forms of long-duration aversive states, such as “anxiety,” but not relatively similar, briefer aversive states, such as “fear.” However, no prior experimental studies in humans consider the unique effects of cortisol on anxiety and fear, using well-validated methods for eliciting these two similar but dissociable aversive states. The current study examines these effects, as instantiated with short- and long-duration threats.
Healthy volunteers (n = 18) received placebo or a low (20 mg) or a high (60 mg) dose of hydrocortisone in a double-blind crossover design. Subjects were exposed repeatedly to three 150-sec duration conditions: no shock; predictable shocks, in which shocks were signaled by a short-duration threat cue; and unpredictable shocks. Aversive states were indexed by acoustic startle. Fear was operationally defined as the increase in startle reactivity during the threat cue in the predictable condition (fear-potentiated startle). Anxiety was operationally defined as the increase in baseline startle from the no shock to the two threat conditions (anxiety-potentiated startle).
Hydrocortisone affected neither baseline nor short-duration, fear-potentiated startle but increased long-duration anxiety-potentiated startle.
These results suggest that hydrocortisone administration in humans selectively increases anxiety but not fear. Possible mechanisms implicated are discussed in light of prior data in rodents. Specifically, hydrocortisone might increase anxiety via sensitization of corticotrophin-releasing hormones in the bed nucleus of the stria terminalis.
PMCID: PMC3116445  PMID: 21277566
Amygdala; anxiety; BNST; corticotropin-releasing hormone (CRH); cortisol; fear; predictability; startle reflex
10.  Exposure to Bioterrorism and Mental Health Response among Staff on Capitol Hill 
The October 2001 anthrax attacks heralded a new era of bioterrorism threat in the U.S. At the time, little systematic data on mental health effects were available to guide authorities' response. For this study, which was conducted 7 months after the anthrax attacks, structured diagnostic interviews were conducted with 137 Capitol Hill staff workers, including 56 who had been directly exposed to areas independently determined to have been contaminated. Postdisaster psychopathology was associated with exposure; of those with positive nasal swab tests, PTSD was diagnosed in 27% and any post-anthrax psychiatric disorder in 55%. Fewer than half of those who were prescribed antibiotics completed the entire course, and only one-fourth had flawless antibiotic adherence. Thirty percent of those not exposed believed they had been exposed; 18% of all study participants had symptoms they suspected were symptoms of anthrax infection, and most of them sought medical care. Extrapolation of raw numbers to large future disasters from proportions with incorrect belief in exposure in this limited study indicates a potential for important public health consequences, to the degree that people alter their healthcare behavior based on incorrect exposure beliefs. Incorrect belief in exposure was associated with being very upset, losing trust in health authorities, having concerns about mortality, taking antibiotics, and being male. Those who incorrectly believe they were exposed may warrant concern and potential interventions as well as those exposed. Treatment adherence and maintenance of trust for public health authorities may be areas of special concern, warranting further study to inform authorities in future disasters involving biological, chemical, and radiological agents.
PMCID: PMC2956562  PMID: 20028246
11.  Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder 
Biological psychiatry  2009;66(1):47-53.
Uncontrollability and unpredictability are key concepts related to re-experiencing, avoidance and hypervigilance symptoms of posttraumatic stress disorder (PTSD). However, little is known about the differential sensitivity of PTSD individuals to unpredictable stressors, relative to either healthy individuals or individuals with other anxiety disorders. This study tested the hypothesis that elevated anxious reactivity, specifically for unpredictable aversive events, is a psychophysiological correlate of PTSD.
Sixteen patients with PTSD (34.5 ± 12.4 years) were compared to 18 patients with GAD (34.0 ± 10.5 years) and 34 healthy controls (30.2 ± 8.5 years). Participants were exposed to three conditions: one in which predictable aversive stimuli were signaled by a cue, a second in which aversive stimuli were administered unpredictably, and a third in which no aversive stimuli were anticipated. Startle magnitude was used to assess anxious responses to the threat cue and to contexts associated with each condition.
