Multimodal Assessment of Smoking cue Reactivity During a Smoking Cue Exposure Task.

Background. Cue-reactivity as a characteristic symptom of substance use disorders (SUD) is highly context dependent. Paradigms with high context validity need to be established for the investigation of underlying neurobiological mechanisms. While craving can be assessed by self-report as one aspect of cue-reactivity (CR), the assessment of biological measures such as the autonomous response and EEG promises a holistic perspective including CR at an automatized level. In a multimodal approach, smoking cue exposure (CE) effects on heart rate variability (HRV), EEG frequency power, and craving as well as their interrelation were assessed. This pilot study focused on the validity of CR measurements in a naturalistic CE paradigm. Methods. EEG frequency power, HRV, and craving were assessed during resting state (RS) and smoking CE in smokers (n = 14) and nonsmoking controls (n = 10) to investigate the psychophysiological and subjective reactions to CE. Results. Increased beta power was found only in smokers during CE compared to the control condition. There was an inverse correlation of beta power and maximum craving. Likewise, HRV correlated negatively with maximum smoking urges in smokers immediately after the measurements, without differentiation between CE and control condition. Conclusion. The increased beta power in smokers during CE is discussed as increased inhibitory control related to reduced craving in smokers. Furthermore, increased craving during CE seems to be associated to decreased vagal activity. The multimodal measurements during the CE showed ecological validity to be fundamental for CE assessment in clinical populations to evaluate its predictive value.

Effects of transcranial direct current stimulation on craving, heart-rate variability and prefrontal hemodynamics during smoking cue exposure.

OBJECTIVE: Drug-related cue exposure elicits craving and risk for relapse during recovery. Transcranial direct current stimulation is a promising research tool and possible treatment for relapse prevention. Enhanced functional neuroconnectivity is discussed as a treatment target. The goal of this research was to examine whether transcranial direct current stimulation affected cortical hemodynamic indicators of functional connectivity, craving, and heart rate variability during smoking-related cue exposure in non-treatment-seeking smokers. METHOD: In vivo smoking cue exposure supported by a 2mA transcranial direct current stimulation (anode: dorsolateral prefrontal cortex, cathode: orbitofrontal cortex; placebo-controlled, randomized, double-blind) in 29 (age: M=25, SD=5) German university students (smoking at least once a week). Cue reactivity was assessed on an autonomous (heart rate variability) and a subjective level (craving ratings). Functional near-infrared spectroscopy measured changes in the concentration of deoxygenated hemoglobin, and seed-based correlation analysis was used to quantify prefrontal connectivity of brain regions involved in cue reactivity. RESULTS: Cue exposure elicited increased subjective craving and heart rate variability changes in smokers. Connectivity between the orbitofrontal and dorsolateral prefrontal cortex was increased in subjects receiving verum compared to placebo stimulation (d=0.66). Hemodynamics in the left dorsolateral prefrontal cortex, however, increased in the group receiving sham stimulation (η2=0.140). Transcranial direct current stimulation did not significantly alter craving or heart rate variability during cue exposure. CONCLUSION: Prefrontal connectivity - between regions involved in the processing of reinforcement value and cognitive control - was increased by anodal transcranial direct current stimulation during smoking cue exposure. Possible clinical implications should be considered in future studies.

Functional co-activation within the prefrontal cortex supports the maintenance of behavioural performance in fear-relevant situations before an iTBS modulated virtual reality challenge in participants with spider phobia.

