Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.

Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system.

Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy-Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose-response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS "top-down" antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.

Disorder specificity despite comorbidity: resting EEG alpha asymmetry in major depressive disorder and post-traumatic stress disorder.

The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N=15) and post-traumatic stress disorder (PTSD) (N=14) relative to healthy controls (N=15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups.

Dissociative responses to conscious and non-conscious fear impact underlying brain function in post-traumatic stress disorder.

BACKGROUND: Dissociative reactions in post-traumatic stress disorder (PTSD) have been regarded as strategic responses that limit arousal. Neuroimaging studies suggest distinct prefrontal responses in individuals displaying dissociative and hyperarousal responses to threat in PTSD. Increased prefrontal activity may reflect enhanced regulation of limbic arousal networks in dissociation. If dissociation is a higher-order regulatory response to threat, there may be differential responses to conscious and automatic processing of threat stimuli. This study addresses this question by examining the impact of dissociation on fear processing at different levels of awareness. METHOD: Functional magnetic resonance imaging (fMRI) with a 1.5-T scanner was used to examine activation to fearful (versus neutral) facial expressions during consciously attended and non-conscious (using backward masking) conditions in 23 individuals with PTSD. Activation in 11 individuals displaying non-dissociative reactions was compared to activation in 12 displaying dissociative reactions to consciously and non-consciously perceived fear stimuli. RESULTS: Dissociative PTSD was associated with enhanced activation in the ventral prefrontal cortex for conscious fear, and in the bilateral amygdala, insula and left thalamus for non-conscious fear compared to non-dissociative PTSD. Comparatively reduced activation in the dissociative group was apparent in dorsomedial prefrontal regions for conscious fear faces. CONCLUSIONS: These findings confirm our hypotheses of enhanced prefrontal activity to conscious fear and enhanced activity in limbic networks to non-conscious fear in dissociative PTSD. This supports the theory that dissociation is a regulatory strategy invoked to cope with extreme arousal in PTSD, but this strategy appears to function only during conscious processing of threat.

Quantitative electroencephalographic changes induced by odor detection and identification tasks: age related effects.

There are no previous studies which have compared quantitative electroencephalographic (QEEG) activity in young adult and normal elderly participants during olfactory tasks. This may be important if QEEG is to have a role in distinguishing between normal and pathological aging associated with this sensory system. Seventeen healthy elderly subjects (mean age 79.00+/-3.54 years) and 16 young adult controls (mean age 22.60+/-2.00 years) participated in the study. As reported in previous studies, beta1 and 2 activity was significantly greater in elderly subjects compared to young adults, thus confirming the reliability and validity of this study's quantitative electroencephalographic (QEEG) methodology. More alpha activity was evident in young adults compared with the elderly, whilst θ activity was distributed differently in the two age groups. These findings support previous literature suggesting EEG bandwidth activity reflect greater attentional capacity in young adults and EEG desynchronization in older people. Elderly subjects who identified two or fewer odors were found to have more beta activity in the olfaction condition compared to resting eyes closed, which may reflect cognitive impairment. These findings stress the importance of distinguishing subgroups of healthy elderly adults when examining the electroencephalographic profile.

Gender differences in the cortical electrophysiological processing of visual emotional stimuli.

The processing of visual emotional stimuli has been investigated previously; however, gender differences in the processing of emotional stimuli remain to be clarified. The aim of the current study was to use steady-state probe topography (SSPT) to examine steady-state visually evoked potentials (SSVEPs) during the processing of pleasant and unpleasant images relative to neutral images, and to determine whether this processing differs between males and females. Thirty participants (15 males and 15 females) viewed 75 images low on the arousal dimension (categorised as pleasant, neutral or unpleasant) selected from the International Affective Picture System (IAPS), whilst a 13-Hz sinusoidal white visual flicker was superimposed over the visual field and brain electrical activity was recorded from 64 electrode sites. Results suggest that pleasant and unpleasant images relative to neutral images are associated with reductions in frontal latency and occipital amplitude. In addition, electrophysiological gender differences were observed despite there being no differences found between males and females on subjective mood or behavioural ratings of presented images (valence and arousal dimensions). The main gender difference reported in the current study related to the processing of unpleasant images (relative to neutral images) which is associated with widespread frontal latency reductions (predominantly right sided) in females but not in males. Our results suggest that gender differences do exist in the processing of visual emotional stimuli, and illustrate the importance of taking these differences into account during investigations of emotional processing. Finally, these gender differences may have implications for the pathophysiology of mood disorders such as depression.

Steady-state visually evoked potential topography during processing of emotional valence in healthy subjects.

The International Affective Picture System (IAPS) is increasingly used in brain imaging studies to examine emotional processes. This task allows valence and arousal content to be systematically investigated; however, previous studies have generally failed to select images that vary in one dimension as well as hold constant the variability on the other dimension. In addition, no studies have investigated the temporal structure associated with the conscious, ongoing processing of emotional stimuli following systematic selection of IAPS images. The aim of the present study was therefore to use steady-state probe topography (SSPT) to examine the steady-state visually evoked potentials (SSVEPs) associated with the processing of pleasant and unpleasant images low in arousal content. Seventy-five IAPS images, categorized as unpleasant, neutral, or pleasant, were presented to 16 healthy subjects while brain activity was recorded from 64 scalp sites. Analysis subtracted the activity associated with the presentation of neutral images from the activity associated with the presentation of pleasant as well as unpleasant images. Results demonstrate that both pleasant and unpleasant valence is associated with transient, widespread, and bilateral frontal SSVEP latency reductions. Unpleasant images were also associated with a transient bilateral anterior frontal amplitude decrease. Latency reductions are interpreted as increases in neural information processing speed, while amplitude reductions are interpreted in the current paper as analogous to an event-related desynchronisation commonly associated with the alpha bandwidth. These key findings support previous literature in terms of there being substantial overlap in frontal neural circuitry when the brain processes pleasant and unpleasant valence relative to neutral valence.

Cortical neurophysiology of anticipatory anxiety: an investigation utilizing steady state probe topography (SSPT).

The precise role of the cortex in human anxiety is not well characterised. Previous imaging research among healthy controls has reported alterations in regional cerebral blood flow (rCBF) within the prefrontal and temporal cortices during periods of anxious anticipation; however, the temporal dynamics of this activity has yet to be examined in detail. The present study examined cortical Steady State Probe Topography (SSPT) changes associated with anticipatory anxiety (AA), allowing examination of the temporal continuity and the excitatory or inhibitory nature of AA activations. We recorded Steady State Visually Evoked Potentials (SSVEPs) at 64 scalp locations, skin conductance, and self reported anxiety among 26 right-handed males while relaxed and during the anticipation of an electric shock. Relative to the baseline condition, the AA condition was associated with significantly higher levels of self-reported anxiety and increased phasic skin conductance levels. Across the seven second imaging window, AA was associated with increased SSVEP latency within medial anterior frontal, left dorsolateral prefrontal and bilateral temporal regions. In contrast, increased SSVEP amplitude and decreased SSVEP latency were observed within occipital regions. The observed SSVEP latency increases within frontal and temporal cortical regions are suggestive of increased localised inhibitory processes within regions reciprocally connected to subcortical limbic structures. Occipital SSVEP latency decreases are suggestive of increased excitatory activity. SSVEP amplitude increases within occipital regions may be associated with an attentional shift from external to internal environment. The current findings provide further support for the involvement of frontal, anterior temporal, and occipital cortical regions during anticipatory anxiety, and suggest that both excitatory and inhibitory processes are associated with AA alterations.