PTSD and GAD patients showed normative enhancement of fear to the predictable threat cue, but the PTSD group displayed elevated anxiety during the unpredictable condition compared to participants with GAD and healthy controls.
Anxious reactivity to unpredictable aversive events was heightened in PTSD, but not in GAD and healthy subjects. Prior works also found signs of increased reactivity to unpredictable threat in panic disorder (PD), suggesting that PTSD and PD may involve shared vulnerability. As such, the current results inform understandings of classification, pathophysiology and psychopharmacology of anxiety disorders, generally, and PTSD and panic disorder specifically.
PMCID: PMC2696581  PMID: 19217076
PTSD; generalized anxiety disorder; predictability; threat; fear-potentiated startle
12.  Reward circuitry in resilience to severe trauma: An fMRI investigation of resilient special forces soldiers 
Psychiatry research  2009;172(1):75-77.
Enhanced brain reward function could contribute to resilience to trauma. Reward circuitry in active duty, resilient special forces (SF) soldiers was evaluated using fMRI during a monetary incentive delay task. Findings in this group of resilient individuals revealed unique patterns of activation during expectation of reward in the subgenual prefrontal cortex and nucleus accumbens area; regions pivotal to reward processes.
PMCID: PMC2760852  PMID: 19243926
reward; resilience; trauma; posttraumatic stress disorder
13.  Response to Emotional Expressions in Generalized Social Phobia and Generalized Anxiety Disorder: Evidence for Separate Disorders 
The American journal of psychiatry  2008;165(9):1193-1202.
Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder.
Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N= 17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment.
The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder.
These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.
PMCID: PMC2855133  PMID: 18483136
14.  Low Cortisol, High DHEA, and High Levels of Stimulated TNFα, and IL-6 in Women with PTSD 
Journal of traumatic stress  2008;21(6):530-539.
PTSD has been associated with HPA axis and immune function alterations; however few studies have simultaneously investigated these systems in participants with PTSD. In this study, HPA axis and immune function in 26 women with PTSD with and without major depressive disorder was compared to 24 traumatized controls and also to 21 non-traumatized controls. PTSD was associated with low cortisol and higher levels of DHEA and greater production of TNF-α, and IL-6 compared to traumatized and healthy controls. Women with PTSD and depression exhibited greater production of IL-6 and higher levels of DHEA than those with PTSD but without depression. These findings suggest dysregulated HPA axis and immune function in women with PTSD, and that co-morbid depression may contribute to these abnormalities.
PMCID: PMC2829297  PMID: 19107725
15.  Neural Response to Self- and Other Referential Praise and Criticism in Generalized Social Phobia 
Archives of general psychiatry  2008;65(10):1176-1184.
Generalized social phobia (GSP) is characterized by fear/avoidance of social situations. Previous studies have examined the neural responses in GSP to one class of social stimuli, facial expressions. However, studies have not examined the neural response in GSP to another equally important class of social stimuli, the communication of praise or criticism.
To examine the neural response to receipt of praise or criticism in GSP; specifically, to determine whether patients with GSP show an increased response to the receipt of both praise and criticism and whether self-relevance modulates this relationship.
Case-control study.
Government clinical research institute.
Unmedicated individuals with GSP (n=17) and age-, IQ-, and sex-matched healthy comparison individuals (n=17).
Main Outcome Measure
Blood oxygenation level–dependent signal, as measured via functional magnetic resonance imaging. During functional magnetic resonance imaging scans, individuals read positive (eg, You are beautiful), negative (eg, You are ugly), and neutral (eg, You are human) comments that could be either about the self or about somebody else (eg, He is beautiful).
Hypothesized significant group×valence×referent interactions were observed within regions of the medial prefrontal cortex and bilateral amygdala. In these regions, the patients with GSP showed significantly increased blood oxygenation level–dependent responses, relative to comparison individuals, to negative comments (criticism) referring to themselves. However, in contrast, there were no significant group differences with respect to negative comments referring to others or neutral or positive comments referring to self or others.
These results implicate the medial prefrontal cortex, involved in the representation of the self, together with the amygdala, in the pathophysiology of GSP. Further, findings demonstrate a meaningful effect of psychological context on neural-circuitry hyperactivity in GSP.