A number of studies/meta-analyses reported moderate antidepressant effects of activating repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex (PFC). Regarding the treatment of anxiety, study outcomes are inconsistent, probably because of the heterogenity of anxiety disorders/study designs. To specifically evaluate the impact of rTMS on emotion regulation in fear-relevant situations we applied a sham-controlled activating protocol (intermittent Theta Burst Stimulation/iTBS) over the left PFC (F3) succeeded by a virtual reality (VR) challenge in n=41 participants with spider phobia and n=42 controls. Prior to/after iTBS and following VR prefrontal activation was assessed by functional near-infrared spectroscopy during an emotional Stroop paradigm. Performance (reaction times/error rates) was evaluated. Stimuli were rated regarding valence/arousal at both measurements. We found diminished activation in the left inferior frontal gyrus (IFG) of participants with spider phobia compared to controls, particularly elicited by emotionally-irrelevant words. Simultaneously, a functional connectivity analysis showed increased co-activation between the left IFG and the contra-lateral hemisphere. Behavioural performance was unimpaired. After iTBS/VR no significant differences in cortical activation between the phobic and control group remained. However, verum-iTBS did not cause an additional augmentation. We interpreted our results in terms of a prefrontal network which gets activated by emotionally-relevant stimuli and supports the maintenance of adequate behavioural reactions. The missing add-on effects of iTBS might be due to a ceiling effect of VR, thereby supporting its potential during exposure therapy. Concurrently, it implies that the efficient application of iTBS in the context of emotion regulation still needs to be studied further.

Psychophysiological effects of an iTBS modulated virtual reality challenge including participants with spider phobia.

Preliminary evidence suggests beneficial effects of transcranial magnetic stimulation (TMS) on anxiety. The objective of this study was to investigate the effects of intermittent theta burst stimulation (iTBS) as a form of TMS on acute anxiety provoked by a virtual reality (VR) scenario. Participants with spider phobia (n=41) and healthy controls (n=42) were exposed to a spider scenario in VR after one session of iTBS over the prefrontal cortex or sham treatment. Participants with spider phobia reacted with more anxiety compared to healthy controls. Their heart rate and skin conductance increased compared to baseline. Contrary to expectations, iTBS did not influence these reactions, but modulated heart rate variability (HRV). Sympathetic influence on HRV showed an increase in the active iTBS group only. This study does not support the idea of beneficial effects of a single session of iTBS on anxiety, although other protocols or repeated sessions might be effective.

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.

Stress-induced neuroplasticity: (mal)adaptation to adverse life events in patients with PTSD--a critical overview.

Stress is an adaptive response to demands of the environment and thus essential for survival. Exposure to stress triggers hypothalamic-pituitary-adrenocortical (HPA) axis activation and associated neurochemical reactions, following glucocorticoid release from the adrenal glands, accompanied by rapid physiological responses. Stimulation of this pathway results in the activation of specific brain regions, including the hippocampus, amygdala and prefrontal cortex which are enriched with glucocorticoid receptors (GRs). Recent findings indicate that the activation of GRs mediates the regulation of the brain-derived neurotrophic factor (BDNF). BDNF is crucial for neural plasticity, as it promotes cellular growth and synaptic changes. Hence stress-induced activation of these pathways leads to neuroplastic changes, including the formation of long-lasting memories of the experiences. As a consequence, organisms can learn from stressful events and respond in an adaptive manner to similar demands in the future. Whereas an optimal stress level leads to enhancement of memory performance, the exposure to extreme, traumatic or chronic stressors is a risk factor for psychopathologies which are associated with memory impairment and cognitive deficits such as posttraumatic stress disorder (PTSD). In this review article, we will outline the implications of stress exposure on memory formation involving the role of glucocorticoids and BDNF. Within this context, potential adverse effects of neuroplastic alterations will be discussed using the example of PTSD.

Reconstructing functional near-infrared spectroscopy (fNIRS) signals impaired by extra-cranial confounds: an easy-to-use filter method.

