Trait-dependent effects of theta burst stimulation after psychosocial stress: a sham-controlled study in healthy individuals.

OBJECTIVE: Previous studies suggest that theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC) might be a promising approach to modulate stress-reactive rumination and the associated psychophysiological stress response. Crucially, individuals showing higher levels of trait rumination might benefit more from prefrontal stimulation. METHODS: In this sham-controlled study, 127 healthy individuals, with varying ruminative tendencies, received a single-session of intermittent TBS (iTBS), continuous TBS (cTBS) or sham TBS (sTBS) over the left DLPFC before being confronted with a Trier Social Stress Test. RESULTS: Results showed significant TBS effects on salivary cortisol as a function of trait rumination. cTBS, as compared to sTBS and iTBS, resulted in an attenuated stress-induced cortisol response in high compared to low trait ruminators. Although independent of trait rumination levels, cTBS showed positive effects on stress-related changes in mood and, both cTBS and iTBS (versus sham) presented an enhanced heart rate recovery following the stressor. We found no evidence for (trait rumination-dependent) TBS effects on stress-reactive rumination, negative affect, subjective stress or heart rate variability. CONCLUSIONS: cTBS shows beneficial effects on certain measures of stress, especially in high trait ruminators. SIGNIFICANCE: These findings highlight the importance of accounting for individual differences when examining TBS effects.

A randomized-controlled neurofeedback trial in adult attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood onset disorder persisting into adulthood for a large proportion of cases. Neurofeedback (NF) has shown promising results in children with ADHD, but randomized controlled trials in adults with ADHD are scarce. We aimed to compare slow cortical potential (SCP)- and functional near-infrared spectroscopy (fNIRS) NF to a semi-active electromyography biofeedback (EMG-BF) control condition regarding changes in symptoms and the impact of learning success, as well as changes in neurophysiological parameters in an adult ADHD population. Patients were randomly assigned to SCP-NF (n = 26), fNIRS-NF (n = 21) or EMG-BF (n = 20). Outcome parameters were assessed over 30 training sessions (pre, intermediate, post) and at 6-months follow-up (FU) including 3 booster sessions. EEG was recorded during two auditory Go/NoGo paradigms assessing the P300 and contingent negative variation (CNV). fNIRS measurements were conducted during an n-back- as well as a Go/NoGo task. All three groups showed equally significant symptom improvements suggesting placebo- or non-specific effects on the primary outcome measure. Only when differentiating between learners and non-learners, fNIRS learners displayed stronger reduction of ADHD global scores compared to SCP non-learners at FU, and fNIRS learners showed specifically low impulsivity ratings. 30.8% in the SCP-NF and 61.9% of participants in the fNIRS-NF learned to regulate the respective NF target parameter. We conclude that some adults with ADHD learn to regulate SCP amplitudes and especially prefrontal hemodynamic activity during NF. We did not find any significant differences in outcome between groups when looking at the whole sample. When evaluating learners only, they demonstrate superior effects as compared to non-learners, which suggests specific effects in addition to non-specific effects of NF when learning occurs.

Neural oscillatory responses to performance monitoring differ between high- and low-impulsive individuals, but are unaffected by TMS.

Higher impulsivity may arise from neurophysiological deficits of cognitive control in the prefrontal cortex. Cognitive control can be assessed by time-frequency decompositions of electrophysiological data. We aimed to clarify neuroelectric mechanisms of performance monitoring in connection with impulsiveness during a modified Eriksen flanker task in high- (n = 24) and low-impulsive subjects (n = 21) and whether these are modulated by double-blind, sham-controlled intermittent theta burst stimulation (iTBS). We found a larger error-specific peri-response beta power decrease over fronto-central sites in high-impulsive compared to low-impulsive participants, presumably indexing less effective motor execution processes. Lower parieto-occipital theta intertrial phase coherence (ITPC) preceding correct responses predicted higher reaction time (RT) and higher RT variability, potentially reflecting efficacy of cognitive control or general attention. Single-trial preresponse theta phase clustering was coupled to RT in correct trials (weighted ITPC), reflecting oscillatory dynamics that predict trial-specific behavior. iTBS did not modulate behavior or EEG time-frequency power. Performance monitoring was associated with time-frequency patterns reflecting cognitive control (parieto-occipital theta ITPC, theta weighted ITPC) as well as differential action planning/execution processes linked to trait impulsivity (frontal low beta power). Beyond that, results suggest no stimulation effect related to response-locked time-frequency dynamics with the current stimulation protocol. Neural oscillatory responses to performance monitoring differ between high- and low-impulsive individuals, but are unaffected by iTBS.

