Eric Vermetten

Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment.

BACKGROUND Depression has been linked to stress, memory deficits, and hypercortisolemia. However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear and the effects of antidepressant treatment on the measures are not well studied. METHODS Whole hippocampal volume, performance on verbal and visual declarative memory function and cortisol status was evaluated in 38 subjects with major depressive disorder (MDD) and 33 healthy subjects. All measures were repeated in a subgroup (n = 22) of depressed patients after successful selective serotonin reuptake inhibitor (SSRI) treatment. RESULTS Hippocampal volume was not significantly different between patients with untreated MMD and healthy subjects, after controlling for whole brain volume, age and gender. However, depressed subjects had significantly greater deficits in delayed memory and percent retention on the verbal portion of the Wechsler Memory Scale-Revised (WMS-R) compared with healthy subjects, without significant differences in visual memory, attention, vigilance, or distractibility. Baseline plasma or urinary free cortisol (UFC) was not related to either hippocampal volume or memory deficits. Successful treatment with antidepressants did not change hippocampal volume but did result in a significant improvement in memory function and a reduction in UFC excretion. CONCLUSIONS Medication-free nonelderly depressed outpatients without alcohol dependence or adverse experiences in childhood had normal hippocampal volume. Focal declarative memory deficits in depression supported localized hippocampal dysfunction in depressed patients. Treatment with antidepressants significantly improved memory and depression but did not alter hippocampal volume, suggesting that antidepressants may improve hippocampal function in the absence of detectable structural changes.

MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders.

Magnetic resonance imaging (MRI) has opened a new window to the brain. Measuring hippocampal volume with MRI has provided important information about several neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. Smaller hippocampal volumes have been reported in epilepsy, Alzheimers disease, dementia, mild cognitive impairment, the aged, traumatic brain injury, cardiac arrest, Parkinsons disease, Huntingtons disease, Cushings disease, herpes simplex encephalitis, Turners syndrome, Downs syndrome, survivors of low birth weight, schizophrenia, major depression, posttraumatic stress disorder, chronic alcoholism, borderline personality disorder, obsessive–compulsive disorder, and antisocial personality disorder. Significantly larger hippocampal volumes have been correlated with autism and children with fragile X syndrome. Preservation of hippocampal volume has been reported in congenital hyperplasia, children with fetal alcohol syndrome, anorexia nervosa, attention-deficit and hyperactivity disorder, bipolar disorder, and panic disorder. Possible mechanisms of hippocampal volume loss in neuropsychiatric disorders are discussed.

Stress and development: behavioral and biological consequences.

Childhood abuse is an important public health problem; however, little is known about the effects of abuse on the brain and neurobiological development. This article reviews the behavioral and biological consequences of childhood abuse and places them in a developmental context. Animal studies show that both positive and negative events early in life can influence neurobiological development in unique ways. Early stressors such as maternal separation result in lasting effects on stress-responsive neurobiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic systems. These studies also implicate a brain area involved in learning and memory, the hippocampus. in the long-term consequences of early stress. Clinical studies of patients with a history of abuse also implicate dysfunction in the HPA axis and the noradrenergic and hippocampal systems; however, there are multiple questions related to chronicity of stress, developmental epoch at the time of the stressor, presence of stress-related psychiatric disorders including posttraumatic stress disorder and depression. and psychological factors mediating the response to trauma that need to be addressed in this field of research. Understanding the effects of abuse on the development of the brain and neurobiology will nevertheless have important treatment and policy implications.

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

BACKGROUND 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). METHOD 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. RESULTS 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. CONCLUSIONS These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.

Structural and functional plasticity of the human brain in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder

BACKGROUND The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.

Cortisol response to a cognitive stress challenge in posttraumatic stress disorder (PTSD) related to childhood abuse

Preclinical studies show that animals with a history of chronic stress exposure have increased hypothalamic-pituitary-adrenal (HPA) axis reactivity following reexposure to stress. Patients with posttraumatic stress disorder (PTSD) have been found to have normal or decreased function of the HPA axis, however no studies have looked at the HPA response to stress in PTSD. The purpose of this study was to assess cortisol responsivity to a stressful cognitive challenge in patients with PTSD related to childhood abuse. Salivary cortisol levels, as well as heart rate and blood pressure, were measured before and after a stressful cognitive challenge in patients with abuse-related PTSD (N=23) and healthy comparison subjects (N=18). PTSD patients had 61% higher group mean cortisol levels in the time period leading up to the cognitive challenge, and 46% higher cortisol levels during the time period of the cognitive challenge, compared to controls. Both PTSD patients and controls had a similar 66-68% increase in cortisol levels from their own baseline with the cognitive challenge. Following the cognitive challenge, cortisol levels fell in both groups and were similar in PTSD and control groups. PTSD patients appeared to have an increased cortisol response in anticipation of a cognitive challenge relative to controls. Although cortisol has been found to be low at baseline, there does not appear to be an impairment in cortisol response to stressors in PTSD.

MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed

The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.

Deficits in verbal declarative memory function in women with childhood sexual abuse-related posttraumatic stress disorder.

Several studies have shown deficits in verbal declarative memory function in posttraumatic stress disorder (PTSD). Most of these studies have been performed in men with combat-related PTSD compared with healthy subjects; relatively little is known about memory function in women with abuse-related PTSD, or whether these effects are specific to PTSD or are a nonspecific outcome of exposure to early abuse. The purpose of this study was to assess declarative memory function in women with and without a history of early childhood sexual abuse and PTSD. Forty-three women with and without a history of early childhood sexual abuse and PTSD underwent neuropsychological testing with subtests of the Wechsler Memory Scale—Revised for measurement of verbal and visual memory and subtests of the Wechsler Adult Intelligence Scale for measurement of IQ, and behavioral ratings of PTSD and other psychiatric symptoms. Abused women with PTSD had deficits in verbal declarative memory as measured with the subtests of the Wechsler Memory Scale—Revised compared with women with early abuse without PTSD and nonabused women without PTSD. There were no significant differences in IQ. These findings suggest that early abuse with PTSD is associated with deficits in verbal declarative memory, and that these effects are not related to the nonspecific effects of childhood abuse.