High efficiency, low distortion 3D diffusion tensor imaging with variable density spiral fast spin echoes (3D DW VDS RARE)

We present an acquisition and reconstruction method designed to acquire high resolution 3D fast spin echo diffusion tensor images while mitigating the major sources of artifacts in DTI-field distortions, eddy currents and motion. The resulting images, being 3D, are of high SNR, and being fast spin echoes, exhibit greatly reduced field distortions. This sequence utilizes variable density spiral acquisition gradients, which allow for the implementation of a self-navigation scheme by which both eddy current and motion artifacts are removed. The result is that high resolution 3D DTI images are produced without the need for eddy current compensating gradients or B_0 field correction. In addition, a novel method for fast and accurate reconstruction of the non-Cartesian data is employed. Results are demonstrated in the brains of normal human volunteers

Disentangling self from pain:mindfulness meditation-induced pain relief is driven by thalamic-default mode network decoupling

For millenniums, mindfulness was believed to diminish pain by reducing the influence of self-appraisals of noxious sensations. Today, mindfulness meditation is a highly popular and effective pain therapy that is believed to engage multiple, nonplacebo-related mechanisms to attenuate pain. Recent evidence suggests that mindfulness meditation-induced pain relief is associated with the engagement of unique cortico-thalamo-cortical nociceptive filtering mechanisms. However, the functional neural connections supporting mindfulness meditation-based analgesia remain unknown. This mechanistically focused clinical trial combined functional magnetic resonance imaging with psychophysical pain testing (49°C stimulation and pain visual analogue scales) to identify the neural connectivity supporting the direct modulation of pain-related behavioral and neural responses by mindfulness meditation. We hypothesized that mindfulness meditation-based pain relief would be reflected by greater decoupling between brain mechanisms supporting appraisal (prefrontal) and nociceptive processing (thalamus). After baseline pain testing, 40 participants were randomized to a well-validated, 4-session mindfulness meditation or book-listening regimen. Functional magnetic resonance imaging and noxious heat (49°C; right calf) were combined during meditation to test study hypotheses. Mindfulness meditation significantly reduced behavioral and neural pain responses when compared to the controls. Preregistered (NCT03414138) whole-brain analyses revealed that mindfulness meditation-induced analgesia was moderated by greater thalamus-precuneus decoupling and ventromedial prefrontal deactivation, respectively, signifying a pain modulatory role across functionally distinct neural mechanisms supporting self-referential processing. Two separate preregistered seed-to-seed analyses found that mindfulness meditation-based pain relief was also associated with weaker contralateral thalamic connectivity with the prefrontal and primary somatosensory cortex, respectively. Thus, we propose that mindfulness meditation is associated with a novel self-referential nociceptive gating mechanism to reduce pain

Remote spatiotemporally controlled and biologically selective permeabilization of blood-brain barrier

The blood-brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system

vmPFC Activation during a Stressor Predicts Positive Emotions during Stress Recovery

Despite accruing evidence showing that positive emotions facilitate stress recovery, the neural basis for this effect remains unclear. To identify the underlying mechanism, we compared stress recovery for people reflecting on a stressor while in a positive emotional context with that for people in a neutral context. While blood–oxygen-level dependent data were being collected, participants (N = 43) performed a stressful anagram task, which was followed by a recovery period during which they reflected on the stressor while watching a positive or neutral video. Participants also reported positive and negative emotions throughout the task as well as retrospective thoughts about the task. Although there was no effect of experimental context on emotional recovery, we found that ventromedial prefrontal cortex (vmPFC) activation during the stressor predicted more positive emotions during recovery, which in turn predicted less negative emotions during recovery. In addition, the relationship between vmPFC activation and positive emotions during recovery was mediated by decentering—the meta-cognitive detachment of oneself from one’s feelings. In sum, successful recovery from a stressor seems to be due to activation of positive emotion-related regions during the stressor itself as well as to their downstream effects on certain cognitive forms of emotion regulation

Brain moderators supporting the relationship between depressive mood and pain.

Pain and depressive mood commonly exhibit a comorbid relationship. Yet, the brain mechanisms that moderate the relationship between dysphoric mood and pain remain unknown. An exploratory analysis of functional magnetic resonance imaging, behavioral, and psychophysical data was collected from a previous study in 76 healthy, nondepressed, and pain-free individuals. Participants completed the Beck Depression Inventory-II (BDI), a measure of negative mood/depressive symptomology, and provided pain intensity and pain unpleasantness ratings in response to noxious heat (49°C) during perfusion-based, arterial spin-labeled functional magnetic resonance imaging. Moderation analyses were conducted to determine neural mechanisms involved in facilitating the hypothesized relationship between depressive mood and pain sensitivity. Higher BDI-II scores were positively associated with pain intensity (R = 0.10; P = 0.006) and pain unpleasantness (R = 0.12; P = 0.003) ratings. There was a high correlation between pain intensity and unpleasantness ratings (r = 0.94; P < 0.001); thus, brain moderation analyses were focused on pain intensity ratings. Individuals with higher levels of depressive mood exhibited heightened sensitivity to experimental pain. Greater activation in regions supporting the evaluation of pain (ventrolateral prefrontal cortex; anterior insula) and sensory-discrimination (secondary somatosensory cortex; posterior insula) moderated the relationship between higher BDI-II scores and pain intensity ratings. This study demonstrates that executive-level and sensory-discriminative brain mechanisms play a multimodal role in facilitating the bidirectional relationship between negative mood and pain