Interoceptive awareness in patients with attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder normally diagnosed in childhood and persisting into adulthood in up to two-thirds of the patients. Its core symptoms comprise inattention and hyperactive-impulsive behaviours. Several studies suggest that patients with ADHD show alterations in self-regulation and self-monitoring. So far, it has not been described whether these deficits also affect the awareness of one's own bodily signals, that is, interoceptive awareness. To investigate possible alterations in interoceptive awareness, 14 adult patients with ADHD and 16 healthy controls performed a heartbeat detection task, in which they had to count their heartbeat without any external help (e.g. visualization on a screen). As an indicator of the individual interoceptive awareness ability, a score based on the comparison between recorded and counted heart beats was calculated. Our results showed that patients with ADHD performed significantly worse on this task than controls, which indicates that they were less aware of internal bodily signals while additionally experiencing deficits in regulating and monitoring their own (overt) behaviours.

Functionally disconnected: A look at how study design influences neurofeedback data and mechanisms in attention-deficit/hyperactivity disorder.

Neurofeedback (NF) is a form of behavioral therapy used to treat e.g. attention-deficit/hyperactivity disorder (ADHD). Briefly, subjects are fed-back a putatively dysfunctional parameter of their brain activity in real time and must learn to control it in a suggested direction. NF protocols for ADHD have been used in practice for decades, though no clear standards on NF design have been implemented. Furthermore, studies often present only data from the general outcome of the NF treatment and do not look at how exactly the NF paradigm affects brain functionality, or what exactly the NF is training. The current study is two-fold: firstly, we look at how the functional connectivity (FC) patterns within key networks associated with ADHD differ between rests, feedback trials, success and failure in a complete functional near-infrared spectroscopy-based NF experiment on adults with ADHD. Secondly, due to methodological concerns discovered during the analysis of our data, we address important considerations in the design of NF that are often ignored in protocols being used widely in therapy and research today. In particular, we examine the common average reference and its impact on network activity as well as the importance of balancing the randomization in a design. Finally, we discuss how these methodological considerations may have influenced our FC results.

Identification of neurophysiological biotypes in attention deficit hyperactivity disorder.

AIM: Findings on neurophysiological alterations in attention deficit hyperactivity disorder (ADHD) have been proposed to underlie ADHD symptoms, with different etiological pathways for different patient biotypes. We aimed at determining whether neurophysiological deviations confirm distinct neurophysiological profiles in ADHD, thus providing direct evidence for the endophenotype concept. METHODS: Neurophysiological biotypes were investigated in 87 adult patients with ADHD using cluster analysis. Parameters fed into the analysis comprised both hemodynamic and electrophysiological data. To validate results, the independent variables of the clusters were compared with healthy controls. RESULTS: Cluster analysis yielded three neurophysiologically based ADHD biotypes showing: (i) above-average functioning in attention allocation; (ii) difficulties in attention allocation and inhibitory control but elevated frontal activation during a working memory task; and (iii) functional impairments in state regulation. CONCLUSION: Classifying patients with ADHD into neurophysiological biotypes sheds light on etiological pathways, with implications for diagnostics and (individualized) treatment options.

EMG biofeedback training in adult attention-deficit/hyperactivity disorder: An active (control) training?

OBJECTIVE: The present study aimed at revealing neurophysiological effects induced by electromyography (EMG) based biofeedback, considered as a semi-active control condition in neurofeedback studies, in adult attention-deficit/hyperactivity disorder (ADHD) patients. METHODS: 20 adult ADHD patients trained their muscle activity in the left and right supraspinatus muscle over the course of 30 EMG biofeedback sessions. Changes induced by the EMG feedback were evaluated at a clinical and neurophysiological level; additionally, the relation between changes in EEG activity recorded at the vertex over the training course and changes of symptom severity over the treatment course were assessed in order to investigate the mechanisms underlying clinical effects of EMG biofeedback. RESULTS: Participants showed significant behavioral improvements on a self-rating scale. There was a significant increase in alpha power, but no significant changes in the delta frequency range; changes in the theta and beta frequency range were not significant after adjustment for multiple comparisons. No statistically significant correlation was found between changes in EEG frequency bands and changes in ADHD symptoms. CONCLUSIONS: The current results assessed by means of a single-electrode EEG constitute a starting point regarding a clearer understanding of mechanisms underlying clinical effects of EMG biofeedback. Although we did not reveal systematic effects induced by EMG feedback on brain activity it remains an open question whether EMG biofeedback induces changes in brain regions or parameters we did not gather in the present study (e.g. motor cortex).

