Anterior cingulate cortex gray matter abnormalities in adults with attention deficit hyperactivity disorder: A voxel-based morphometry study

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disease that affects children and persists in 50% of cases into adulthood. Magnetic Resonance Imaging (MRI) studies in children suggest that ADHD is associated with structural abnormalities in the brain. However, very little research has been carried out on adult ADHD. Using high-resolution MRI, we tested the hypothesis that adult ADHD patients exhibit gray and/or white matter volume (GMV, WMV) abnormalities in the prefrontal cortex (PFC), cingulate cortex (CC), hippocampus and amygdala, also evaluating putative associations between volumetric data and symptoms of ADHD. We investigated 20 adult patients with ADHD and 20 age-matched healthy controls. We found significantly smaller GMV in the right and left anterior cingulate cortex (ACC) but no GMV/WMV difference in the PFC, hippocampus and amygdala. No correlation was found between ADHD behavioral measures and MRI data. Our results might suggest that adults with ADHD exhibit smaller GMV in the ACC, as measured by VBM. Volumetric abnormalities in the brain of adult ADHD patients might be less pronounced than those found in children and adolescents, although the role played by chronic stimulant treatment needs further investigation.     

Alterations of brain activity in fibromyalgia patients

Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients.     

Fronto-limbic function in unaffected offspring at familial risk for bipolar disorder during an emotional working memory paradigm

Evidence from neuroimaging studies indicate that individuals with bipolar disorder (BD) exhibit altered functioning of fronto-limbic systems implicated in voluntary emotion regulation. Few studies, however, have examined the extent to which unaffected youth at familial risk for BD exhibit such alterations. Using an fMRI emotional working memory paradigm, we investigated the functioning of fronto-limbic systems in fifteen healthy bipolar offspring (8–17 years old) with at least one parent diagnosed with BD (HBO), and 16 age-matched healthy control (HC) participants. Neural activity and functional connectivity analyses focused on a priori neural regions supporting emotion processing (amygdala and ventral striatum) and voluntary emotion regulation (ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC)). Relative to HC, HBO exhibited greater right VLPFC (BA47) activation in response to positive emotional distracters and reduced VLPFC modulation of the amygdala to both the positive and negative emotional distracters; there were no group differences in connectivity for the neutral distracters. These findings suggest that alterations in the functioning of fronto-limbic systems implicated in voluntary emotion regulation are present in unaffected bipolar offspring. Future longitudinal studies are needed to determine the extent to which such alterations represent neurodevelopmental markers of risk for future onset of BD.     

Neuroanatomical abnormalities as risk factors for bipolar disorder

OBJECTIVE: Neuroimaging studies show structural brain abnormalities in bipolar patients. Some of the abnormalities may represent biological risk factors conveying vulnerability for the disease. This paper aims to identify neuroanatomical risk factors for bipolar disorder (BD). METHODS: We reviewed magnetic resonance imaging (MRI) findings in populations in which the effects of the disease or treatment are minimal or where the chances of finding genetically coded risk factors shared within the families are increased. Such populations include unaffected relatives of bipolar patients, first-episode patients, children or adolescents with BD and patients with familial BD. RESULTS: MEDLINE search revealed 30 relevant scientific papers. Abnormalities in the volume of the striatum, left hemispheric white matter, thalamus and anterior cingulate as well as quantitative MRI signal hyperintensities were identified already in unaffected relatives of bipolar patients. Subjects in the early stages of the disease showed volume changes of the ventricles, white matter, caudate, putamen, amygdala, hippocampus and the subgenual prefrontal cortex. Reduction in the subgenual prefrontal cortex volume was replicated in three of four studies in patients with familial BD. CONCLUSIONS: Possible candidates for neuroanatomical risk factors for BD are volumetric abnormalities of the subgenual prefrontal cortex, striatum, white matter, and probably also the hippocampus and amygdala. Qualitative finding of white matter hyperintensities was already utilized as an endophenotype.     

Neuroimaging of emotional brain circuitry in bipolar disorder

Abnormalities in the regulation of emotion and motivational behavior are core features of bipolar disorder (BD) implicating the brain structures that subserve these functions. Converging neuroimaging evidence supports the involvement in BD of a neural system comprised of ventral prefrontal cortex, amygdala, and ventral striatum. Neuroimaging studies demonstrate abnormalities in both the structure and function of these brain regions. Findings in amygdala and ventral striatum in adolescents with BD suggest a neurodevelopmental trajectory for the appearance of regional abnormalities in this neural system. Preliminary studies suggest that mood-stabilizing medications may provide beneficial effects for the structure and functioning of this circuitry. New research directions, including those that integrate genetic studies with neuroimaging research, may provide important insights into the pathophysiologic mechanisms contributing to BD, and point to new strategies for its detection and treatment.     

Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia: Preliminary studies

1. 1. Studies of first-degree relatives of persons with schizophrenia provide an opportunity to characterize risk factors for the development of this illness. In this report the authors will provide preliminary data from an ongoing study of neurobiological alterations in the offspring of schizophrenia patients.

2. 2. A series of offspring of schizophrenic patients (OS) were compared with age and sex matched healthy controls (HC) without psychiatric history in first degree relatives on psychiatric, volumetric Magnetic Resonance Imaging (MRI) of whole brain and proton Magnetic Resonance Spectroscopy (¹H MRS) evaluations of the ventral prefrontal cortex.

3. 3. Compared with HC group, high risk subjects had reduced left amygdala volume, enlarged third ventricular volume, and smaller overall brain volume. 4. ¹H MRS studies showed a trend for decreased NAA/choline ratios in the anterior cingulate region in the OS group as compared to HC subjects.

4. Follow-up studies of these subjects are needed to confirm the predictive value of these measures for future emergence of schizophrenia in subjects at risk for this illness.

     

State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge.

BACKGROUND: Even in remission, patients with bipolar disorder (BD) remain sensitive to external stressors that can trigger new episodes. Imitating such stressors by the controlled transient exposure to an emotional stimulus may help to identify brain regions modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were measured using (15)O-water positron emission tomography. RESULTS: Common changes in both groups were increased rCBF in anterior insula and cerebellum and decreased rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal, and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred in both groups, but subjects in remission showed a greater magnitude of change. Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes in remitted and depressed subjects identifies potential sites of disease vulnerability. Unique cingulate and orbitofrontal changes both at baseline and with induced sadness seen in the absence of prefrontal rCBF decreases may identify regional interactions important to the euthymic state in this population.     

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.     

A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects

Périco CA‐M, Duran FLS, Zanetti MV, Santos LC, Murray RM, Scazufca M, Menezes PR, Busatto GF, Schaufelberger MS. A population‐based morphometric MRI study in patients with first‐episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects.
Bipolar Disord 2011: 13: 28–40. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent‐onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first‐onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls. Methods: A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM‐IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel‐based morphometry. Results: The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right‐sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left‐sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p = 0.01, corrected for multiple comparisons). Conclusions: These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.     

Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimized voxel-based morphometry.

BACKGROUND: Structural magnetic resonance imaging (MRI) studies of regions of interest in brain have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder (BD). Voxel-based morphometry (VBM) provides an unbiased survey of the brain, can identify novel brain areas, and validates previously hypothesized regions. We conducted both optimized VBM, comparing MRI gray matter volume, and traditional VBM, comparing MRI gray matter density, in 11 BD subjects and 31 healthy volunteers. To our knowledge, these are the first VBM analyses of BD. METHODS: Segmented MRI gray matter images were normalized into standardized stereotactic space, modulated to allow volumetric analysis (optimized only), smoothed, and compared at the voxel level with statistical parametric mapping. RESULTS: Optimized VBM showed that BD subjects had smaller volume in left ventromedial temporal cortex and bilateral cingulate cortex and larger volume in left insular/frontoparietal operculum cortex and left ventral occipitotemporal cortex. Traditional VBM showed that BD subjects had less gray matter density in left ventromedial temporal cortex and greater gray matter density in left insular/frontoparietal operculum cortex and bilateral thalamic cortex. Exploratory analyses suggest that these abnormalities might differ according to gender. CONCLUSIONS: Bipolar disorder is associated with volumetric and gray matter density changes that involve brain regions hypothesized to influence mood.     

An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder

Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information.     

Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review

The most prevalent mental disorders, anxiety and mood disorders, are associated with both functional and morphological brain changes that commonly involve the ‘fear network’ including the (medial) prefrontal cortex, hippocampus and amygdala. Patients suffering from anxiety disorders and major depressive disorder often show excessive amygdala and reduced prefrontal cortex functioning. It is, however, still unclear whether these brain abnormalities disappear or diminish following effective treatment. This review aims to compare the effects of psychotherapy and pharmacotherapy on functional and morphological brain measures in these disorders. Sixty-three studies were included, 30 investigating psychotherapy effects and 33 investigating pharmacotherapy effects. Despite methodological differences, results suggest a functional normalization of the ‘fear network’. Pharmacotherapy particularly decreases over-activity of limbic structures (bottom-up effect) while psychotherapy tends to increase activity and recruitment of frontal areas (top-down effect), especially the anterior cingulate cortex. Additionally, pharmacotherapy, but not psychotherapy, has been associated with morphological changes, depending on the disorder. These findings suggest that both types of treatments normalize (functional) brain abnormalities each in specific ways.     

