Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

BACKGROUND: Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. METHODS: Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. RESULTS: PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. CONCLUSIONS: We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Voluntary suppression of thoughts is influenced by anxious and ruminative tendencies in healthy volunteers.

Replicating thought suppression effects with the Think/No-Think paradigm (TNT) has failed in some studies investigating the phenomenon of below-baseline recall of suppressed stimuli. Attempts have been made to isolate factors that might explain inter-individual differences in suppression performance. Certain personality traits, whether associated with a pathological state or investigated in a community sample, have been shown to interfere with successful thought suppression and might be responsible for some of the negative results obtained in TNT studies. In the present study we investigate the influence of psychometric measures of depression and anxiety in a fairly large sample of healthy volunteers. We show that high brooding and anxious tendencies predict worse suppression performance. While no suppression was shown when investigating the TNT not taking the psychometric measures into account, including these two traits in the analysis resulted in a pattern of below-baseline recall only for low brooders and low anxious participants. We argue that inclusion of variables measuring personality traits is warranted using the TNT and that these variables already exert their influence at minimal levels of variance, significantly improving the interpretability of the results. Future research should therefore cautiously investigate potential confounding personality characteristics before analysing their data.

Towards robust in vivo quantification of oscillating biomagnetic fields using Rotary Excitation based MRI.

Spin-lock based functional magnetic resonance imaging (fMRI) has the potential for direct spatially-resolved detection of neuronal activity and thus may represent an important step for basic research in neuroscience. In this work, the corresponding fundamental effect of Rotary EXcitation (REX) is investigated both in simulations as well as in phantom and in vivo experiments. An empirical law for predicting optimal spin-lock pulse durations for maximum magnetic field sensitivity was found. Experimental conditions were established that allow robust detection of ultra-weak magnetic field oscillations with simultaneous compensation of static field inhomogeneities. Furthermore, this work presents a novel concept for the emulation of brain activity utilizing the built-in MRI gradient system, which allows REX sequences to be validated in vivo under controlled and reproducible conditions. Via transmission of Rotary EXcitation (tREX), we successfully detected magnetic field oscillations in the lower nano-Tesla range in brain tissue. Moreover, tREX paves the way for the quantification of biomagnetic fields.

BNST and amygdala activation to threat: Effects of temporal predictability and threat mode.

Recent animal and human studies highlight the uncertainty about the onset of an aversive event as a crucial factor for the involvement of the centromedial amygdala (CM) and bed nucleus of the stria terminalis (BNST) activity. However, studies investigating temporally predictable or unpredictable threat anticipation and confrontation processes are rare. Furthermore, the few existing fMRI studies analyzing temporally predictable and unpredictable threat processes used small sample sizes or limited fMRI paradigms. Therefore, we measured functional brain activity in 109 predominantly female healthy participants during a temporally predictable-unpredictable threat paradigm, which aimed to solve limited aspects of recent studies. Results showed higher BNST activity compared to the CM during the cue indicating that the upcoming confrontation is aversive relative to the cue indicating an upcoming neutral confrontation. Both the CM and BNST showed higher activity during the confrontation with unpredictable and aversive stimuli, but the reaction to aversive confrontation relative to neutral confrontation was stronger in the CM compared to the BNST. Additional modulation analyses by NPSR1 rs324981 genotype revealed higher BNST activity relative to the CM in unpredictable anticipation relative to predictable anticipation in T-carriers compared to AA carriers. Our results indicate that during the confrontation with aversive or neutral stimuli, temporal unpredictability modulates CM and BNST activity. Further, there is a differential activity concerning threat processing, as BNST is more involved when focussing on fear-related anticipation processes and CM is more involved when focussing on threat confrontation.

Centromedial amygdala is more relevant for phobic confrontation relative to the bed nucleus of stria terminalis in patients with spider phobia.

