Brain functional connectivity of hypnosis without target suggestion. An intrinsic hypnosis rs-fMRI study.

OBJECTIVE: During hypnosis, significant changes in the BOLD signal associated with the anterior default mode network (DMN) and prefrontal attentional systems have been reported as evidence of dissociation defined since Charcot. However, it remains uncertain whether these changes are mainly attributable to the hypnotic state per se or to the target suggestions used to verify subject's state during neuroimaging studies. The aim of the present study is to evidence the brain in hypnosis, contrasting the common resting state versus neutral hypnosis (hypnosis in the absence of target suggestions). METHODS: Twenty-four healthy right-handed volunteers (age 28.3 y.o., 12 females) rated moderate hypnotic responsiveness underwent resting state fMRI at 3.0 T in two sessions, once in neutral hypnosis and the other in the common resting state. Each subject's functional data were analyzed for low-frequency BOLD signal correlations seed-to-voxel for the whole brain in the first-level analysis, and seed-to-voxel in a second-level analysis to estimate group results using seeds for five resting state networks: the default mode (DMN), the central executive (CEN), the salience (SaN), the dorso-lateral attention (DAN), and the sensorimotor (SMN) networks. RESULTS: In general, all network maps of the hypnotic condition presented higher connectivity than those of the resting condition. However, only contrasts for the DAN, SaN, and SMN were statistically significant, including correlated out-of-the-network regions. CONCLUSION: Parietal and occipital regions displayed increased connectivity across networks, implying dissociation from the frontal cortices. This is the first fMRI intrinsic study of hypnosis without target suggestion.

Mindfulness-based real-time fMRI neurofeedback: a randomized controlled trial to optimize dosing for depressed adolescents.

BACKGROUND: Adolescence is characterized by a heightened vulnerability for Major Depressive Disorder (MDD) onset, and currently, treatments are only effective for roughly half of adolescents with MDD. Accordingly, novel interventions are urgently needed. This study aims to establish mindfulness-based real-time fMRI neurofeedback (mbNF) as a non-invasive approach to downregulate the default mode network (DMN) in order to decrease ruminatory processes and depressive symptoms. METHODS: Adolescents (N = 90) with a current diagnosis of MDD ages 13-18-years-old will be randomized in a parallel group, two-arm, superiority trial to receive either 15 or 30 min of mbNF with a 1:1 allocation ratio. Real-time neurofeedback based on activation of the frontoparietal network (FPN) relative to the DMN will be displayed to participants via the movement of a ball on a computer screen while participants practice mindfulness in the scanner. We hypothesize that within-DMN (medial prefrontal cortex [mPFC] with posterior cingulate cortex [PCC]) functional connectivity will be reduced following mbNF (Aim 1: Target Engagement). Additionally, we hypothesize that participants in the 30-min mbNF condition will show greater reductions in within-DMN functional connectivity (Aim 2: Dosing Impact on Target Engagement). Aim 1 will analyze data from all participants as a single-group, and Aim 2 will leverage the randomized assignment to analyze data as a parallel-group trial. Secondary analyses will probe changes in depressive symptoms and rumination. DISCUSSION: Results of this study will determine whether mbNF reduces functional connectivity within the DMN among adolescents with MDD, and critically, will identify the optimal dosing with respect to DMN modulation as well as reduction in depressive symptoms and rumination. TRIAL REGISTRATION: This study has been registered with clinicaltrials.gov, most recently updated on July 6, 2023 (trial identifier: NCT05617495).

Reducing default mode network connectivity with mindfulness-based fMRI neurofeedback: a pilot study among adolescents with affective disorder history.

