Real-time fMRI neurofeedback (rtfMRI-NF) has emerged as a promising intervention for psychiatric disorders, yet its clinical efficacy remains underexplored due to an incomplete mechanistic understanding. This study aimed to delineate the whole-brain mechanisms underpinning the effects of rtfMRI-NF on repetitive negative thinking in depression. In a double-blind randomized controlled trial, forty-three depressed individuals underwent NF training targeting the functional connectivity (FC) between the posterior cingulate cortex and the right temporoparietal junction, linked to rumination severity. Participants were randomly assigned to active or sham groups, with the sham group receiving synthesized feedback mimicking real NF signal patterns. The active group demonstrated a significant reduction in brooding rumination scores (d = -1.52, p < 0.001), whereas the sham group did not (d = -0.23, p = 0.503). While the target FC did not show discernible training effects or group differences, connectome-based predictive modeling (CPM) analysis revealed that the interaction between brain activity during regulation and brain response to the feedback signal was the critical factor in explaining treatment outcomes. The model incorporating this interaction successfully predicted rumination changes across both groups. The FCs significantly contributing to the prediction were distributed across brain regions, notably the frontal control, salience network, and subcortical reward processing areas. These results underscore the importance of considering the interplay between brain regulation activities and brain response to the feedback signal in understanding the therapeutic mechanisms of rtfMRI-NF. The study affirms rtfMRI-NF\'s potential as a therapeutic intervention for repetitive negative thinking and highlights the need for a nuanced understanding of the whole-brain mechanisms contributing to its efficacy.

OBJECTIVE: A new closed-loop functional magnetic resonance imaging method called multivoxel neuroreinforcement has the potential to alleviate the subjective aversiveness of exposure-based interventions by directly inducing phobic representations in the brain, outside of conscious awareness. The current study seeks to test this method as an intervention for specific phobia.
METHODS: In a randomized, double-blind, controlled single-university trial, individuals diagnosed with at least two (one target, one control) animal subtype-specific phobias were randomly assigned (1:1:1) to receive one, three, or five sessions of multivoxel neuroreinforcement in which they were rewarded for implicit activation of a target animal representation. Amygdala response to phobic stimuli was assessed by study staff blind to target and control animal assignments. Pretreatment to posttreatment differences were analyzed with a two-way repeated-measures anova.
RESULTS: A total of 23 participants (69.6% female) were randomized to receive one (n = 8), three (n = 7), or five (n = 7) sessions of multivoxel neuroreinforcement. Eighteen (n = 6 each group) participants were analyzed for our primary outcome. After neuroreinforcement, we observed an interaction indicating a significant decrease in amygdala response for the target phobia but not the control phobia. No adverse events or dropouts were reported as a result of the intervention.
CONCLUSIONS: Results suggest that multivoxel neuroreinforcement can specifically reduce threat signatures in specific phobia. Consequently, this intervention may complement conventional psychotherapy approaches with a nondistressing experience for patients seeking treatment. This trial sets the stage for a larger randomized clinical trial to replicate these results and examine the effects on real-life exposure.
BACKGROUND: The now-closed trial was prospectively registered at ClinicalTrials.gov with ID NCT03655262.

OBJECTIVE: This study aims to investigate the effects of a neurofeedback system on cognitive skills, as measured by the Wechsler Intelligence Scale for Children-Revised (WISC-R), in a cohort of 100 children aged 8 to 12 who were diagnosed with attention deficit.
METHODS: A randomized single-blind sham control group design was employed, with 50 participants assigned to the experimental group receiving neurofeedback training and 50 participants assigned to the sham group receiving simulated training. Participants were selected through random sampling from individuals seeking assistance at a specialized education center over the course of one year (May 2021-2022). Pre- and post-test WISC-R assessments were administered to both groups to evaluate participants\' mental performance. The experimental group underwent a total of 60 sessions of quantitative electroencephalography-based infralow frequency neurofeedback training, with half-hour sessions conducted three days a week over a five-month period. The post-test WISC-R was administered at the end of the sixth month.
RESULTS: The results revealed significant differences between the pre- and post-training test scores, specifically in terms of verbal IQ, picture arrangement, performance IQ, and total IQ (p = 0.016, p = 0.001, p < 0.001, and p = 0.002, respectively), when comparing the differences between the two groups.
CONCLUSIONS: These findings indicate a notable improvement in performance IQ, total IQ, and a reduction in attention deficits among the neurofeedback group based on the WISC-R assessments. Future studies should consider employing larger sample sizes, including appropriate control groups, and conducting long-term follow-ups to further elucidate the clinical significance of these results.