Near-Infrared Spectroscopy based Neurofeedback of Prefrontal Cortex Activity: A Proof-of-Concept Study.

Neurofeedback is a promising tool for treatment and rehabilitation of several patient groups. In this proof of principle study, near-infrared spectroscopy (NIRS) based neurofeedback of frontal cortical areas was investigated in healthy adults. Main aims were the assessment of learning, the effects on performance in a working memory (n-back) task and the impact of applied strategies on regulation. 13 healthy participants underwent eight sessions of NIRS based neurofeedback within 2 weeks to learn to voluntarily up-regulate hemodynamic activity in prefrontal areas. An n-back task in pre-/post measurements was used to monitor neurocognitive changes. Mean oxygenated hemoglobin (O2Hb) amplitudes over the course of the sessions as well as during the n-back task were evaluated. 12 out of 13 participants were able to regulate their frontal hemodynamic response via NIRS neurofeedback. However, no systematic learning effects were observed in frontal O2Hb amplitudes over the training course in our healthy sample. We found an impact of applied strategies in only 5 out of 13 subjects. Regarding the n-back task, neurofeedback appeared to induce more focused and specific brain activation compared to pre-training measurement. NIRS based neurofeedback is a feasible and potentially effective method, with an impact on activation patterns in a working memory task. Ceiling effects might explain the lack of a systematic learning pattern in healthy subjects. Clinical studies are needed to show effects in patients exhibiting pathological deviations in prefrontal function.

Brain self-regulation in criminal psychopaths.

Psychopathic individuals are characterized by impaired affective processing, impulsivity, sensation-seeking, poor planning skills and heightened aggressiveness with poor self-regulation. Based on brain self-regulation studies using neurofeedback of Slow Cortical Potentials (SCPs) in disorders associated with a dysregulation of cortical activity thresholds and evidence of deficient cortical functioning in psychopathy, a neurobiological approach seems to be promising in the treatment of psychopathy. The results of our intensive brain regulation intervention demonstrate, that psychopathic offenders are able to gain control of their brain excitability over fronto-central brain areas. After SCP self-regulation training, we observed reduced aggression, impulsivity and behavioral approach tendencies, as well as improvements in behavioral-inhibition and increased cortical sensitivity for error-processing. This study demonstrates improvements on the neurophysiological, behavioral and subjective level in severe psychopathic offenders after SCP-neurofeedback training and could constitute a novel neurobiologically-based treatment for a seemingly change-resistant group of criminal psychopaths.

Revisiting [(RSn(IV))6Sn(III)2S12]: directed synthesis, crystal transformation, and luminescence properties.

We report the synthesis of the mixed-valence cluster [(R(5)Sn(IV))6Sn(III)2S12] [1; R(5) = CMe2CH2C(O)Me] under optimization of the reaction conditions. A new crystalline form of 1 in the orthorhombic space group Pbca was found at 250 K, which undergoes crystal transformation into the known monoclinic one at lower temperature. Further, we have studied the luminescence properties of 1. Time-resolved photoluminescence measurements confirm the lability of the tin-chalcogenide bonds to UV irradiation, while the organic ligands are much less affected by it.

Imaging genetics in adult attention-deficit/hyperactivity disorder (ADHD): a way towards pathophysiological understanding?