Adolescents experience alarmingly high rates of major depressive disorder (MDD), however, gold-standard treatments are only effective for ~50% of youth. Accordingly, there is a critical need to develop novel interventions, particularly ones that target neural mechanisms believed to potentiate depressive symptoms. Directly addressing this gap, we developed mindfulness-based fMRI neurofeedback (mbNF) for adolescents that aims to reduce default mode network (DMN) hyperconnectivity, which has been implicated in the onset and maintenance of MDD. In this proof-of-concept study, adolescents (n = 9) with a lifetime history of depression and/or anxiety were administered clinical interviews and self-report questionnaires, and each participant's DMN and central executive network (CEN) were personalized using a resting state fMRI localizer. After the localizer scan, adolescents completed a brief mindfulness training followed by a mbNF session in the scanner wherein they were instructed to volitionally reduce DMN relative to CEN activation by practicing mindfulness meditation. Several promising findings emerged. First, mbNF successfully engaged the target brain state during neurofeedback; participants spent more time in the target state with DMN activation lower than CEN activation. Second, in each of the nine adolescents, mbNF led to significantly reduced within-DMN connectivity, which correlated with post-mbNF increases in state mindfulness. Last, a reduction of within-DMN connectivity mediated the association between better mbNF performance and increased state mindfulness. These findings demonstrate that personalized mbNF can effectively and non-invasively modulate the intrinsic networks associated with the emergence and persistence of depressive symptoms during adolescence.

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Mindfulness training preserves sustained attention and resting state anticorrelation between default-mode network and dorsolateral prefrontal cortex: A randomized controlled trial.

Mindfulness training can enhance cognitive control, but the neural mechanisms underlying such enhancement in children are unknown. Here, we conducted a randomized controlled trial (RCT) with sixth graders (mean age 11.76 years) to examine the impact of 8 weeks of school-based mindfulness training, relative to coding training as an active control, on sustained attention and associated resting-state functional brain connectivity. At baseline, better performance on a sustained-attention task correlated with greater anticorrelation between the default mode network (DMN) and right dorsolateral prefrontal cortex (DLPFC), a key node of the central executive network. Following the interventions, children in the mindfulness group preserved their sustained-attention performance (i.e., fewer lapses of attention) and preserved DMN-DLPFC anticorrelation compared to children in the active control group, who exhibited declines in both sustained attention and DMN-DLPFC anticorrelation. Further, change in sustained-attention performance correlated with change in DMN-DLPFC anticorrelation only within the mindfulness group. These findings provide the first causal link between mindfulness training and both sustained attention and associated neural plasticity. Administered as a part of sixth graders' school schedule, this RCT supports the beneficial effects of school-based mindfulness training on cognitive control.

Consensus on the reporting and experimental design of clinical and cognitive-behavioural neurofeedback studies (CRED-nf checklist).

Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

Real-time fMRI neurofeedback reduces auditory hallucinations and modulates resting state connectivity of involved brain regions: Part 2: Default mode network -preliminary evidence.

Auditory hallucinations (AHs) are one of the most distressing symptoms of schizophrenia (SZ) and are often resistant to medication. Imaging studies of individuals with SZ show hyperactivation of the default mode network (DMN) and the superior temporal gyrus (STG). Studies in SZ show DMN hyperconnectivity and reduced anticorrelation between DMN and the central executive network (CEN). DMN hyperconnectivity has been associated with positive symptoms such as AHs while reduced DMN anticorrelations with cognitive impairment. Using real-time fMRI neurofeedback (rt-fMRI-NFB) we trained SZ patients to modulate DMN and CEN networks. Meditation is effective in reducing AHs in SZ and to modulate brain network integration and increase DMN anticorrelations. Consequently, patients were provided with meditation strategies to enhance their abilities to modulate DMN/CEN. Results show a reduction of DMN hyperconnectivity and increase in DMNCEN anticorrelation. Furthermore, the change in individual DMN connectivity significantly correlated with reductions in AHs. This is the first time that meditation enhanced through rt-fMRI-NFB is used to reduce AHs in SZ. Moreover, it provides the first empirical evidence for a direct causal relation between meditation enhanced rt-fMRI-NFB modulation of DMNCEN activity and post-intervention modulation of resting state networks ensuing in reductions in frequency and severity of AHs.

Mindfulness training reduces stress and amygdala reactivity to fearful faces in middle-school children.

