Bernet M. Elzinga

Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)

A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala. Chronic stress also affects the hippocampus, a brain area involved in declarative memories, suggesting that hippocampal dysfunction may partly account for the deficits in declarative memory in PTSD-patients. Deficits in the medial prefrontal cortex, a structure that normally inhibits the amygdala, may further enhance the effects of the amygdala, thereby increasing the frequency and intensity of the traumatic memories. Thus, by way of its influence on these brain structures, exposure to severe stress may simultaneously result in strong emotional reactions and in difficulties to recall the emotional event. This model is also relevant for understanding the distinction between declarative and non-declarative memory-functions in processing trauma-related information in PTSD. Implications of our model are reviewed.

Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects.

BACKGROUND Animal and human studies have found that prior stressful events can result in an altered reactivity in the HPA axis. The aim of the present study was to investigate the role of adverse events in childhood on cortisol reactivity to psychosocial stress in young healthy subjects (n=80). METHODS Salivary cortisol levels were measured before, during and after exposure to a psychosocial stress task in healthy men and women with high (n=33) and low (n=47) exposure to adverse childhood events. RESULTS A significant blunted cortisol response was found in individuals with a history of adverse events compared to individuals with no adverse life events, with no differences in baseline cortisol levels. This finding appeared to be primarily driven by men. The groups did not differ on any other physiological or subjective stress measure, including heart rate, blood pressure, and subjective tension. CONCLUSIONS These findings suggest that, at least in healthy young males, adverse childhood events are associated with changes in HPA-axis functioning. Longitudinal studies are needed to investigate whether the blunted cortisol response is a risk factor in the etiology of psychiatric disorders or rather reflects resiliency with regard to the development of psychopathology.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

Recent evidence supports ‘the neurotrophin hypothesis of depression’ in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (⩾6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St Johns wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

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.

Psychosocial stress impairs working memory at high loads: An association with cortisol levels and memory retrieval

Stress and cortisol are known to impair memory retrieval of well-consolidated declarative material. The effects of cortisol on memory retrieval may in particular be due to glucocorticoid (GC) receptors in the hippocampus and prefrontal cortex (PFC). Therefore, effects of stress and cortisol should be observable on both hippocampal-dependent declarative memory retrieval and PFC-dependent working memory (WM). In the present study, it was tested whether psychosocial stress would impair both WM and memory retrieval in 20 young healthy men. In addition, the association between cortisol levels and cognitive performance was assessed. It was found that stress impaired WM at high loads, but not at low loads in a Sternberg paradigm. High cortisol levels at the time of testing were associated with slow WM performance at high loads, and with impaired recall of moderately emotional, but not of highly emotional paragraphs. Furthermore, performance at high WM loads was associated with memory retrieval. These data extend previous results of pharmacological studies in finding WM impairments after acute stress at high workloads and cortisol-related retrieval impairments.

Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder

Borderline personality disorder (BPD) is a common disorder associated with emotional dysregulation and other symptoms that have been hypothesized to be related to dysfunction of limbic brain areas including hippocampus and amygdala. The purpose of this study was to measure hippocampal and amygdala volumes in BPD. Hippocampal and amygdala volumes were measured with magnetic resonance imaging (MRI) in 10 patients with BPD and 23 control subjects. Patients with BPD had a 21.9% smaller mean amygdala volume and a 13.1% smaller hippocampal volume, compared to controls. These findings are consistent with the hypothesis that alterations in the hippocampus and amygdala are associated with BPD.

