Improved laminar specificity and sensitivity by combining SE and GE BOLD signals.

The most widely used gradient-echo (GE) blood oxygenation level-dependent (BOLD) contrast has high sensitivity, but low specificity due to draining vein contributions, while spin-echo (SE) BOLD approach at ultra-high magnetic fields is highly specific to neural active sites but has lower sensitivity. To obtain high specificity and sensitivity, we propose to utilize a vessel-size-sensitive filter to the GE-BOLD signal, which suppresses macrovascular contributions and to combine selectively retained microvascular GE-BOLD signals with the SE-BOLD signals. To investigate our proposed idea, fMRI with 0.8 mm isotropic resolution was performed on the primary motor and sensory cortices in humans at 7 T by implementing spin- and gradient-echo (SAGE) echo planar imaging (EPI) acquisition. Microvascular-passed sigmoidal filters were designed based upon the vessel-size-sensitive ΔR2*/ΔR2 value for retaining GE-BOLD signals originating from venous vessels with ≤ 45 µm and ≤ 65 µm diameter. Unlike GE-BOLD fMRI, the laminar profile of SAGE-BOLD fMRI with the vessel-size-sensitive filter peaked at ∼ 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity over GE-BOLD fMRI. Also, the functional sensitivity of SAGE BOLD at middle layers (0.75-1.5 mm) was improved by ∼ 80% to ∼100% when compared with SE BOLD. In summary, we showed that combined GE- and SE-BOLD fMRI with the vessel-size-sensitive filter indeed yielded improved laminar specificity and sensitivity and is therefore an excellent tool for high spatial resolution ultra-high filed (UHF)-fMRI studies for resolving mesoscopic functional units.

Deactivation of the attention-shifting ventromedial prefrontal cortex during the encoding and hold phases predicts working memory performance.

OBJECTIVES: Recent neuroimaging studies have suggested that the deactivation of the ventromedial prefrontal cortex (VMPFC) works with the attention shifting area to facilitate the encoding of behaviorally relevant inputs. These findings have led to the notion that the deactivation of VMPFC substantially contributes to the cognitive control of emotions. Although VMPFC deactivation during working memory tasks is established, whether it contributes to performance in emotionally distracted working memory tasks remains unclear. This study aimed to investigate whether the magnitude of VMPFC deactivation predicts better performance in emotionally distracted working memory tasks. METHODS: Twenty-nine female participants performed delayed-response working memory tasks with emotional distracters presented during the hold phase of working memory while undergoing functional MRI. A GLM and a paired t-test were used to observe brain responses to emotional distracters. The correlation between brain response and working memory performance was also computed to investigate brain areas that predict working memory performance in emotionally distracted tasks. RESULTS: Three trends in brain activity were strongly correlated with high working memory performance: (1) increased activity in cognitive control areas (dorsolateral prefrontal cortex), (2) lower activity in emotional reactivity areas (fusiform gyrus), and (3) deactivation of the attention shifting area, mainly VMPFC. In addition, all three trends correlated with high working memory performance during the hold phase of working memory, whereas only (2) and (3) correlated with high working memory performance during the encoding phase. CONCLUSIONS: These results provide further evidence of the functional importance of VMPFC and demonstrate that VMPFC deactivation is particularly important during the encoding and hold phases of working memory.

Improvement of sensitivity and specificity for laminar BOLD fMRI with double spin-echo EPI in humans at 7 T.

Mapping mesoscopic cortical functional units such as columns or laminae is increasingly pursued by ultra-high field (UHF) functional magnetic resonance imaging (fMRI). The most popular approach for high-resolution fMRI is currently gradient-echo (GE) blood oxygenation level-dependent (BOLD) fMRI. However, its spatial accuracy is reduced due to its sensitivity to draining vessels, including pial veins, whereas spin-echo (SE) BOLD signal is expected to have higher spatial accuracy, albeit with lower sensitivity than the GE-BOLD signal. Here, we introduce a new double spin-echo (dSE) echo-planar imaging (EPI) method to improve the sensitivity of SE-BOLD contrast by averaging two spin-echoes using three radiofrequency pulses. Human fMRI experiments were performed with slices perpendicular to the central sulcus between motor and sensory cortices at 7 T during fist-clenching with touching. First, we evaluated the feasibility of single-shot dSE-EPI for BOLD fMRI with 1.5 mm isotropic resolution and found that dSE-BOLD fMRI has higher signal-to-noise ratio (SNR), temporal SNR (tSNR), and higher functional sensitivity than conventional SE-BOLD fMRI. Second, to investigate the laminar specificity of dSE-BOLD fMRI, we implemented a multi-shot approach to achieve 0.8-mm isotropic resolution with sliding-window reconstruction. Unlike GE-BOLD fMRI, the cortical profile of dSE-BOLD fMRI peaked at ~ 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity in humans over GE-BOLD fMRI. The proposed multi-shot dSE-EPI method is viable for high spatial resolution UHF-fMRI studies in the pursuit of resolving mesoscopic functional units.

Brain functional connectivity changes by low back extension pain model in low back pain patients.

