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1.  Stress and Brain Atrophy 
Studies in animals showed that stress is associated with changes in hippocampal function and structure, an effect mediated through decreased neurogenesis, increased glucocorticoids, and/or decreased brain derived neurotrophic factor. Antidepressants and some anticonvulsants block the effects of stress and/or promote neurogenesis in animal studies. Patients with posttraumatic stress disorder (PTSD) have been shown to have smaller hippocampal volume on magnetic resonance imaging and deficits in hippocampal-based memory. Symptom activation is associated with decreased anterior cingulate and medial prefrontal function, which is proposed as the neural correlate of a failure of extinction seen in these patients. Treatment with antidepressants and phenytoin reverse hippocampal volume reduction and memory deficits in PTSD patients, suggesting that these agents may promote neurogenesis in humans.
PMCID: PMC3269810  PMID: 17073653
2.  Traumatic stress: effects on the brain 
Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Traumatic stress can be associated with lasting changes in these brain areas. Traumatic stress is associated with increased cortisol and norepinephrine responses to subsequent stressors. Antidepressants have effets on the hippocampus that counteract the effects of stress. Findings from animal studies have been extended to patients with post-traumatic stress disorder (PTSD) showing smaller hippocampal and anterior cingulate volumes, increased amygdala function, and decreased medial prefrontal/anterior cingulate function. In addition, patients with PTSD show increased cortisol and norepinephrine responses to stress. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, as well as promotion of memory and increased hippocampal volume in PTSD.
PMCID: PMC3181836  PMID: 17290802
positron emission tomography; depression; stress; post-traumatic stress disorder
3.  Neural Correlates of Exposure to Traumatic Pictures and Sound in Vietnam Combat Veterans with and without Posttraumatic Stress Disorder: A Positron Emission Tomography Study 
Biological psychiatry  1999;45(7):806-816.
Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD.
Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD.
Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas.
The findings suggest that functional alterations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.
PMCID: PMC3233761  PMID: 10202567
Positron emission tomography; memory; postttraumatic stress disorder; frontal cortex; cingulate; function
4.  The Relationship Between Cognitive and Brain Changes in Posttraumatic Stress Disorder 
Preclinical studies show that stress is associated with changes in structure of the hippocampus, a brain area that plays a critical role in memory, inhibition of neurogenesis, and memory deficits. Studies in animals showed that both serotonin reuptake inhibitors (SSRIs) and the epilepsy medication phenytoin (dilantin) block the effects of stress on the hippocampus. Imaging studies in posttraumatic stress disorder (PTSD) have found smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI) in patients with PTSD related to both combat and childhood abuse. These patients were also found to have deficits in memory on neuropsychological testing. Functional imaging studies using positron emission tomography (PET) found decreased hippocampal activation with memory tasks. In an initial study, we found that a year of treatment with paroxetine led to a 5% increase in hippocampal volume and a 35% increase in memory function. A second study showed that phenytoin was efficacious for symptoms of PTSD and led to a significant 6% increase in both right hippocampal and right whole brain volume, with no significant change in memory. These studies suggest that medications may counteract the effects of stress on the brain in patients with PTSD.
PMCID: PMC3233753  PMID: 16891564
PTSD; hippocampus; pharmacotherapy; stress; neurogenesis; paroxetine; depression
5.  Neural Correlates of Memories of Childhood Sexual Abuse in Women With and Without Posttraumatic Stress Disorder 
The American journal of psychiatry  1999;156(11):1787-1795.
Childhood sexual abuse is very common in our society, but little is known about the long-term effects of abuse on brain function. The purpose of this study was to measure neural correlates of memories of childhood abuse in sexually abused women with and without the diagnosis of posttraumatic stress disorder (PTSD).
Twenty-two women with a history of childhood sexual abuse underwent injection of [15O]H2O, followed by positron emission tomography imaging of the brain while they listened to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic and neutral scripts was compared for sexually abused women with and without PTSD.
Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri—areas 6 and 9), posterior cingulate (area 31), and motor cortex in sexually abused women with PTSD than in sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus (area 25), and a failure of activation in anterior cingulate (area 32). There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supramarginal gyrus, and visual association cortex in women with PTSD relative to women without PTSD.