Functional near-infrared spectroscopy (fNIRS) is an optical neuroimaging method that detects temporal concentration changes of oxygenated and deoxygenated hemoglobin within the cortex, so that neural activation can be inferred. However, even though fNIRS is a very practical and well-tolerated method with several advantages particularly in methodically challenging measurement situations (e.g., during tasks involving movement or open speech), it has been shown to be confounded by systemic compounds of non-cerebral, extra-cranial origin (e.g. changes in blood pressure, heart rate). Especially event-related signal patterns induced by dilation or constriction of superficial forehead and temple veins impair the detection of frontal brain activation elicited by cognitive tasks. To further investigate this phenomenon, we conducted a simultaneous fNIRS-fMRI study applying a working memory paradigm (n-back). Extra-cranial signals were obtained by extracting the BOLD signal from fMRI voxels within the skin. To develop a filter method that corrects for extra-cranial skin blood flow, particularly intended for fNIRS data sets recorded by widely used continuous wave systems with fixed optode distances, we identified channels over the forehead with probable major extra-cranial signal contributions. The averaged signal from these channels was then subtracted from all fNIRS channels of the probe set. Additionally, the data were corrected for motion and non-evoked systemic artifacts. Applying these filters, we can show that measuring brain activation in frontal brain areas with fNIRS was substantially improved. The resulting signal resembled the fMRI parameters more closely than before the correction. Future fNIRS studies measuring functional brain activation in the forehead region need to consider the use of different filter options to correct for interfering extra-cranial signals.

Reliability of the emotional Stroop task: an investigation of patients with panic disorder.

Despite its popularity in clinical research, the emotional Stroop task's reliability in patient groups is unknown. Given the low reliability of interference scores in healthy subjects, correlations with other variables pose a problem, especially as reliability in clinical samples is unknown. To assess reliability in panic disorder for the first time, we used the spilt-half method in two independent samples of patients and controls. As expected, only patients showed the behavioral interference effect. Reliability of interference scores (i.e. mean response latency emotional minus neutral words) was insufficiently low for patient and control samples; however, reliability scores derived from the conditions' response latencies (i.e. mean response latency emotional or neutral words) were much higher. The assumption that reliability scores in patients might differ from controls was not supported. This finding questions the use of correlations with external variables and suggests the use of response latencies instead of interference scores.

Influence of muscle activity on brain oxygenation during verbal fluency assessed with functional near-infrared spectroscopy.

A large part of the literature of functional near-infrared spectroscopy (fNIRS) deals with overt verbal fluency. It has been claimed that fNIRS has a low susceptibility to movement related artefacts as, for example, associated with overt speech. However, so far, no study has investigated this assumption in an experimental design. Therefore, we examined a group of 16 healthy subjects during performance of two verbal fluency tasks (experiment 1: phonological fluency; experiment 2: semantical fluency, paced answers, pronouncing vs. writing). We measured changes of oxygenated (O(2)Hb) and deoxygenated haemoglobin (HHb) over fronto-temporal (brain) areas via fNIRS, while temporalis muscle activity was simultaneously assessed by means of electromyography (EMG). Statistical analyses indicated comparable word production, higher increases of O(2)Hb and higher decreases of HHb over fronto-temporal areas during word fluency in contrast to the control task weekday reciting. This fNIRS pattern indicates fluency related activation and was found for pronouncing and for writing in both experiments. Regarding the EMG data, fluency related activity was only found for pronouncing, not for writing. Thus, muscle activity cannot account for fluency related fNIRS activity during writing. Additionally, correlation analyses showed no systematic associations of fNIRS and EMG signals. In conclusion, we found arguments that fNIRS actually allows for the measurement of brain activity over fronto-temporal areas during verbal fluency. Nonetheless, further studies should evaluate more direct associations between fNIRS and EMG signals by specific experimental manipulations and data analysing approaches that allow dealing fNIRS and EMG raw data simultaneously.

DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias.

Dysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.

Cortical correlates of auditory sensory gating: a simultaneous near-infrared spectroscopy event-related potential study.