Enhancing tissue permeability with MRI guided preclinical focused ultrasound system in rabbit muscle: From normal tissue to VX2 tumor

High Intensity Focused Ultrasound (HIFU) is an emerging noninvasive, nonionizing physical energy based modality to ablate solid tumors with high power, or increase local permeability in tissues/tumors in pulsed mode with relatively low power. Compared with traditional ablative HIFU, nondestructive pulsed HIFU (pHIFU) is present in the majority of novel applications recently developed for enhancing the delivery of drugs and genes. Previous studies have demonstrated the capability of pHIFU to change tissue local permeability for enhanced drug delivery in both mouse tumors and mouse muscle. Further study based on bulk tissues in large animals and clinical HIFU system revealed correlation between therapeutic effect and thermal parameters, which was absent in the previous mouse studies. In this study, we further investigated the relation between the therapeutic effect of pHIFU and thermal parameters in bulky normal muscle tissues based on a rabbit model and a preclinical HIFU system. Correlation between therapeutic effect and thermal parameters was confirmed in our study on the same bulk tissues although different HIFU systems were used. Following the study in bulky normal muscle tissues, we further created bulky tumor model with VX2 tumors implanted on both hind limbs of rabbits and investigated the feasibility to enhance tumor permeability in bulky VX2 tumors in a rabbit model using pHIFU technique. A radiolabeled peptidomimetic integrin antagonist, 111In-DOTA-IA, was used following pHIFU treatment in our study to target VX2 tumor and serve as the radiotracer for follow-up single-photon emission computed tomography (SPECT) scanning. The results have shown significantly elevated uptake of 111In-DOTA-IA in the area of VX2 tumors pretreated by pHIFU compared with the control VX2 tumors not being pretreated by pHIFU, and statistical analysis revealed averaged 34.5% enhancement 24h after systematic delivery of 111In-DOTA-IA in VX2 tumors pretreated by pHIFU compared with the control VX2 tumors

Neural mechanisms supporting the relationship between dispositional mindfulness and pain

Inter-individual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective and dispositional factors. Trait mindfulness, characterized as the innate capacity to non-reactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo-analgesia, we sought to determine if dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six, meditation-naïve and healthy volunteers completed the Freiburg Mindfulness Inventory (FMI) and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher FMI ratings were associated with lower pain intensity (p =.005) and pain unpleasantness ratings (p =.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex (PCC) during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive and affective appraisals. We propose that mindfulness and the PCC should be considered as important mechanistic targets for pain therapies

Neural predictors of emotional inertia in daily life.

Assessing emotional dynamics in the brain offers insight into the fundamental neural and psychological mechanisms underlying emotion. One such dynamic is emotional inertia-the influence of one's emotional state at one time point on one's emotional state at a subsequent time point. Emotion inertia reflects emotional rigidity and poor emotion regulation as evidenced by its relationship to depression and neuroticism. In this study, we assessed changes in cerebral blood flow (CBF) from before to after an emotional task and used these changes to predict stress, positive and negative emotional inertia in daily life events. Cerebral blood flow changes in the lateral prefrontal cortex (lPFC) predicted decreased non-specific emotional inertia, suggesting that the lPFC may feature a general inhibitory mechanism responsible for limiting the impact that an emotional state from one event has on the emotional state of a subsequent event. CBF changes in the ventromedial prefrontal cortex and lateral occipital cortex were associated with positive emotional inertia and negative/stress inertia, respectively. These data advance the blossoming literature on the temporal dynamics of emotion in the brain and on the use of neural indices to predict mental health-relevant behavior in daily life

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the “gold standard” for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy

Neural predictors of emotional inertia in daily life.

Assessing emotional dynamics in the brain offers insight into the fundamental neural and psychological mechanisms underlying emotion. One such dynamic is emotional inertia-the influence of one's emotional state at one time point on one's emotional state at a subsequent time point. Emotion inertia reflects emotional rigidity and poor emotion regulation as evidenced by its relationship to depression and neuroticism. In this study, we assessed changes in cerebral blood flow (CBF) from before to after an emotional task and used these changes to predict stress, positive and negative emotional inertia in daily life events. Cerebral blood flow changes in the lateral prefrontal cortex (lPFC) predicted decreased non-specific emotional inertia, suggesting that the lPFC may feature a general inhibitory mechanism responsible for limiting the impact that an emotional state from one event has on the emotional state of a subsequent event. CBF changes in the ventromedial prefrontal cortex and lateral occipital cortex were associated with positive emotional inertia and negative/stress inertia, respectively. These data advance the blossoming literature on the temporal dynamics of emotion in the brain and on the use of neural indices to predict mental health-relevant behavior in daily life