These findings implicate dysfunction of medial prefrontal cortex (subcallosal gyrus and anterior cingulate), hippocampus, and visual association cortex in pathological memories of childhood abuse in women with PTSD. Increased activation in posterior cingulate and motor cortex was seen in women with PTSD. Dysfunction in these brain areas may underlie PTSD symptoms provoked by traumatic reminders in subjects with PTSD.
PMCID: PMC3233772  PMID: 10553744
6.  Decreased Premotor Cortex Volume in Victims of Urban Violence with Posttraumatic Stress Disorder 
PLoS ONE  2012;7(8):e42560.
Studies addressing posttraumatic stress disorder (PTSD) have demonstrated that PTSD patients exhibit structural abnormalities in brain regions that relate to stress regulation and fear responses, such as the hippocampus, amygdala, anterior cingulate cortex, and ventromedial prefrontal cortex. Premotor cortical areas are involved in preparing to respond to a threatening situation and in representing the peripersonal space. Urban violence is an important and pervasive cause of human suffering, especially in large urban centers in the developing world. Violent events, such as armed robbery, are very frequent in certain cities, and these episodes increase the risk of PTSD. Assaultive trauma is characterized by forceful invasion of the peripersonal space; therefore, could this traumatic event be associated with structural alteration of premotor areas in PTSD?
Methodology/Principal Findings
Structural magnetic resonance imaging scans were acquired from a sample of individuals that had been exposed to urban violence. This sample consisted of 16 PTSD patients and 16 age- and gender-matched controls. Psychometric questionnaires differentiated PTSD patients from trauma-exposed controls with regard to PTSD symptoms, affective, and resilience predispositions. Voxel-based morphometric analysis revealed that, compared with controls, the PTSD patients presented significant reductions in gray matter volume in the ventral premotor cortex and in the pregenual anterior cingulate cortex.
Volume reduction in the premotor cortex that is observed in victims of urban violence with PTSD may be associated with a disruption in the dynamical modulation of the safe space around the body. The finding that PTSD patients presented a smaller volume of pregenual anterior cingulate cortex is consistent with the results of other PTSD neuroimaging studies that investigated different types of traumatic events.
PMCID: PMC3432060  PMID: 22952599
7.  PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample☆ 
NeuroImage : Clinical  2014;7:19-27.
Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment.
Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded.
Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex.
We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions.
•Greater PTSD symptoms associated with increased amygdala activation to emotional stimuli•PTSD symptoms associated with greater top down attention response in task and emotion conditions•PTSD symptoms were associated with slower reaction times.•Increased top down attention recruitment may compensate for heightened emotional responses.
PMCID: PMC4299952  PMID: 25610763
Post-traumatic stress disorder; Emotion attention; Amygdala; Top down attention
8.  Structural alterations in lateral prefrontal, parietal and posterior midline regions of men with chronic posttraumatic stress disorder 
So far, the neural network associated with posttraumatic stress disorder (PTSD) has been suggested to mainly involve the amygdala, hippocampus and medial prefrontal cortex. However, increasing evidence indicates that cortical regions extending beyond this network might also be implicated in the pathophysiology of PTSD. We aimed to investigate PTSD-related structural alterations in some of these regions.
We enrolled highly traumatized refugees with and without (traumatized controls) PTSD and non-traumatized controls in the study. To increase the validity of our results, we combined an automatic cortical parcellation technique and voxel-based morphometry.
In all, 39 refugees (20 with and 19 without PTSD) and 13 controls participated in the study. Participants were middle-aged men who were free of psychoactive substances and consumed little to no alcohol. Patients with PTSD (and to a lesser extent traumatized controls) showed reduced volumes in the right inferior parietal cortex, the left rostral middle frontal cortex, the bilateral lateral orbitofrontal cortex and the bilateral isthmus of the cingulate. An influence of cumulative traumatic stress on the isthmus of the cingulate and the lateral orbitofrontal cortex indicated that, at least in these regions, structural alterations might be associated with repeated stress experiences. Voxel-based morphometry analyses produced largely consistent results, but because of a poorer signal-to-noise ratio, conventional statistics did not reach significance.