Neurofeedback (NF) is a promising intervention for improvements in motor performance in Parkinson\'s disease. This NF pilot study in healthy participants aimed to achieve the following: (1) determine participants\' ability to bi-directionally modulate sensorimotor beta power and (2) determine the effect of NF on movement performance. A real-time EEG-NF protocol was used to train participants to increase and decrease their individual motor cortex beta power amplitude, using a within-subject double-blind sham-controlled approach. Movement was assessed using a Go/No-go task. Participants completed the NASA Task Load Index and provided verbal feedback of the NF task difficulty. All 17 participants (median age = 38 (19-65); 10 females) reliably reduced sensorimotor beta power. No participant could reliably increase their beta activity. Participants reported that the NF task was challenging, particularly increasing beta. A modest but significant increase in reaction time correlated with a reduction in beta power only in the real condition. Findings suggest that beta power control difficulty varies by modulation direction, affecting participant perceptions. A correlation between beta power reduction and reaction times only in the real condition suggests that intentional beta power reduction may shorten reaction times. Future research should examine the minimum beta threshold for meaningful motor improvements, and the relationship between EEG mechanisms and NF learning to optimise NF outcomes.

Due to its central role in cognitive control, the dorso-lateral prefrontal cortex (dlPFC) has been the target of multiple brain modulation studies. In the context of the present pilot study, the dlPFC was the target of eight repeated neurofeedback (NF) sessions with functional near infrared spectroscopy (fNIRS) to assess the brain responses during NF and with functional and resting state magnetic resonance imaging (task-based fMRI and rsMRI) scanning. Fifteen healthy participants were recruited. Cognitive task fMRI and rsMRI were performed during the 1st and the 8th NF sessions. During NF, our data revealed an increased activity in the dlPFC as well as in brain regions involved in cognitive control and self-regulation learning (pFWE < 0.05). Changes in functional connectivity between the 1st and the 8th session revealed increased connectivity between the posterior cingulate cortex and the dlPFC, and between the posterior cingulate cortex and the dorsal striatum (pFWE < 0.05). Decreased left dlPFC-left insula connectivity was also observed. Behavioural results revealed a significant effect of hunger and motivation on the participant control feeling and a lower control feeling when participants did not identify an effective mental strategy, providing new insights on the effects of behavioural factors that may affect the NF learning.

Arterial spin labelling (ASL) is the only non-invasive technique that allows absolute quantification of perfusion and is increasingly used in brain activation studies. Contrary to the blood oxygen level-dependent (BOLD) effect ASL measures the cerebral blood flow (CBF) directly. However, the ASL signal has a lower signal-to-noise ratio (SNR), than the BOLD signal, which constrains its utilization in neurofeedback studies. If successful, ASL neurofeedback can be used to aid in the rehabilitation of health conditions with impaired blood flow, for example, stroke. We provide the first ASL-based neurofeedback study incorporating a double-blind, sham-controlled design. A pseudo-continuous ASL (pCASL) approach with background suppression and 3D GRASE readout was combined with a real-time post-processing pipeline. The real-time pipeline allows to monitor the ASL signal and provides real-time feedback on the neural activity to the subject. In total 41 healthy adults (19-56 years) divided into three groups underwent a neurofeedback-based emotion imagery training of the left anterior insula. Two groups differing only in the explicitness level of instruction received real training and a third group received sham feedback. Only those participants receiving real feedback with explicit instruction showed significantly higher absolute CBF values in the trained region during neurofeedback than participants receiving sham feedback. However, responder analyses of percent signal change values show no differences in activation between the three groups. Persisting limitations, such as the lower SNR, confounding effects of arterial transit time and partial volume effects still impact negatively the implementation of ASL neurofeedback.