Regional cerebral glucose metabolic abnormalities in bipolar II depression.

BACKGROUND: Functional neuroimaging studies of bipolar disorder (BD) performed in conjunction with antidepressant treatment trials generally require that patients remain on mood stabilizers to reduce the risk of inducing mania; yet, it is unknown whether the metabolic abnormalities evident in unmedicated BD depressives remain detectable in patients receiving mood stabilizers. This study investigated whether cerebral metabolic abnormalities previously reported in unmedicated BD subjects are evident in depressed bipolar disorder type II (BD II) subjects receiving lithium or divalproex. METHODS: Using [18F]-fluorodeoxyglucose-positron-emission tomography, cerebral glucose metabolism was compared between 13 depressed BD II subjects on therapeutic doses of lithium or divalproex and 18 healthy control subjects. Regional metabolism was compared between groups in predefined regions of interest. RESULTS: Metabolism was increased in the bilateral amygdala, accumbens area, and anteroventral putamen, left orbitofrontal cortex and right pregenual anterior cingulate cortex in depressives versus control subjects. Post hoc exploratory analysis additionally revealed increased metabolism in left parahippocampal, posterior cingulate, and right anterior insular cortices in depressives versus control subjects. Correlational analyses showed multiple limbic-cortical-striatal interactions in the BD sample not evident in the control sample, permitting sensitive and specific classification of subjects by discriminant analysis. CONCLUSIONS: These results confirm previous reports that bipolar depression is associated with abnormally increased metabolism in the amygdala, ventral striatum, orbitofrontal cortex, anterior cingulate, and anterior insula, and extend these results to bipolar disorder type II depressives on lithium or divalproex. They also implicate an extended functional anatomical network known to modulate visceromotor function in the pathophysiology of BD II depression.     

Rethinking the Use of Neutral Faces as a Baseline in fMRI Neuroimaging Studies of Axis‐I Psychiatric Disorders

Major Axis‐I disorders including major depressive disorder (MDD), bipolar disorder (BD), anxiety disorder, and schizophrenia are associated with a host of aberrations in the way social stimuli are processed. Face perception tasks are often used in neuroimaging research of emotion processing in both healthy and patient populations, and to date, there exists a mounting body of evidence, both behavioral and within the brain, indicating that emotional faces compared to neutral faces are processed abnormally by those with Axis‐I disorders relative to healthy control (HC) groups. The use of neutral faces as a “baseline control condition” is predicated on the assumption that neutral faces are processed in the same way HCs and individuals with major Axis‐I disorders. In this paper, existing fMRI studies examining the way neutral faces are processed in groups with Axis‐I disorders involving socioaffective perception are reviewed. In reviewing available studies, a consistent pattern of results demonstrated that these disorders are associated with abnormal frontolimbic activity in response to neutral faces and in particular within the amygdala and prefrontal regions such as the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) compared to HC groups. Specifically, increased amygdala activation was consistently reported in response to neutral faces in anxiety disorders and schizophrenia. Abnormal medial PFC activity was reported in patients with MDD, and patients with BD exhibit decreased activity in the DLPFC and ACC relative to HCs. In addition, specific suggestions to overcome these obstacles with new research and additional analyses are discussed.     

Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study.

BACKGROUND: Dual frontolimbic brain pathology has been suggested as a possible correlate of impulsivity and aggressive behavior. One previous study reported volume loss of the hippocampus and the amygdala in patients with borderline personality disorder. We measured limbic and prefrontal brain volumes to test the hypothesis that frontolimbic brain pathology might be associated with borderline personality disorder. METHODS: Eight unmedicated female patients with borderline personality disorder and eight matched healthy controls were studied. The volumes of the hippocampus, amygdala, and orbitofrontal, dorsolateral prefrontal, and anterior cingulate cortex were measured in the patients using magnetic resonance imaging volumetry and compared to those obtained in the controls. RESULTS: We found a significant reduction of hippocampal and amygdala volumes in borderline personality disorder. There was a significant 24% reduction of the left orbitofrontal and a 26% reduction of the right anterior cingulate cortex in borderline personality disorder. Only left orbitofrontal volumes correlated significantly with amygdala volumes. CONCLUSIONS: While volume loss of a single brain structure like the hippocampus is quite an unspecific finding in neuropsychiatry, the patterns of volume loss of the amygdala, hippocampus, and left orbitofrontal and right anterior cingulate cortex might differentiate borderline personality disorder from other neuropsychiatric conditions.     