Although we controlled for several important confounding variables (e.g., sex, alcohol abuse) with our particular sample, this might limit the generalizibility of our data. Moreover, high comorbidity of PTSD and major depression hinders a definite separation of these conditions in our findings. Finally, the results concerning the lateral orbitofrontal cortex should be interpreted with caution, as magnetic resonance imaging acquisition in this region is affected by a general signal loss.
Our results indicate that lateral prefrontal, parietal and posterior midline structures are implicated in the pathophysiology of PTSD. As these regions are particularly involved in episodic memory, emotional processing and executive control, this might have important implications for the understanding of PTSD symptoms.
PMCID: PMC3080513  PMID: 21118656
9.  Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD 
Journal of psychiatric research  2010;45(5):660-669.
Neurobiological models of posttraumatic stress disorder (PTSD) suggest that altered activity in the medial temporal lobes (MTL) during encoding of traumatic memories contribute to the development and maintenance of the disorder. However, there is little direct evidence in the PTSD literature to support these models. The goal of the present study was to examine MTL activity during trauma encoding in combat veterans using the subsequent memory paradigm. Fifteen combat veterans diagnosed with PTSD and 14 trauma-exposed control participants viewed trauma-related and neutral pictures while undergoing event-related fMRI. Participants returned one week after scanning for a recognition memory test. Region-of-interest (ROI) and voxel-wise whole brain analyses were conducted to examine the neural correlates of successful memory encoding. Patients with PTSD showed greater false alarm rates for novel lures than the trauma-exposed control group, suggesting reliance on gist-based representations in lieu of encoding contextual details. Imaging analyses revealed reduced activity in the amygdala and hippocampus in PTSD patients during successful encoding of trauma-related stimuli. Reduction in left hippocampal activity was associated with high arousal symptoms on the Clinician-Administered PTSD Scale (CAPS). The behavioral false alarm rate for traumatic stimuli co-varied with activity in the bilateral precuneus. These results support neurobiological theories positing reduced hippocampal activity under conditions of high stress and arousal. Reduction in MTL activity for successfully encoded stimuli and increased precuneus activity may underlie reduced stimulus specific encoding and greater gist memory in patients with PTSD, leading to maintenance of the disorder.
PMCID: PMC3081889  PMID: 21047644
fMRI; gist; contextual memory; military; subsequent memory paradigm; precuneus
10.  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
11.  Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder 
Biological psychiatry  2009;66(12):1075-1082.
A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC).
Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response.
SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing.
These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.
PMCID: PMC2787650  PMID: 19748076
conditioning, classical; stress disorders, post-traumatic; magnetic resonance imaging; amygdala; hippocampus; prefrontal cortex
12.  Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder 
Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure.
Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD.
Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC.
Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non–combat related PTSD.
These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD.
PMCID: PMC3380095  PMID: 22313617
13.  Structural brain abnormalities common to posttraumatic stress disorder and depression 
Posttraumatic stress disorder (PTSD) and major depression are reliably associated with reductions in brain volume in markedly similar areas. To our knowledge, no volumetric studies have directly contrasted these conditions. We investigated which, if any, grey matter reductions would be uniquely associated with each disorder. We also investigated more subtle independent effects: specifically, correlations between brain volume and self-report measures of psychopathology.
We obtained structural magnetic resonance imaging scans from participants with PTSD, major depression and healthy controls exposed to trauma. Participants completed standardized self-report measures of anxiety and depression. We used voxel-based morphometry, applying the DARTEL algorithm within SPM5 to identify associated volumetric changes.
We enrolled 24 patients with PTSD, 29 with major depression and 29 controls in our study. The clinical groups had regions of markedly smaller volume compared with the control group, particularly in prefrontal areas, but did not differ from each other. Greater self-reported anxiety was inversely related to volume in several areas, particularly the inferior temporal cortex, among patients with PTSD, but was associated with some volume increases in patients with major depression. Greater self-reported depression showed similar but weaker effects, being inversely related to brain volume in patients with PTSD but positively related to volume in the cuneus and precuneus of those with major depression.
To maintain the representativeness of the sample, patients with PTSD were not excluded if they had typical comorbid conditions, such as depression. Patients were not all medication-free, but we controlled for group differences in antidepressant use in the analyses.