The impact of mindfulness training on stress and associated brain plasticity has been shown in adults, whereas the impact of such training in the developing brain remains unknown. To address this open question, 40 middle-school children were randomized to either mindfulness or coding training (active control) interventions during the school day for eight weeks. Outcome measures were ratings of self-perceived stress and right amygdala activation while viewing fearful, happy, and neutral facial expressions during functional MRI. Prior to intervention, greater stress correlated with greater right amygdala activation in response to fearful versus neutral facial expressions across all children. After intervention, children who received mindfulness training reported lower stress associated with reduced right amygdala activation to fearful faces relative to children in the control condition. Amygdala responses to happy faces were unrelated to either initial stress or mindfulness reduction of stress. Moreover, mindfulness training led to relatively stronger functional connectivity between the right amygdala and ventromedial prefrontal cortex during the viewing of fearful facial expressions. Changes in perceived stress and neuroplasticity occurred in nonmeditative states, indicating that the benefits of mindfulness training generalized beyond the active meditative state. This study provides initial evidence that mindfulness training in children reduces stress and promotes functional brain changes and that such training can be integrated into the school curriculum for entire classes. This study also reveals first evidence that a neurocognitive mechanism for both stress and its reduction by mindfulness training is related specifically to reduced amygdala responses to negative stimuli. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Applying novel technologies and methods to inform the ontology of self-regulation.

Self-regulation is a broad construct representing the general ability to recruit cognitive, motivational and emotional resources to achieve long-term goals. This construct has been implicated in a host of health-risk behaviors, and is a promising target for fostering beneficial behavior change. Despite its clear importance, the behavioral, psychological and neural components of self-regulation remain poorly understood, which contributes to theoretical inconsistencies and hinders maximally effective intervention development. We outline a research program that seeks to define a neuropsychological ontology of self-regulation, articulating the cognitive components that compose self-regulation, their relationships, and their associated measurements. The ontology will be informed by two large-scale approaches to assessing individual differences: first purely behaviorally using data collected via Amazon's Mechanical Turk, then coupled with neuroimaging data collected from a separate population. To validate the ontology and demonstrate its utility, we will then use it to contextualize health risk behaviors in two exemplar behavioral groups: overweight/obese adults who binge eat and smokers. After identifying ontological targets that precipitate maladaptive behavior, we will craft interventions that engage these targets. If successful, this work will provide a structured, holistic account of self-regulation in the form of an explicit ontology, which will better clarify the pattern of deficits related to maladaptive health behavior, and provide direction for more effective behavior change interventions.

Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.

Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.

Functional brain basis of hypnotizability.

CONTEXT: Focused hypnotic concentration is a model for brain control over sensation and behavior. Pain and anxiety can be effectively alleviated by hypnotic suggestion, which modulates activity in brain regions associated with focused attention, but the specific neural network underlying this phenomenon is not known. OBJECTIVE: To investigate the brain basis of hypnotizability. DESIGN: Cross-sectional, in vivo neuroimaging study performed from November 2005 through July 2006. SETTING: Academic medical center at Stanford University School of Medicine. PATIENTS: Twelve adults with high and 12 adults with low hypnotizability. MAIN OUTCOME MEASURES: Functional magnetic resonance imaging to measure functional connectivity networks at rest, including default-mode, salience, and executive-control networks; structural T1 magnetic resonance imaging to measure regional gray and white matter volumes; and diffusion tensor imaging to measure white matter microstructural integrity. RESULTS: High compared with low hypnotizable individuals had greater functional connectivity between the left dorsolateral prefrontal cortex, an executive-control region of the brain, and the salience network composed of the dorsal anterior cingulate cortex, anterior insula, amygdala, and ventral striatum, involved in detecting, integrating, and filtering relevant somatic, autonomic, and emotional information using independent component analysis. Seed-based analysis confirmed elevated functional coupling between the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex in high compared with low hypnotizable individuals. These functional differences were not due to any variation in brain structure in these regions, including regional gray and white matter volumes and white matter microstructure. CONCLUSIONS: Our results provide novel evidence that altered functional connectivity in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex may underlie hypnotizability. Future studies focusing on how these functional networks change and interact during hypnosis are warranted.

Cross auditory-spatial learning in early-blind individuals.