Attention-deficit/hyperactivity disorder (ADHD) is a common, early-onset and enduring developmental disorder whose underlying etiological and neurobiological processes are the current focus of major research. Research strategies have made considerable effort in elucidating the complex genetic architecture of ADHD and indicate various pathways from genotype to phenotype. Understanding ADHD as a neuropsychiatric disorder enabled to investigate markers of neural activity as endophenotypes to better explain the link from gene to symptomatology (the so-called imaging genetics approach). Overcoming the originally rather restrictive requirements for an endophenotype, imaging genetics studies are supposed to offer a much more flexible and hypothesis-driven approach towards the etiology of ADHD. Although 1) ADHD often persists into adulthood, thus remaining a prevalent disorder, and 2) imaging genetics provides a promising research approach, a review on imaging genetics in adult ADHD - as available for childhood ADHD (Durston 2010) - is lacking. In this review, therefore, findings from the few available imaging genetics studies in adult ADHD will be summarized and complemented by relevant findings from healthy controls and children with ADHD that are considered important for the adult ADHD imaging genetics approach. The studies will be reviewed regarding implications for basic research and possible practical applications. Imaging genetics studies in adult ADHD have the potential to further clarify pathophysiological pathways and mechanisms, to derive new testable hypotheses, to investigate genetic interaction effects and to partly influence practical applications. In combination with other research strategies, they can incrementally foster the understanding of relevant processes in a more comprehensive way. Current limitations comprise the incapability to discover new genes, a high genetic load in patients potentially obscuring the effect of single candidate genes, the mostly unknown heritability of the endophenotype and the heterogeneous manifestation of ADHD.

Deficient fear conditioning in psychopathy as a function of interpersonal and affective disturbances.

The diminished fear reactivity is one of the most valid physiological findings in psychopathy research. In a fear conditioning paradigm, with faces as conditioned stimulus (CS) and electric shock as unconditioned stimulus (US), we investigated a sample of 14 high psychopathic violent offenders. Event related potentials, skin conductance responses (SCR) as well as subjective ratings of the CSs were collected. This study assessed to which extent the different facets of the psychopathy construct contribute to the fear conditioning deficits observed in psychopaths. Participants with high scores on the affective facet subscale of the Psychopathy Checklist-Revised (PCL-R) showed weaker conditioned fear responses and lower N100 amplitudes compared to low scorers. In contrast, high scorers on the affective facet rated the CS+ (paired) more negatively than low scorers regarding the CS- (unpaired). Regarding the P300, high scores on the interpersonal facet were associated with increased amplitudes to the CS+ compared to the CS-, while the opposed pattern was found for the antisocial facet. Both, the initial and terminal contingent negative variation indicated a divergent pattern: participants with pronounced interpersonal deficits, showed increased cortical negativity to the CS+ compared to the CS-, whereas a reversed CS+/CS- differentiation was found in offenders scoring high on the antisocial facet. The present study revealed that deficient fear conditioning in psychopathy was most pronounced in offenders with high scores on the affective facet. Event related potentials suggest that participants with distinct interpersonal deficits showed increased information processing, whereas the antisocial facet was linked to decreased attention and interest to the CS+. These data indicate that an approach to the facets of psychopathy can help to resolve ambiguous findings in psychopathy research and enables a more precise and useful description of this disorder.

Functionalized organotin-chalcogenide complexes that exhibit defect heterocubane scaffolds: formation, synthesis, and characterization.

The synthesis of new functionalized organotin-chalcogenide complexes was achieved by systematic optimization of the reaction conditions. The structures of compounds [(R(1, 2) Sn)3 S4 Cl] (1, 2), [((R(2) Sn)2 SnS4 )2 (µ-S)2 ] (3), [(R(1, 2) Sn)3 Se4 ][SnCl3 ] (4, 5), and [Li(thf)n ][(R(3) Sn)(HR(3) Sn)2 Se4 Cl] (6), in which R(1) =CMe2 CH2 C(O)Me, R(2) =CMe2 CH2 C(NNH2 )Me, and R(3) =CH2 CH2 COO, are based on defect heterocubane scaffolds, as shown by X-ray diffraction, (119) Sn NMR spectroscopy, and ESI mass spectrometry analyses. Compounds 4, 5, and 6 constitute the first examples of defect heterocubane-type metal-chalcogenide complexes that are comprised of selenide ligands. Comprehensive DFT calculations prompted us to search for the formal intermediates [(R(1) SnCl2 )2 (µ-S)] (7) and [(R(1) SnCl)2 (µ-S)2 ] (8), which were isolated and helped to understand the stepwise formation of compounds 1-6.

Towards the installation of transition metal ions on donor ligand decorated tin sulfide clusters.

Decoration of tetrelchalcogenide T-E clusters with chelating donor ligands was achieved to capture transition metal ions on their surfaces. We demonstrate that by covalent linking of bispyridyl ligands to an Sn-S complex, [ZnX](+) units can be trapped and incorporated into the cluster framework. Intermediates that were identified using spectroscopy and/or X-ray diffraction gave insight into the formation processes.