We identified commonalities in areas of brain volume in patients with PTSD and those with major depression, suggesting that existing findings concerning reductions in prefrontal areas in particular may not be specific to PTSD but rather related to features of the disorder that are shared with other conditions, such as depression. More subtle differences between patients with PTSD and those with major depression were represented by distinct structural correlates of self-reported anxiety and depression.
PMCID: PMC3120894  PMID: 21418787
14.  Patterns Of Altered Cortical Perfusion And Diminished Subcortical Integrity In Posttraumatic Stress Disorder: A MRI Study 
NeuroImage  2010;54S1:S62-S68.
Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010; 67(3):296–303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion and diffusion MRI together may provide a signature for a PTSD marker.
PMCID: PMC2945438  PMID: 20483375
15.  Altered Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes in Posttraumatic Stress Disorder 
Neuropsychopharmacology  2013;39(2):361-369.
The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD.
PMCID: PMC3870774  PMID: 23929546
basolateral amygdala; biological psychiatry; centromedial amygdala; fMRI; imaging; clinical or preclinical; mood/anxiety/stress disorders; neuroanatomy; PTSD; resting state; PTSD; resting state; amygdala; basolateral amygdala; centromedial amygdala; functional connectivity
16.  Exaggerated and Disconnected Insular-Amygdalar BOLD Response to Threat-Related Emotional Faces in Women with Intimate-Partner Violence PTSD 
Biological psychiatry  2010;68(5):433-441.
Imaging studies of posttraumatic stress disorder (PTSD) have identified functional differences in the amygdala and anterior cingulate (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. Intimate-partner violence (IPV) is one of the most common causes of PTSD among women. This study examined the hypothesis that women with IPV-PTSD show a dysregulation of this limbic sensory system while processing threat-related emotional faces.
12 women with IPV-PTSD and 12 non-traumatized comparison women underwent BOLD functional magnetic resonance imaging while completing an emotional-face matching task.
IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdalae, and ACC while matching to fearful vs. happy target faces. A similar pattern of activation differences was also observed for angry vs. happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dACC/mPFC activation and decreased vACC activation when matching to a male vs. a female target, and the extent of increased dACC activation correlated positively with hyperarousal symptoms.
Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e. male gender, which relate to past trauma.
PMCID: PMC2921473  PMID: 20573339
posttraumatic stress; anxiety; emotion; insula; amygdala; anterior cingulate
17.  Sleep disturbances and PTSD: a perpetual circle? 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.19142.
Sleep facilitates the consolidation of fear extinction memory. Nightmares and insomnia are hallmark symptoms of posttraumatic stress disorder (PTSD), possibly interfering with fear extinction and compromising recovery. A perpetual circle may develop when sleep disturbances increase the risk for PTSD and vice versa. To date, therapeutic options for alleviating sleep disturbances in PTSD are limited.
We conducted three studies to examine the relationship between sleep and posttraumatic symptoms: (1) a prospective longitudinal cohort study examining the impact of pre-deployment insomnia symptoms and nightmares on the development of PTSD; (2) a cross-sectional study examining subjective sleep measures, polysomnography, endocrinological parameters, and memory in veterans with PTSD, veterans without PTSD, and healthy controls (HCs); (3) a randomized controlled trial (RCT) (n=14) comparing the effect of prazosin and placebo on sleep disturbances in veterans with PTSD. In addition to these studies, we systematically reviewed the literature on treatment options for sleep disturbances in PTSD.
Pre-deployment nightmares predicted PTSD symptoms at 6 months post-deployment; however, insomnia symptoms did not. Furthermore, in patients with PTSD, a correlation between the apnea index and PTSD severity was observed, while obstructive sleep apnea syndrome was not more prevalent. We observed a significant increase in awakenings during sleep in patients with PTSD, which were positively correlated with adrenocorticotropic hormone (ACTH) levels, negatively correlated with growth hormone (GH) secretion, and the subjective perception of sleep depth. Also, heart rate was significantly increased in PTSD patients. Interestingly, plasma levels of GH during the night were decreased in PTSD. Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD. In our RCT, prazosin was not associated with improvement of any subjective and objective sleep parameters. Only a few RCTs have been published. They show promising results for atypical antipsychotics and prazosin, the latter especially on nightmare reduction.