Cross-modal processing enables the utilization of information received via different sensory organs to facilitate more complicated human actions. We used functional MRI on early-blind individuals to study the neural processes associated with cross auditory-spatial learning. The auditory signals, converted from echoes of ultrasonic signals emitted from a navigation device, were novel to the participants. The subjects were trained repeatedly for 4 weeks in associating the auditory signals with different distances. Subjects' blood-oxygenation-level-dependent responses were captured at baseline and after training using a sound-to-distance judgment task. Whole-brain analyses indicated that the task used in the study involved auditory discrimination as well as spatial localization. The learning process was shown to be mediated by the inferior parietal cortex and the hippocampus, suggesting the integration and binding of auditory features to distances. The right cuneus was found to possibly serve a general rather than a specific role, forming an occipital-enhanced network for cross auditory-spatial learning. This functional network is likely to be unique to those with early blindness, since the normal-vision counterparts shared activities only in the parietal cortex.

Brain basis of phonological awareness for spoken language in children and its disruption in dyslexia.

Phonological awareness, knowledge that speech is composed of syllables and phonemes, is critical for learning to read. Phonological awareness precedes and predicts successful transition from language to literacy, and weakness in phonological awareness is a leading cause of dyslexia, but the brain basis of phonological awareness for spoken language in children is unknown. We used functional magnetic resonance imaging to identify the neural correlates of phonological awareness using an auditory word-rhyming task in children who were typical readers or who had dyslexia (ages 7-13) and a younger group of kindergarteners (ages 5-6). Typically developing children, but not children with dyslexia, recruited left dorsolateral prefrontal cortex (DLPFC) when making explicit phonological judgments. Kindergarteners, who were matched to the older children with dyslexia on standardized tests of phonological awareness, also recruited left DLPFC. Left DLPFC may play a critical role in the development of phonological awareness for spoken language critical for reading and in the etiology of dyslexia.

Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression.

BACKGROUND: Women have approximately twice the risk of major depressive disorder (MDD) than men, yet this difference remains largely unexplained. Previous MDD research suggests high rates of endocrine dysfunction, which may be related to deficits in brain activity in stress response circuitry [hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC)]. This functional magnetic resonance imaging (fMRI) study investigated the relationship between hypothalamic-pituitary-gonadal (HPG)-axis hormones and stress response circuitry dysfunction in MDD in women. METHODS: During the late follicular/midcycle phase of the menstrual cycle, female participants (10 with extensive histories of MDD, in remission, 10 healthy controls) were scanned while viewing negative and neutral arousal pictures. Group differences in blood oxygen-level dependent (BOLD) signal changes were analyzed using SPM2. Baseline gonadal hormones included estradiol, progesterone, and testosterone. RESULTS: fMRI results showed greater BOLD signal intensity changes in controls versus MDD in hypothalamus, amygdala, hippocampus, OFC, ACC, and subgenual ACC, findings unrelated to medication status. MDD women had a lower serum estradiol and higher serum progesterone compared to controls. Hypoactivations in hypothalamus, subgenual ACC, amygdala and OFC in MDD were associated with low estradiol and high progesterone. LIMITATIONS: Generalizability of our findings is limited by small sample size and restriction to females, although this did not affect the internal validity of the results. CONCLUSIONS: Hypoactivation of the stress response circuitry in MDD women is associated with dysregulation of the HPG-axis. Associations between brain activity deficits and hormonal disruption in MDD may ultimately contribute to understanding sex differences in MDD.

Computing moment-to-moment BOLD activation for real-time neurofeedback.

Estimating moment-to-moment changes in blood oxygenation level dependent (BOLD) activation levels from functional magnetic resonance imaging (fMRI) data has applications for learned regulation of regional activation, brain state monitoring, and brain-machine interfaces. In each of these contexts, accurate estimation of the BOLD signal in as little time as possible is desired. This is a challenging problem due to the low signal-to-noise ratio of fMRI data. Previous methods for real-time fMRI analysis have either sacrificed the ability to compute moment-to-moment activation changes by averaging several acquisitions into a single activation estimate or have sacrificed accuracy by failing to account for prominent sources of noise in the fMRI signal. Here we present a new method for computing the amount of activation present in a single fMRI acquisition that separates moment-to-moment changes in the fMRI signal intensity attributable to neural sources from those due to noise, resulting in a feedback signal more reflective of neural activation. This method computes an incremental general linear model fit to the fMRI time series, which is used to calculate the expected signal intensity at each new acquisition. The difference between the measured intensity and the expected intensity is scaled by the variance of the estimator in order to transform this residual difference into a statistic. Both synthetic and real data were used to validate this method and compare it to the only other published real-time fMRI method.