Magnetic resonance imaging studies in early-onset bipolar disorder: a critical review

BACKGROUND: Neuroimaging studies of early-onset bipolar disorder (BD) are important in order to establish a fuller understanding of the underlying pathophysiology of the illness. The advantages of studying BD in children and adolescents include the relative absence of some confounds present in adult-onset research, such as lengthy duration of illness and exposure to treatments, greater number of mood episodes, and the presence of substance abuse or dependence. Finally, studying youths with the disorder may enhance our knowledge about the neural mechanisms of affective dysregulation and may specifically elucidate whether there are abnormalities that are unique to the early-onset form of the illness. METHODS: PubMed was used to identify peer-reviewed publications from the past 15 years (January 1990 to January 2005) that used brain-imaging techniques (anatomic, functional, and biochemical) to research early-onset BD. RESULTS: Eleven studies using anatomic magnetic resonance imaging (MRI), seven using magnetic resonance spectroscopy (MRS), and two using functional MRI (fMRI) were identified. Structural abnormalities were reported in total cerebral, white matter, superior temporal gyrus, putamen, thalamus, amygdala, and hippocampal volumes. Deficits in cortical gray matter were also reported. Using MRS, abnormalities were reported in the dorsolateral prefrontal cortex, anterior cingulate, and basal ganglia. One fMRI study found increased activation in the putamen and thalamus of BD youths compared to controls, and a second found abnormal prefrontal-subcortical activation in familial pediatric BD. CONCLUSION: Published MRI studies of early-onset BD are few. Nonetheless, extant data implicate abnormalities in brain regions thought to regulate mood and cognition. Synthesis of the findings into an overall model of anatomic and functional disruption is difficult due to the methodological variations among studies and the limitations of individual studies, such as the use of small sample sizes, the heterogeneity of sample characteristics, and the wide range of brain structures selected for analysis. Recommendations are offered to guide future research. It will be important for future studies to reproduce prior findings and determine which findings are unique to early-onset BD, relative to adult-onset illness. In addition, studies will need to establish the extent to which early-onset BD may overlap with comorbid disruptive, mood, anxiety, or psychotic disorders.     

Neurobiology of emotion perception II: Implications for major psychiatric disorders.

To date, there has been little investigation of the neurobiological basis of emotion processing abnormalities in psychiatric populations. We have previously discussed two neural systems: 1) a ventral system, including the amygdala, insula, ventral striatum, ventral anterior cingulate gyrus, and prefrontal cortex, for identification of the emotional significance of a stimulus, production of affective states, and automatic regulation of emotional responses; and 2) a dorsal system, including the hippocampus, dorsal anterior cingulate gyrus, and prefrontal cortex, for the effortful regulation of affective states and subsequent behavior. In this critical review, we have examined evidence from studies employing a variety of techniques for distinct patterns of structural and functional abnormalities in these neural systems in schizophrenia, bipolar disorder, and major depressive disorder. In each psychiatric disorder, the pattern of abnormalities may be associated with specific symptoms, including emotional flattening, anhedonia, and persecutory delusions in schizophrenia, prominent mood swings, emotional lability, and distractibility in bipolar disorder during depression and mania, and with depressed mood and anhedonia in major depressive disorder. We suggest that distinct patterns of structural and functional abnormalities in neural systems important for emotion processing are associated with specific symptoms of schizophrenia and bipolar and major depressive disorder.     

The effects of antidepressants on human brain as detected by imaging studies. Focus on major depression

Recent brain imaging studies have shed light on understanding the pathogenesis of mood disorders. Evidence of structural, chemical, and functional brain changes, particularly in prefrontal cortex, cingulate, and amygdala, has been revealed in major depressive disorder (MDD). Furthermore, imaging techniques have been applied to monitor the effects of antidepressants (ADs) both in the brains of healthy volunteers and MDD patients. Although with some discrepancies due to the differences in study designs and patient samples, imaging findings have shown that ADs, particularly those having effects on the serotonergic system, modulate the volumes, functions and biochemistry of brain structures, i.e. dorsolateral prefrontal cortex, anterior cingulate and amygdala, which have been demonstrated abnormal in MDD by earlier imaging studies. This paper reviews imaging studies conducted in MDD patients and healthy controls treated with different ADs.     

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 effects 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.