Recent studies indicate differential involvement of the centromedial amygdala (CM) and the bed nucleus of the stria terminalis (BNST) during processing (anticipation and confrontation) of threat stimuli. Here, temporal predictability was shown to be a relevant factor. In this study, we want to investigate the relevance of these effects, which were found in healthy subjects, for anxiety disorders. Therefore, we investigated the differential involvement of CM and BNST in the anticipation and confrontation of phobic stimuli under variation of temporal predictability in spider phobia. 21 patients with spider phobia and 21 healthy controls underwent a temporally predictable/unpredictable phobic and neutral anticipation and confrontation paradigm using functional magnetic resonance imaging (fMRI) and ROI analyses. During the anticipation phase, healthy controls showed higher CM and BNST activity during the predictable compared with the unpredictable condition compared with the anxiety patients. During a confrontation phase that followed the anticipation phase, CM was more activated than BNST during the phobic compared with the neutral confrontation. While this effect was independent of threat predictability in patients, healthy controls showed higher activation in the CM compared with the BNST only during the predictable spider confrontation compared with the predictable bird confrontation. The results contribute to a better understanding of the separate roles of the CM and BNST during phobic processes. The CM was found to be more relevant to phobic confrontation in patients with spider phobia compared with the BNST.

The impact of prefrontal cortex for selective attention in a visual working memory task.

In this study, a variant of the n-back task was used to investigate electrophysiological correlates of top-down processes in visual-object working memory. Event-related potentials were used to replicate results concerning an attention related modulation of neural processes and to investigate the involvement of prefrontal cortex in this modulation. 16 healthy subjects executed an n-back task with sequentially presented faces and scenes. Attention was selectively directed to only one stimulus category. We found an enhancement of the N170 amplitudes for relevant stimuli compared to irrelevant or neutral stimuli. Late frontal amplitudes were stronger positive for relevant compared to neutral stimuli indicating selective attention processes of working memory. Evidence for selective inhibition was not found.

The other-race effect for face perception: an event-related potential study.

It is well known that a recognition bias can be observed whenever subjects have to decide whether they have seen a person before that belongs to a different ethnical group. Although this "other-race effect" is well documented on a behavioural level, its underlying mechanisms remain unclear. One plausible explanation might be that cortical areas involved in face processing are not as effective for other-race faces due to a missing experience with individuals from other ethnical groups. This interpretation is strongly supported by a functional magnetic resonance imaging study showing decreased brain activity on other-race faces. Furthermore, two event-related potential studies revealed differences in brain activity in the first 250 ms after face presentation, but with inconsistent results. Therefore, we investigated 12 Caucasian subjects, showing them faces of Asian and Caucasian subjects in a perceptual priming paradigm and measured the event-related brain potentials. On a behavioural level we found slower reaction times to Asian faces compared to Caucasian faces in the unprimed condition, reflecting a deficit for Caucasian subjects to process other-race faces. In accordance with these behavioural data we see a significantly reduced late N250r amplitude in the unprimed condition to the Asian faces compared to the Caucasian faces. These results clearly indicate that the other-race effect was present in our sample and very specific only in the unprimed condition around 350-450 ms after stimulus onset.

Cerebral oxygenation changes in the prefrontal cortex: effects of age and gender.

Multi-channel near-infrared spectroscopy (NIRS) is an optical method, which allows non-invasive in vivo measurements of changes in the concentration of oxygenated (O(2)Hb) and deoxygenated (HHb) hemoglobin in living brain tissue, simultaneously from multiple measurement points. In the present study, 44 young and 42 elderly subjects were investigated by means of multi-channel NIRS (optical topography) during performance of the verbal fluency task (VFT). The aim of the study was to analyze the effects of the subjects' age and gender on functional brain activation during this cognitive task. In summary, the results clearly show that the VFT activated the left and right dorsolateral prefrontal cortex (increases in O(2)Hb and more localized decreases in HHb), with an obvious left-hemispheric dominance. The elderly subjects generally exhibited less activation and no left hemispheric lateralization effect. In contrast to a previous study, we did not find a clear influence of the subjects' gender on the brain activation pattern.

Near-infrared optical topography to assess activation of the parietal cortex during a visuo-spatial task.