Disturbed sleep due to nightmares increases the risk for PTSD. PTSD in turn leads to increased sleep fragmentation, decreased GH secretion, and frequent nightmares, which may again compromise fear extinction, synaptic plasticity, and recovery. This suggests that disturbed sleep is a precipitating and perpetuating factor in PTSD symptomatology, creating a perpetual circle. This dissertation suggests that activity of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system (SNS) is involved in disturbed sleep in patients with PTSD.
PMCID: PMC3464455  PMID: 23050070
PTSD; sleep; nightmares; polysomnography; cortisol; growth hormone; memory; noradrenalin
18.  Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia 
The American Journal of Psychiatry  2007;164(10):1476-1488.
The study of human anxiety disorders has benefited greatly from functional neuroimaging approaches. Individual studies, however, vary greatly in their findings. The authors searched for common and disorder-specific functional neurobiological deficits in several anxiety disorders. The authors also compared these deficits to the neural systems engaged during anticipatory anxiety in healthy subjects.
Functional magnetic resonance imaging and positron emission tomography studies of posttraumatic stress disorder (PTSD), social anxiety disorder, specific phobia, and fear conditioning in healthy individuals were compared by quantitative meta-analysis. Included studies compared negative emotional processing to baseline, neutral, or positive emotion conditions.
Patients with any of the three disorders consistently showed greater activity than matched comparison subjects in the amygdala and insula, structures linked to negative emotional responses. A similar pattern was observed during fear conditioning in healthy subjects. Hyperactivation in the amygdala and insula were, of interest, more frequently observed in social anxiety disorder and specific phobia than in PTSD. By contrast, only patients with PTSD showed hypoactivation in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex—structures linked to the experience and regulation of emotion.
This meta-analysis allowed us to synthesize often disparate findings from individual studies and thereby provide neuroimaging evidence for common brain mechanisms in anxiety disorders and normal fear. Effects unique to PTSD furthermore suggested a mechanism for the emotional dysregulation symptoms in PTSD that extend beyond an exaggerated fear response. Therefore, these findings help refine our understanding of anxiety disorders and their interrelationships.
PMCID: PMC3318959  PMID: 17898336
19.  Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder 
Psychiatry research  2008;162(2):147-157.
Magnetic resonance spectroscopic imaging (MRSI) studies suggest hippocampal abnormalities in posttraumatic stress disorder (PTSD), whereas findings of volume deficits in the hippocampus, as revealed with magnetic resonance imaging (MRI), have been inconsistent. Co-morbidities of PTSD, notably alcohol abuse, may have contributed to the inconsistency. The objective was to determine whether volumetric and metabolic abnormalities in the hippocampus and other brain regions are present in PTSD, independent of alcohol abuse. Four groups of subjects, PTSD patients with (n=28) and without (n=27) alcohol abuse and subjects negative for PTSD with (n=23) and without (n=26) alcohol abuse, were enrolled in this observational MRI and MRSI study of structural and metabolic brain abnormalities in PTSD. PTSD was associated with reduced N-acetylaspartate (NAA) in both the left and right hippocampus, though only when normalized to creatine levels in the absence of significant hippocampal volume reduction. Furthermore, PTSD was associated with reduced NAA in the right anterior cingulate cortex regardless of creatine. NAA appears to be a more sensitive marker for neuronal abnormality in PTSD than brain volume. The alteration in the anterior cingulate cortex in PTSD has implications for fear conditioning and extinction.
PMCID: PMC2443727  PMID: 18201876
Magnetic resonance imaging; Magnetic resonance spectroscopy; Brain metabolites; Brain atrophy; Alcoholism
20.  Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms 
Biological Psychiatry  2010;69(6):541-548.
Decreased hippocampal volume is described in posttraumatic stress disorder (PTSD) and depression. However, it is not known whether it is a risk factor for the development of PTSD or a consequence of PTSD. We sought to determine the effects of PTSD and depressive symptoms on hippocampal volume.
Clinical and magnetic resonance imaging data were collected in a cross sectional study of 244 Gulf War veterans. Measures included lifetime and current Clinician Administered PTSD Scale, Hamilton Depression Scale, Life Stressor Checklist, and Lifetime Drinking History. Magnetic resonance imaging data were acquired with a 1.5-T scanner and analyzed with automated and semiautomated image processing techniques.