Higher Cortisol Levels Following Exposure to Traumatic Reminders in Abuse-Related PTSD

Animal studies have found that prior stressful events can result in increased reactivity in the HPA-axis. However, baseline function of the HPA-axis has typically been normal or decreased in post-traumatic stress disorder (PTSD). The first purpose of this study was to assess cortisol responsivity to traumatic reminders in women with PTSD related to childhood abuse. The second aim was to assess the relationship between stress-induced cortisol levels and neutral and emotional memory. Salivary cortisol levels were measured before, during and after exposure to personalized trauma scripts in abused women with (N=12) and without current PTSD (N=12). Memory for neutral and emotional material was assessed immediately after trauma scripts exposure and 3 days later. PTSD patients had 122% higher cortisol levels during script exposure, 69% higher cortisol levels during recovery, and 60% higher levels in the period leading up to the script exposure compared to controls. PTSD symptoms were highly predictive of cortisol levels during trauma script exposure (r=0.70), but not during periods of rest. Both in PTSD patients and controls, memory consolidation after the trauma scripts was impaired relative to baseline (P<0.001), with no differences between the two groups on memory performance. There was no association between memory performance and cortisol levels. These results are consistent with higher cortisol levels following exposure to traumatic stressors in PTSD.

Hair cortisol, stress exposure, and mental health in humans: A systematic review

The deleterious effects of chronic stress on health and its contribution to the development of mental illness attract broad attention worldwide. An important development in the last few years has been the employment of hair cortisol analysis with its unique possibility to assess the long-term systematic levels of cortisol retrospectively. This review makes a first attempt to systematically synthesize the body of published research on hair cortisol, chronic stress, and mental health. The results of hair cortisol studies are contrasted and integrated with literature on acutely circulating cortisol as measured in bodily fluids, thereby combining cortisol baseline concentration and cortisol reactivity in an attempt to understand the cortisol dynamics in the development and/or maintenance of mental illnesses. The studies on hair cortisol and chronic stress show increased hair cortisol levels in a wide range of contexts/situations (e.g. endurance athletes, shift work, unemployment, chronic pain, stress in neonates, major life events). With respect to mental illnesses, the results differed between diagnoses. In major depression, the hair cortisol concentrations appear to be increased, whereas for bipolar disorder, cortisol concentrations were only increased in patients with a late age-of-onset. In patients with anxiety (generalized anxiety disorder, panic disorder), hair cortisol levels were reported to be decreased. The same holds true for patients with posttraumatic stress disorder, in whom - after an initial increase in cortisol release - the cortisol output decreases below baseline. The effect sizes are calculated when descriptive statistics are provided, to enable preliminary comparisons across the different laboratories. For exposure to chronic stressors, the effect sizes on hair cortisol levels were medium to large, whereas for psychopathology, the effect sizes were small to medium. This is a first implication that the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the development and/or maintenance of psychopathology may be more subtle than it is in healthy but chronically stressed populations. Future research possibilities regarding the application of hair cortisol research in mental health and the need for multidisciplinary approaches are discussed.

Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations ( N =9484)

Meta-analyses, published in 2008–2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis, which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen’s d=−0.71 and −0.56, P-values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller (d=−0.47 and −0.34, respectively, P-values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.

Reduced Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment

BACKGROUND Childhood emotional maltreatment (CEM) has been associated with a profound and enduring negative impact on behavioral and emotional functioning. Animal models have shown that adverse rearing conditions, such as maternal separation, can induce a cascade of long-term structural alterations in the brain, particularly in the hippocampus, amygdala, and prefrontal cortex. However, in humans, the neurobiological correlates of CEM are unknown. METHODS Using high-resolution T1-weighted 3T magnetic resonance imaging, anatomical scans and a whole-brain optimized voxel-based morphometry approach, we examined whether healthy control subjects and unmedicated patients with depression and/or anxiety disorders reporting CEM before age 16 (n = 84; age: mean = 38.7) displayed structural brain changes compared with control subjects and patients who reported no childhood abuse (n = 97; age: mean = 36.6). RESULTS We found that self-reported CEM is associated with a significant reduction in predominantly left dorsal medial prefrontal cortex volume, even in the absence of physical or sexual abuse during childhood. In addition, reduced medial prefrontal cortex in individuals reporting CEM is present in males and females, independent of concomitant psychopathology. CONCLUSIONS In this study, we show that CEM is associated with profound reductions of medial prefrontal cortex volume, suggesting that sustained inhibition of growth or structural damage can occur after exposure to CEM. Given the important role of the medial prefrontal cortex in the regulation of emotional behavior, our finding might provide an important link in understanding the increased emotional sensitivity in individuals reporting CEM.