Multi-channel near-infrared spectroscopy (NIRS) is a relatively new method to investigate the brain activation, based on changes in oxygenated haemoglobin (O2Hb) and deoxygenated haemoglobin (HHb). Recently, it has been shown that NIRS seems to be able to detect even small changes in O2Hb and HHb concentration due to cognitive demands. This study aimed at investigating the changes in O2Hb and HHb concentrations of the parietal cortex during a spatial task, a modified version of the Benton Line Orientation Task [Gur, R. C., Alsop, D., Glahn, D., Petty, R., Swanson, C. L., Maldjian, J. A., et al. (2000). An fMRI study of sex differences in regional activation to a verbal and a spatial task. Brain & Language, 74(2), 157-170.]. Twenty-four subjects were measured with NIRS while they had to estimate the orientation of a given line or to name the colour of the line in the control condition. Both conditions consisted of three activation phases each lasting 30 s, with a 10 s baseline and a 20 s post resting period. For assessing the changes in O2Hb and HHb concentrations, we measured with 24 NIRS channels over the parietal cortex using the NIRS apparatus ETG-100 (Hitachi Medical Ltd.). O2Hb concentration significantly increased during the active phase compared to the baseline for both conditions, but was significantly higher in the active phase for the line orientation condition compared to the colour naming condition bilaterally parieto-occipital. For the HHb concentrations, we only found significant decreases for both conditions but no differences between the conditions. The results of our study underscore the value of multi-channel NIRS for assessing cortical activation during cognitive tasks.

Multi-channel near-infrared spectroscopy detects specific inferior-frontal activation during incongruent Stroop trials.

Near-infrared spectroscopy (NIRS) is an optical method, which allows non-invasive in vivo measurements of changes in the concentration of oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin in brain tissue. In the present study we investigated 10 healthy subjects by means of multi-channel NIRS (Optical Topography; ETG-100, Hitachi Medical Co., Japan) during performance of congruent and incongruent trials of the Stroop color word task. With a similar pattern of activation for both congruent and incongruent Stroop trials in the NIRS channels located left superior-frontally, the results for O2Hb and the total amount of hemoglobin (Hb-tot) indicate specific activation for interference trials in inferior-frontal areas of the left hemisphere. This result is in line with several neuroimaging studies (fMRI, PET) that have already investigated the frontal activation related to Stroop interference, which further supports the assumption that multi-channel NIRS is sensitive enough to detect spatially specific activation during the performance of cognitive tasks.

Prevention of graft-versus-host disease in allogeneic bone marrow transplantation by pretreatment with 2'-deoxycoformycin.

Germ-free mice were used as a model for acute graft-versus-host disease (GVHD) in allogeneic bone marrow transplantation (BMT). C3H/He recipients of DBA/2 cells showed typical symptoms of acute GVHD and died within 8 days. Incubation of the cells with 10 microM 2'-deoxycoformycin (2dCF) + 100 microM deoxyadenosine (dAdo) for 1 h inhibited all T-cell functions as well as T-cell-dependent B-cell functions, but had no effect on B-cell functions that are T-cell independent, nor on the hemopoietic stem cells (CFU-S). Recipients of allogeneic cells that had been incubated with 2dCF + dAdo for 1 h prior to inoculation showed no signs, gross or histological, of acute or chronic GVHD up to 15 months after transplantation. The recovery patterns of the blood and bone marrow were not affected by the treatment, and were similar to those of recipients of treated and untreated syngeneic cells.

Serotonin transporter polymorphism modulates neural correlates of real-life joint action. An investigation with functional near-infrared spectroscopy (fNIRS).