Eighty-two veterans had lifetime PTSD, 44 had current PTSD, and 38 had current depression. In the linear regression analysis, current PTSD symptoms (standardized coefficient β = −.25, p = .03) but neither lifetime PTSD symptoms nor current depression were associated with smaller hippocampal volume. Gender, age, history of early life trauma, education, lifetime and current alcohol use, current marijuana use, and treatment with antidepressants did not have independent effects. Participants with chronic PTSD had, on average, a smaller hippocampus compared with those with remitted PTSD.
The finding that current but not lifetime PTSD symptom severity explains hippocampal size raises two possibilities: either a small hippocampus is a risk factor for lack of recovery from PTSD (trait) or PTSD effects on hippocampal volume are reversible once PTSD symptoms remit and the patient recovers (state).
PMCID: PMC3259803  PMID: 21094937
Depression; Gulf War veterans; hippocampus; magnetic resonance imaging; posttraumatic stress disorder
21.  Posttraumatic Stress Disorder: A Theoretical Model of the Hyperarousal Subtype 
Posttraumatic stress disorder (PTSD) is a frequent and distressing mental disorder, about which much remains to be learned. It is a heterogeneous disorder; the hyperarousal subtype (about 70% of occurrences and simply termed PTSD in this paper) is the topic of this article, but the dissociative subtype (about 30% of occurrences and likely involving quite different brain mechanisms) is outside its scope. A theoretical model is presented that integrates neuroscience data on diverse brain regions known to be involved in PTSD, and extensive psychiatric findings on the disorder. Specifically, the amygdala is a multifunctional brain region that is crucial to PTSD, and processes peritraumatic hyperarousal on grounded cognition principles to produce hyperarousal symptoms. Amygdala activity also modulates hippocampal function, which is supported by a large body of evidence, and likewise amygdala activity modulates several brainstem regions, visual cortex, rostral anterior cingulate cortex (rACC), and medial orbitofrontal cortex (mOFC), to produce diverse startle, visual, memory, numbing, anger, and recklessness symptoms. Additional brain regions process other aspects of peritraumatic responses to produce further symptoms. These contentions are supported by neuroimaging, neuropsychological, neuroanatomical, physiological, cognitive, and behavioral evidence. Collectively, the model offers an account of how responses at the time of trauma are transformed into an extensive array of the 20 PTSD symptoms that are specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition. It elucidates the neural mechanisms of a specific form of psychopathology, and accords with the Research Domain Criteria framework.
PMCID: PMC3983492  PMID: 24772094
PTSD; fear; amygdala; insula; ACC; RDoC
22.  Voxel-Based Morphometric Gray Matter Correlates of Posttraumatic Stress Disorder 
Journal of anxiety disorders  2013;27(4):413-419.
Posttraumatic stress disorder (PTSD) is associated with functional abnormalities within aneurocircuitry that includes the hippocampus, amygdala, and medial prefrontal cortex. Evidence of structural abnormalities within these regions, and their association with PTSD severity and symptom burden is, however, sparse. The present study evaluated the relation between indices of gray matter volume and PTSD symptom severity using voxel-based morphometry. Fifteen individuals meeting DSM-IV criteria for PTSDcompleted the Clinician Administered PTSD Scale and underwent structural magnetic resonance imaging. Greater PTSD severity and avoidance/numbing were correlated withincreasedgray matter volume of the right amygdala-hippocampal complex. Greater hyper-arousal was associated with reducedgray matter volume in the left superior medial frontal gyrus. Findings are consistent with current neurocircuitry models of PTSD, which posit that the disorder is associated with structural and functional variance within this distributed network.
PMCID: PMC3782384  PMID: 23746489
magnetic resonance imaging; chronic post-traumatic stress disorder; prefrontal cortex; hippocampus; amygdala
23.  Early Altered Resting-State Functional Connectivity Predicts the Severity of Post-Traumatic Stress Disorder Symptoms in Acutely Traumatized Subjects 
PLoS ONE  2012;7(10):e46833.
The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject’s Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.