Sensory gating refers to the ability of cerebral networks to inhibit responding to irrelevant environmental stimuli, a mechanism that protects the brain from information overflow. The reduction of the P50 amplitude (an early component of the event-related potential/ERP in electrophysiological recordings) after repeated occurrence of a particular acoustic stimulus is one means to quantitatively assess gating mechanisms. Even though P50 suppression has been extensively investigated, neuroimaging studies on the cortical correlates of auditory sensory gating are so far very sparse. Near-infrared spectroscopy (NIRS) is an optical imaging technique perfectly suitable for the investigation of auditory paradigms, since it involves virtually no noise. We conducted a simultaneous NIRS-ERP measurement to assess cortical correlates of auditory sensory gating in humans. The multi-channel NIRS recording indicated a specific activation of prefrontal and temporo-parietal cortices during conditions of increased sensory gating (dual-click trials). Combining the hemodynamic data with an electrophysiological index of the "gating quality" (gating quotient Q) revealed a positive correlation between the amount of sensory gating and the strength of the hemodynamic response during dual-clicks in the left prefrontal and temporal cortices. The results are in line with previous findings and confirm a possible inhibitory influence of the prefrontal cortex on primary auditory cortices.

Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals.

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n=124) and healthy controls (n=84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go- and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

D4 receptor gene variation modulates activation of prefrontal cortex during working memory.

It has been shown that dopamine (DA) influences performance on neurocognitive tests, which are thought to rely on prefrontal activity. The purpose of this study was to explore the effects of gene polymorphisms related to DA activity, namely the D4 DA receptor (DRD4) gene exon III polymorphisms, on prefrontal cortex (PFC) activation. In this study we measured the brain oxygenation of the PFC during an n-back task with near-infrared spectroscopy (NIRS). We investigated 40 young healthy subjects, 12 of which carried the DRD4 exon III 7-repeat allele (group 7). These were compared with subjects without a 7-repeat allele (n=28, group 4). Additionally, we compared good and bad performers with respect to brain activation. As expected, we found significant increases in the concentration of oxygenated haemoglobin [O2Hb] during the 1-back and 2-back condition compared with baseline, and a corresponding significant decrease of deoxyhaemoglobin concentration. As a main result of this study we also found an interaction effect between task condition and DRD4 genotype with higher increases of [O2Hb] during the 2-back version compared with the 1-back version for the subjects of the 7-repeat allele group only. The same effect was seen as a statistical trend, when we compared bad performers with good performers. Therefore, we interpret the effects of the 7-repeat allele group of DRD4 as a sign of ineffective brain activity, perhaps even as a sign of prefrontal noise.

Non-invasive measurement of vagus activity in the brainstem - a methodological progress towards earlier diagnosis of dementias?

In Alzheimer's disease (AD), mild functional disturbances should precede gross structural damage and even more clinical symptoms, possibly by decades. Moreover, alterations in the brainstem are supposed to occur earlier as cortical affections. Based on these considerations, we developed a new method aiming at the measurement of vagal brainstem functioning by means of evoked potentials after electrical stimulation of the cutaneous representation of the vagus nerve in the external auditory channel. In the current study, a first sample of patients with Alzheimer's disease (n = 7) and mild cognitive impairment (n = 3) were investigated (6m, 4f, range from 57 to 78 y, mean age 68.6 years). Vagus somatosensory evoked potentials (VSEP) were characterized by significantly longer latencies as compared to healthy age- and gender-matched controls (p < 0.05). Future large scale studies - also including preclinical stages of AD - have to assess the value of this non-invasive, fast and cheap method in the early diagnosis of neurodegenerative disorders.

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.

Model-based analysis of rapid event-related functional near-infrared spectroscopy (NIRS) data: a parametric validation study.