A functional polymorphism (5-HTTLPR) within the serotonin transporter gene (SERT) has been associated with personality dimensions such as neuroticism, with emotional reactivity to negative events, and with an increased risk of affective disorders. More specifically, the short (S) allele of 5-HTTLPR has been linked to increased amygdala activity and has been identified as a risk allele for depressive disorders. Recently, Homberg and Lesch (2011) urged for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR S-allele and argued that the S-allele could be considered adaptive in certain contexts. They postulated that S-allele carriers show hypervigilant behavior in social situations and should thus show increased social conformity. Therefore, we tested whether 5-HTTLPR modulates the neural correlates of real-life social joint action through functional near-infrared spectroscopy (fNIRS). Thirty participants, homozygote for 5-HTTLPR, were measured and analyzed while they were involved in a previously published joint-action paradigm, which reliably leads to an activation of the left parietal cortex. We found that homozygote S-allele carriers showed increased inferior parietal lobe activation, compared to the LL-allele carriers for the contrast "joint action greater solo action". Therefore, our results provide evidence for beneficial effects of the S-allele on the neural correlates of social interactions.

Electrophysiological assessment of impulsive behavior in healthy subjects.

The different concepts of impulsivity cover a wide range of divergent behaviors. In clinical terms, aspects of impulsivity are both an important feature in several psychiatric conditions related to a low central serotonergic neurotransmission like aggressive behavior and suicidality, and a core symptom of frontal lobe syndromes of various etiologies. Assessment of the different forms of impulsivity so far relies on clinical observations and self-rating questionnaires. Measurements of a distinct brain function associated with impulsive behavior are not available yet, however, electrophysiological parameters of cognitive response control elicited with the execution (Go-condition) and the inhibition (NoGo-condition) of a prepared motor response within the Continuous Performance Test (CPT) might be suitable candidates. By means of a spatial analysis method the centers of gravity (centroids) of the brain electrical fields evoked with Go- and NoGo-responses can be localized and quantified. In the present study, the Go- and NoGo-centroids and the impulsivity score in Eysenck's I(7)-scale were determined in 22 healthy subjects (10 women, 12 men, mean age 42.0+/-10.1 years). Impulsivity was correlated with both, a more anterior location of the Go- (r=0.58, P<0.01) and the NoGo-centroid (r=0.53, P=0.01). These results indicate, that in healthy subjects the amount of I(7)-impulsivity is associated with differences in the prefrontal brain activation pattern during cognitive response control. However, a replication study with a larger sample and an investigation of psychiatric patients with pathological levels of impulsivity are necessary to qualify these topographical ERP-parameters of cognitive response control as valid measures of the brain electrical basis of impulsive behavior.

Americans' health priorities: curing cancer and controlling costs.

In this paper we provide a comprehensive examination of Americans' priorities within both health and health care. We find that Americans do have a clear set of priorities in each of these areas. Americans rated cancer, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and heart disease, and medical research to address these conditions, as top priorities among eighty health problems. However, they did not rank many leading causes of death very high as serious problems. On the issue of health care, problems of costs, prescription drugs, and the uninsured top the list. Americans are very concerned about emerging international infectious diseases that they believe threaten their health.

Test-retest reliability of electrophysiological parameters related to cognitive motor control.

Previously, the continuous performance test was demonstrated to elicit distinct electrophysiological correlates of cognitive response during execution (Go) and inhibition (NoGo) of an anticipated motor response. A robust method for topographical quantification of these brain electrical microstates has been established recently. Test reliability is crucial to allow application in the assessment of neuropsychiatric disorders. The present study evaluates the reliability of the Go and NoGo centroid locations as well as the NoGo anteriorisation (NGA) in 23 healthy individuals. Our results show supreme test-alternate retest reliabilities of Pearson's product moment correlations and intraclass correlation coefficients of r> or =0.63 (P< or =0.001) for these parameters which assert a quality well within the range reported for those of other electrophysiological standard paradigms. Go and NoGo centroid locations as well as the NGA are, therefore, reliable correlates of prefrontal motor control and may contribute to the understanding of disorders with allied impairments.