PMCID: PMC3462752  PMID: 23056477
24.  Scalp Acupuncture Treatment Protocol for Anxiety Disorders: A Case Report 
Anxiety disorders are among the most common psychiatric illnesses, and acupuncture treatment is widely accepted in the clinic without the side effects seen from various medications. We designed a scalp acupuncture treatment protocol by locating two new stimulation areas. The area one is between Yintang (M-HN-3) and Shangxing (DU-23) and Shenting (DU-24), and the area two is between Taiyang (M-HN-9) and Tianchong (GB-9) and Shuaigu (GB-8). By stimulating these two areas with high-frequency continuous electric waves, remarkable immediate and long-term effects for anxiety disorders have been observed in our practice. The first case was a 70-year-old male with general anxiety disorder (GAD) and panic attacks at night. The scalp acupuncture treatment protocol was applied with electric stimulation for 45 minutes once every week. After four sessions of acupuncture treatments, the patient reported that he did not have panic attacks at night and he had no feelings of anxiety during the day. Follow-up 4 weeks later confirmed that he did not have any episodes of panic attacks and he had no anxiety during the day since his last acupuncture treatment. The second case was a 35-year-old male who was diagnosed with posttraumatic stress disorder (PTSD) with a history of providing frontline trauma care as a Combat Medics from the Iraq combat field. He also had 21 broken bones and multiple concussions from his time in the battlefield. He had symptoms of severe anxiety, insomnia, nightmares with flashbacks, irritability, and bad temper. He also had chest pain, back pain, and joint pain due to injuries. The above treatment protocol was performed with 30 minutes of electric stimulation each time in combination with body acupuncture for pain management. After weekly acupuncture treatment for the first two visits, the patient reported that he felt less anxious and that his sleep was getting better with fewer nightmares. After six sessions of acupuncture treatments, the patient completely recovered from PTSD, went back to work, and now lives a healthy and happy family life. The above cases and clinical observation show that the scalp acupuncture treatment protocol with electric stimulation has a significant clinic outcome for GAD, panic disorder and PTSD. The possible mechanism of action of scalp acupuncture on anxiety disorder may be related to overlapping modulatory effects on the cortical structures (orbitofrontal cortex [OFC]) and medial prefrontal cortex [mPFC]) and subcortical/limbic regions (amygdala and hippocampus), and biochemical effect of acupuncture through immunohistochemistry (norepinephrine, serotonin) performed directly to the brain tissue for anxiety disorders.
PMCID: PMC4104565  PMID: 25105075
Anxiety disorders; scalp acupuncture; electric stimulation
25.  In Search of the Trauma Memory: A Meta-Analysis of Functional Neuroimaging Studies of Symptom Provocation in Posttraumatic Stress Disorder (PTSD) 
PLoS ONE  2013;8(3):e58150.
Notwithstanding some discrepancy between results from neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD), there is broad agreement as to the neural circuit underlying this disorder. It is thought to be characterized by an exaggerated amygdalar and decreased medial prefrontal activation to which the elevated anxiety state and concomitant inadequate emotional regulation are attributed. However, the proposed circuit falls short of accounting for the main symptom, unique among anxiety disorders to PTSD, namely, reexperiencing the precipitating event in the form of recurrent, distressing images and recollections. Owing to the technical demands, neuroimaging studies are usually carried out with small sample sizes. A meta-analysis of their findings is more likely to cast light on the involved cortical areas. Coordinate-based meta-analyses employing ES-SDM (Effect Size Signed Differential Mapping) were carried out on 19 studies with 274 PTSD patients. Thirteen of the studies included 145 trauma-exposed control participants. Comparisons between reactions to trauma-related stimuli and a control condition and group comparison of reactions to the trauma-related stimuli were submitted to meta-analysis. Compared to controls and the neutral condition, PTSD patients showed significant activation of the mid-line retrosplenial cortex and precuneus in response to trauma-related stimuli. These midline areas have been implicated in self-referential processing and salient autobiographical memory. PTSD patients also evidenced hyperactivation of the pregenual/anterior cingulate gyrus and bilateral amygdala to trauma-relevant, compared to neutral, stimuli. Patients showed significantly less activation than controls in sensory association areas such as the bilateral temporal gyri and extrastriate area which may indicate that the patients’ attention was diverted from the presented stimuli by being focused on the elicited trauma memory. Being involved in associative learning and priming, the retrosplenial cortex may have an important function in relation to trauma memory, in particular, the intrusive reexperiencing of the traumatic event.
PMCID: PMC3607590  PMID: 23536785

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