PMCID: PMC2785901  PMID: 18838634
Psychopharmacology  2009;204(3):445-455.
Research in rodents and non-human primates implicates the noradrenergic system and hypothalamic-pituitary-adrenal axis in stress, anxiety, and attention to threat. Few studies examine how these two neurochemical systems interact to influence anxiety and attention in humans.
To examine the effects of exogenous yohimbine and hydrocortisone, as well as their combination (Y+H) on panic symptoms and attention to social threat cues.
32 healthy adults underwent a pharmacological challenge in which they were blindly randomized to either: yohimbine, hydrocortisone, Y+H, or placebo. Thirty minutes after drug infusion, attention to threat was measured using the dot probe task, a visual attention task that presents angry, happy and neutral faces and measures the degree of attention allocated towards or away from the emotional faces. Panic and autonomic measures were assessed before and 30 minutes after drug infusion.
There was a significant increase in panic symptoms in the yohimbine and Y+H groups but not in the hydrocortisone or placebo groups. Yohimbine resulted in a greater increase in panic symptoms than Y+H. On the dot probe task, the placebo group exhibited an attention bias to angry faces whereas this bias was absent after yohimbine. When collapsing across groups, increased panic symptoms was associated with less attention to angry faces.
Exogenous hydrocortisone may attenuate noradrenergic-induced panic symptoms. The inverse relationship between panic symptoms and attention to angry faces extends prior research demonstrating attention modulation by stressful conditions.
PMCID: PMC2740930  PMID: 19266185
yohimbine; hydrocortisone; panic symptoms; attention; threat cues; adults
17.  Association between Level of Emotional Intelligence and Severity of Anxiety in Generalized Social Phobia 
Journal of anxiety disorders  2008;22(8):1487-1495.
Generalized Social Phobia (GSP) is characterized by a marked fear of most social situations. It is associated with an anomalous neural response to emotional stimuli, and individuals with the disorder frequently show interpretation bias in social situations. From this it might be suggested that GSP involves difficulty in accurately perceiving, using, understanding and managing emotions. Here we applied the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) to medication-free GSP (n=28) and no pathology (n=21) individuals. Patients with GSP performed within the normal range on the measure however severity of social anxiety significantly correlated with emotional intelligence (EI). Specifically, there was a negative correlation between social anxiety severity and Experiential (basic-level emotional processing) EI. In contrast, there was no significant correlation between social anxiety severity and Strategic (higher-level conscious emotional processing) EI. These results suggest that EI may index emotional processing systems that mitigate the impact of systems causally implicated in GSP.
PMCID: PMC2606035  PMID: 18439799
generalized social phobia; emotional responding; emotional intelligence; MSCEIT
18.  Reduced Posterior Hippocampal Volume in Posttraumatic Stress Disorder 
The Journal of clinical psychiatry  2008;69(7):1087-1091.
Hippocampal volume is reduced in posttraumatic stress disorder (PTSD). In the present study, we sought to determine whether volume loss is homogenously distributed or confined to certain part of the structure.
Twenty-two adult outpatients with PTSD (11 after prolonged prepubertal trauma and 11 after single adult trauma) and 22 matched healthy subjects were scanned at the National Institute of Mental Health using high-resolution 3T magnetic resonance imaging between September 2003 and August 2004. PTSD diagnosis was conferred using the Structured Clinical Interview for DSM-IV. Volumes of whole, anterior, and posterior hippocampus and subiculum were compared between groups.
Total hippocampal volume was lower in patients with PTSD (p = .2), with a significant diagnosis by hippocampal-subregion interaction (p = .2). Post hoc analysis revealed significantly smaller posterior hippocampi in PTSD (p = .006), with no difference in the volumes of anterior hippocampus or subiculum. No volume differences were found between PTSD participants with prolonged childhood abuse compared to single adult trauma exposure.
The posterior hippocampus has been associated with storage, processing, and retrieval of spatiotemporal memories, central to the protective function of fear conditioning. Volume deficit in the posterior hippocampus may indicate malfunction in this faculty, leading to the exaggerated conditioned fear response observed in PTSD.