Frontal activation during a verbal-fluency task as measured by near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) is an optical method which allows non-invasive in vivo measurements of concentration changes of oxygenated hemoglobin (O(2)Hb) and deoxygenated hemoglobin (HHb) in brain tissue. The present study investigated the blood oxygenation changes that were associated with the execution of the Verbal-Fluency Test (VFT) in left and right prefrontal brain areas of 14 healthy subjects by means of NIRS. During the VFT, subjects were required to pronounce as many nouns as possible beginning with the letters "A," "F," and "S." Compared to a baseline resting condition, we found a significant increase of O2Hb (left hemisphere: baseline, 1.2+/-1.1microm; VFT(letterS), 3.56+/-2.02microm; right hemisphere: baseline, 1.26+/-1.08microm; VFT(letterS), 3.67+/-2.03microm) and a significant decrease of HHb (left hemisphere: baseline, -0.21+/-0.59microm; VFT(letterS), -0.67+/-0.60microm; right hemisphere: baseline, -0.29+/-0.53microm; VFT(letterS), -0.68+/-0.44microm) during the execution of the VFT over both hemispheres. No lateralization effects were observed. The results confirm that NIRS is suitable for the measurement of blood oxygenation changes in frontal brain areas that are associated with cognitive tasks.

Long-term reliability of electrophysiologic response control parameters.

The execution (Go) and the inhibition (NoGo) of a motor response are basic cognitive processes that can be assessed by means of a simple neuropsychological Go-NoGo task: the Continuous Performance Test (CPT). Simultaneous electrophysiologic investigations revealed that the NoGo condition of the CPT is associated with a clearly more anterior brain electrical activity compared with the Go condition. Recently, it has been shown that this NoGo anteriorization effect during a response control paradigm can be measured quantitatively with the electrophysiologic centroid method. The objective of the current study, therefore, was to determine the long-term reliability of the topographic measures of cognitive response control (i.e., location of the Go and the NoGo centroid and the NoGo anteriorization). For this purpose, a 21-channel EEG was recorded twice from 13 healthy volunteers during their execution of a cued CPT (O-X version). The time interval between test and retest was 2.74 years (range, 2.41 to 2.97 years). Statistical analysis of the event-related Go and NoGo potentials revealed an excellent test-retest reliability, as expressed by Pearson's product moment correlation coefficients of more than 0.85 (P < or = 0.0005) and intraclass correlation coefficients of more than 0.90 (P

Prefrontal activation through task requirements of emotional induction measured with NIRS.

The medial prefrontal cortex is believed to be involved in emotional experiences, but also in situations in which attention and self-monitoring is required. Therefore, it might be that the medial prefrontal cortex is not only activated by the emotional state per se, but rather through the task requirements that were used to induce emotions in the laboratory. The present study investigated the change of oxygenation in the left and right prefrontal cortex measured with near-infrared spectroscopy (NIRS) from 14 subjects during two kinds of emotional induction, which differed in the self-monitoring requirements. The task with the higher self-monitoring requirements resulted in an increased concentration of oxygenated hemoglobin (O(2)HB). This activation pattern was not observed during the emotional induction with the fewer self-monitoring requirements, although the subjective ratings indicated that both tasks induced comparable emotional states. The results indicate that task requirements should be taken into account when investigating the neural substrate of emotions.

Repeated exposure of flight phobics to flights in virtual reality.

The present study examined the effects of repeated exposure of flight phobics to flights in virtual reality (VR). Flight phobics were randomly assigned either to complete one VR test flight followed by four VR exposure flights (VR group; N=15) in one lengthy session or to complete one VR test flight followed by a lengthy relaxation training session (relaxation group; N=15). All participants completed a second VR test flight at the end of the session. Fear reports and physiological fear reactions (heart rate, skin conductance level) during VR exposures were registered, and fear of flying was assessed psychometrically from 3 weeks before to 3 months after exposure. Exposure to VR flights elicited subjective and physiological fear responses in flight phobics, and these responses attenuated within and across VR flights. Fear reduction associated with repeated VR exposure was greater than fear reduction caused by relaxation training. Fear of flying improved in both treatment groups, but several outcome measures indicated greater effects in the VR treated group than in the relaxation group. These findings indicate that exposure in virtual reality may offer a new and promising approach for the treatment of fear of flying.