To validate the usefulness of a model-based analysis approach according to the general linear model (GLM) for functional near-infrared spectroscopy (fNIRS) data, a rapid event-related paradigm with an unpredictable stimulus sequence was applied to 15 healthy subjects. A parametric design was chosen wherein four differently graded contrasts of a flickering checkerboard were presented, allowing directed hypotheses about the rank order of the evoked hemodynamic response amplitudes. The results indicate the validity of amplitude estimation by three main findings (a) the GLM approach for fNIRS data is capable to identify human brain activation in the visual cortex with inter-stimulus intervals of 4-9 s (6.5 s average) whereas in non-visual areas no systematic activation was detectable; (b) the different contrast level intensities lead to the hypothesized rank order of the GLM amplitude parameters: visual cortex activation evoked by highest contrast>moderate contrast>lowest contrast>no stimulation; (c) analysis of null-events (no stimulation) did not produce any significant activation in the visual cortex or in other brain areas. We conclude that a model-based GLM approach delivers valid fNIRS amplitude estimations and enables the analysis of rapid event-related fNIRS data series, which is highly relevant in particular for cognitive fNIRS studies.

Event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations: reproducibility of activation?

The purpose of the present study was to assess the retest reliability of cortical activation detected by event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations. Isolated functional activation was evoked in the motor cortex by a periodically performed finger-tapping task. During 44-channel fNIRS recording, 12 subjects performed 30 trials of right and left index finger tapping in two sessions. The retest interval was set to 3 weeks. Simple correlations of the contrast t-values supplemented by scatterplots, channel-wise intraclass correlation coefficients (ICC), as well as reproducibility indices for the size and the location of the detected activation were calculated. The results at the group level showed sufficient single measure ICCs (up to 0.80) and excellent reproducibility of the size and the location (up to 89% were reproducible). Comparisons of the intersession group amplitudes demonstrate that the fNIRS signals were stable across time in a retest study design: the number of significant differences was less than randomly occurring false-positive activated channels if an alpha level of 5% is chosen. Effect size analyses indicated that the intersession amplitude differences are small (mean < 0.25). For deoxyhemoglobin and oxyhemoglobin distinct statistical power profiles were revealed regarding the activation vs. baseline contrast as well as the intersession amplitude differences, indicating a higher sensitivity of deoxyhemoglobin for local hemodynamic changes. The results suggest that sensorimotor activation assessed by event-related fNIRS based on craniocerebral correlations is sufficiently reproducible at the group level.

Event-related visual versus blocked motor task: detection of specific cortical activation patterns with functional near-infrared spectroscopy.

The purpose of this study was to investigate the regional specificity of multi-channel functional near-infrared spectroscopy (fNIRS) in the detection of cortical activation in humans. Therefore, brain activation evoked by a visual as well as a motor task was examined using 52-channel fNIRS. Analyses demonstrated an isolated activation in the occipital area during visual stimulation, whereas other regions exhibited little or no activation. Analyses of the motor task data clearly identified a differential activation pattern. The observation of an extensive cortical area by multi-channel measurement during two different tasks made it possible to examine the extent to which fNIRS measurements detect regional specific activations. We conclude that fNIRS measurements can detect regionally isolated cortical activation.

Event-related functional near-infrared spectroscopy (fNIRS): are the measurements reliable?

The purpose of the present study was to investigate the retest reliability of event-related functional near-infrared spectroscopy (fNIRS). Therefore, isolated functional activation was evoked in the occipital cortex by a periodic checkerboard stimulation. During a 52-channel fNIRS recording, 12 subjects underwent 60 trials of visual stimulation in two sessions. The retest interval was set to 3 weeks. Linear correlations of the contrast t values supplemented by scatter plots, channel-wise intraclass correlation coefficients (ICC) as well as reproducibility indices for the quantity of activated channels (RQUANTITY) and the location (ROVERLAP) of the detected activation were calculated. The results at the group level showed good reliability in terms of the single measure ICCs (up to 0.84) and excellent reproducibility quantified by RQUANTITY and ROVERLAP (up to 96% of the quantity and the location were reproducible), whereas the results at the single subjects' level were mediocre. Furthermore, the reliability assessed by single measurement ICCs improved if regarded at a cluster level.