PMCID: PMC2684983  PMID: 18572983
19.  Response options and expectations of reward in decision-making: The differential roles of dorsal and rostral anterior cingulate cortex 
NeuroImage  2007;35(2):979-988.
This study examined the functional specificity of dorsal anterior cingulate cortex (dACC) and medial prefrontal cortex (mPFC) regarding two elements of decision-making: the number of available decision options and the level of expected reward. Eighteen healthy participants were trained to recognize the reward value associated with several visual stimuli, and then were presented with groups of two, three, or four of these stimuli and asked to select the object associated with the highest reward. BOLD activation in dorsomedial prefrontal cortex (dmFC)/dACC was strongly positively associated with increases in the number of decision options but only weakly associated with increases in the level of expected reward. Activation in rostral anterior cingulate cortex (rACC)/mPFC and amygdala was related to increases in the level of expected reward but not increases in the number of decision options. The current results suggest functional specificity with respect to the roles of dACC/dmFC and rACC/mPFC in decision-making.
PMCID: PMC1868682  PMID: 17292631
decision; FMRI; anterior cingulate; caudate; medial prefrontal cortex; amygdala
20.  Common regions of dorsal anterior cingulate and prefrontal-parietal cortices provide attentional control of distracters varying in emotionality and visibility 
NeuroImage  2007;38(3):631-639.
Top-down attentional control is necessary to ensure successful task performance in the presence of distracters. Lateral prefrontal cortex, parietal cortex and anterior cingulate cortex have been previously implicated in top-down attentional control. However, it is unclear whether these regions are engaged independent of distracter type or whether, as has been suggested for anterior cingulate cortex, different regions provide attentional control over emotional versus other forms of salient distracter. In the current task, subjects viewed targets that were preceded by distracters that varied in both emotionality and visibility. We found that behaviorally, the presence of preceding distracters significantly interfered with target judgment. At the neural level, increases in the emotional and visual saliency of distracters were both associated with increased activity in proximal regions of prefrontal, parietal and cingulate cortex. Moreover, a conjunction analysis indicated considerable overlap in the regions of prefrontal, parietal cortex and anterior cingulate cortex responding to distracters of increased emotionality and visibility.
PMCID: PMC2071928  PMID: 17889565
attention; emotion; visibility; top-down attentional control; fMRI
Indian Journal of Psychiatry  1992;34(4):388-391.
Childhood sexual abuse may have a significant impact on psychological well being in later life. In this report, we describe 5 women who had a variety of psychological symptoms that were related to childhood sexual trauma. These factors were explored during psychotherapy. Persistent feeling of depression, anxiety and problems in socio-sexual functioning, were prominent. Therapy varied from counselling and ventilation, to prolonged dynamically oriented therapy.
PMCID: PMC2982982  PMID: 21776153
Indian Journal of Psychiatry  1989;31(4):293-295.
In a double-blind, prospective study, 29 patients with endogenous depression were treated with electroconvulsive therapy (ECT). The degree of attenuation in Hamilton Rating Scale for Depression scores after the first ECT was compared between ECT responders and non-responders at the end of the treatment course; a significant difference was obtained, indicating higher initial response in ECT responders. It is therefore suggested that response to a single trial ECT may form the basis for prediction of response of endogenous depression to a course of ECT. An operationalization of this concept is proposed, its sensitivity and specificity calculated, and its implications discussed.
PMCID: PMC3172016  PMID: 21927403
Indian Journal of Psychiatry  1988;30(4):395-401.
The pattern of psychiatric syndromes/mental illnesses among the 61 clinical autopsies carried out during the past decade in a psychiatric Institute in South India, is documented. Among the cases autopsied, 26.2% had clinical diagnosis of Schizophrenia, 21.3% dementia, 19.67% manic depressive Psychosis, the rest being cases of neurosis, mental retardation, alcoholism and other Psychosis. The importance of an autopsy study in understanding the pathomorphological basis of mental illness is highlighted.
PMCID: PMC3008796  PMID: 21927343

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