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Gamma-band (> 30 Hz) brain oscillatory activity is linked with sensory and cognitive processes and exhibits abnormalities in neuropsychiatric disorders. Therefore, neuromodulation techniques targeting gamma activity are being developed. One promising approach is neurofeedback (NFB) which is based on the alteration of brain responses via online feedback. However, the existing gamma-based NFB systems lack individualized approach. In the present work, we developed and tested an individualized EEG-NFB system. 46 healthy volunteers participated in three sessions on separate days. Before NFB training, individual gamma frequency (IGF) was estimated using chirp-modulated auditory stimulation (30-60 Hz). Participants were subjected to IGF-increase (if IGF was ≤ 45 Hz) or IGF-decrease conditions (if IGF was > 45 Hz). Gamma-band responses were targeted during NFB training, in which participants received auditory steady-state stimulation at frequency slightly above or below IGF and were instructed to try to increase their response while receiving real-time visual feedback. Each time a pre-defined response goal was reached, stimulation frequency was either increased or decreased. After training, IGF was reassessed. Experimental group participants were divided into equal groups based on the median success rate during NFB training. The results showed that high-responders had a significantly higher IGF modulation compared to control group, while low-responders did not differ from controls. No differences in IGF modulation were found between sessions and between NFB repetitions in all participant groups. The initial evaluation of the proposed EEG-NFB system showed potential to modulate IGF. Future studies could investigate longer-lasting electrophysiological and behavioural effects of the application of ASSR/IGF-based NFB system in clinical populations.

This parallel, two-arm, blinded, randomized controlled superiority trial examined whether, when added to usual care, active- electroencephalography neurofeedback (EEG NFB) was safe and more effective than sham control-EEG NFB for chronic pain. 116 participants with chronic pain were randomly assigned (1:1) to usual care plus ≥ 32 sessions of active-EEG NFB upregulating relative alpha power over C4 or usual care plus ≥ 32 sessions of sham control-EEG NFB. Per protocol analyses revealed no significant between-group differences in the primary outcome, brief pain inventory (BPI) average pain (mean difference [95% CI]: -0.04 [-0.39 to 0.31], p=0.90), or any secondary outcomes. However, 44% of participants in the active-EEG NFB group and 45% in the control-EEG NFB group reported at least a moderate (≥30%), clinically important improvement in BPI average pain. The number of treatment emergent adverse events were similar in both groups (p = 0.83), and none were serious. Post-hoc analyses revealed similar upregulated relative alpha power in both groups during training, with concordant positive rewards delivered to the active-EEG group 100% of the time and the control-EEG group ~25% of the time, suggesting a partially active sham intervention. When added to usual care, the active-EEG NFB intervention used in this study was not superior to the sham control-EEG NFB intervention. However, a large proportion of participants in both groups reported a clinically important reduction in pain intensity. A partially active sham intervention may have obscured between-group differences. The intervention was free of important side effects, with no safety concerns identified. PERSPECTIVES: This study is the first attempt at an appropriately blinded, randomized, sham-controlled trial of alpha EEG NFB for the treatment of chronic pain. The findings may interest people living with chronic pain, clinicians involved in chronic pain management, and may inform the design of future EEG NFB trials. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000667819.

Even before the advent of fMRI, the amygdala occupied a central space in the affective neurosciences. Yet this amygdala-centred view on emotion processing gained even wider acceptance after the inception of fMRI in the early 1990s, a landmark that triggered a goldrush of fMRI studies targeting the amygdala in vivo. Initially, this amygdala fMRI research was mostly confined to task-activation studies measuring the magnitude of the amygdala\'s response to emotional stimuli. Later, interest began to shift more towards the study of the amygdala\'s resting-state functional connectivity and task-based psychophysiological interactions. Later still, the test-retest reliability of amygdala fMRI came under closer scrutiny, while at the same time, amygdala-based real-time fMRI neurofeedback gained widespread popularity. Each of these major subdomains of amygdala fMRI research has left its marks on the field of affective neuroscience at large. The purpose of this review is to provide a critical assessment of this literature. By integrating the insights garnered by these research branches, we aim to answer the question: What part (if any) can amygdala fMRI still play within the current landscape of affective neuroscience? Our findings show that serious questions can be raised with regard to both the reliability and validity of amygdala fMRI. These conclusions force us to cast doubt on the continued viability of amygdala fMRI as a core pilar of the affective neurosciences.