PURPOSE: Low back pain (LBP) is a common ailment in most developed countries. Because most cases of LBP are known as 'non-specific', it has been challenging to develop experimental pain models of LBP which reproduce patients' clinical pain. In addition, previous models have limited applicability in a steady-pain-state neuroimaging environment. Thus, this study aims to devise a low back pain model with a simple methodology to induce experimental LBP, which has similar pain properties to patients' clinical pain, and to apply the model in a steady-pain-state neuroimaging study. METHODS: Our low back extension (LBE) pain model was tested on 217 LBP patients outside the magnetic resonance imaging (MRI) scanner to determine the reproducibility of endogenous pain and the similarity to their own clinical pain (STUDY1), and applied in a steady-pain-state functional MRI study (47 LBP patients and 23 healthy controls) to determine its applicability (induced head motions and brain functional connectivity changes; STUDY2). RESULTS: By the LBE pain model, 68.2% of the LBP patients reported increased LBP with high similarity of sensations to their own clinical pain (STUDY1), and the head motions were statistically similar to and correlated with those in resting state (STUDY2). Furthermore, the LBE model altered brain functional connectivity by decreasing the default-mode and the sensorimotor networks, and increasing the salience network, which was significantly associated with the intensity of the induced pain. Conversely, the healthy controls showed increased somatosensory network (but not of the cognitive pain processing). CONCLUSION: Our investigations suggest that our LBE pain model, which increased LBP with high similarity to the LBP patients' own pain sensation and induced patient-specific brain responses with acceptable head motion, could be applied to neuroimaging studies investigating brain responses to different levels of endogenous LBP.

Differential Influence of Acupuncture Somatosensory and Cognitive/Affective Components on Functional Brain Connectivity and Pain Reduction During Low Back Pain State.

The underlying mechanism of pain reduction by acupuncture is still unclear, because acupuncture treatment involves multidimensional factors. In this study, we investigated the differential influence of acupuncture components on brain functional connectivity and on pain reduction. We used a specific form of sham acupuncture (phantom acupuncture; PHNT), which only has a needling-credibility (a belief that they were treated with real acupuncture needles), while real acupuncture (REAL) has a somatosensory needling stimulation, as well as a needling-credibility. Forty-three patients with low back pain were randomized into the REAL group (n = 25) and the PHNT group (n = 18). They underwent two pain steady-state fMRI runs implemented by a low back extension (LBE) pain model (lifting the low back using air-cuff inflation) before and after REAL or PHNT stimulation. Subjective pain ratings, perceived throughout the LBE runs due to the posture, were reported (LBEpain). The regions of interest (ROI) were (1) the main nodes of the default mode network (DMN) - the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), (2) the main nodes of the salience network (SN) - the anterior/posterior insular cortices (a/pINS), and (3) the low back-specific region of sensorimotor network (SMN), S1back. Significant reductions in LBEpain were observed in both groups (REAL = -1.02 ± 1.53, PHNT = -1.26 ± 2.20). In REAL group, decreased LBEpain was positively correlated with decreased functional connectivity between the mPFC and pINS (r = 0.58, P < 0.05). Reduced LBEpain in PHNT was negatively correlated with increased PCC-aINS connectivity (r = -0.48, P < 0.05) and tended toward positive correlation with decreased S1back-pINS connectivity (r = 0.44, P = 0.07). Our findings might suggest different brain mechanisms of observed pain reduction; REAL seems to involve detachment of the self from the sensory aspect of pain, while PHNT does to shift attention to self and disengages physical pain processing hubs. This exploratory study proposes a sham methodology to dissociate the influence of different acupuncture components in acupuncture research. Further studies need to be followed with more elaborated hypothesis, study design, and analysis considering various cognitive/affective factors for better understanding of brain mechanisms of pain reduction regarding the different acupuncture aspects.

Effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica: protocol for a randomized, patient-assessor blind, sham-controlled clinical trial.

BACKGROUND: Sciatica is a relatively frequent illness that easily becomes a chronic and relapsing condition. Although numerous systematic reviews have analyzed various therapies for sciatica, the validity of their included studies is limited. Considering the limitations of conventional treatment options for sciatica, acupuncture is a possible option; however, evidence supporting its efficacy and mechanism in patients with sciatica is lacking. The aim of this proposed protocol is to investigate the effect and neurophysiological mechanism of acupuncture in patients with chronic sciatica. METHODS/DESIGN: This study is a randomized, patient-assessor blind, two-arm, parallel, non-penetrating, sham-controlled clinical trial. Eligible participants will include adults (aged 19-70 years old) with a clinical diagnosis of chronic sciatica (40 mm or more of a 100-mm visual analog scale (VAS) for bothersomeness) blinded to the treatment received. Patients will be randomly allocated into the acupuncture treatment group (manual acupuncture plus electroacupuncture (EA), n = 34) or the sham acupuncture control group (sham acupuncture plus placebo EA without electrical stimulation, n = 34). Groups will receive treatment twice a week for a total of eight sessions over 4 weeks. Functional magnetic resonance imaging will be implemented at baseline and endpoint to investigate the mechanism of acupuncture. The primary outcome measure is the VAS for bothersomeness and secondary outcomes include the VAS for pain intensity, Oswestry Disability Index, EuroQol 5-Dimension, Coping Strategy Questionnaire, Beck's Depression Inventory, and State-Trait Anxiety Inventory. Adverse events will be assessed at every visit. DISCUSSION: The results of this trial (which will be available in 2020) should provide important clinical evidence for the effect of acupuncture and demonstrate how acupuncture can be helpful for the treatment of chronic sciatica. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03350789 . Registered on 15 November 2017.

Phantom Acupuncture Induces Placebo Credibility and Vicarious Sensations: A Parallel fMRI Study of Low Back Pain Patients.

Although acupuncture is an effective therapeutic intervention for pain reduction, the exact difference between real and sham acupuncture has not been clearly understood because a somatosensory tactile component is commonly included in the existing sham acupuncture protocols. In an event-related fMRI experiment, we implemented a novel form of sham acupuncture, phantom acupuncture, that reproduces the acupuncture needling procedure without somatosensory tactile stimulation while maintaining the credibility of the acupuncture treatment context. Fifty-six non-specific low back pain patients received either real (REAL) or phantom (PHNT) acupuncture stimulation in a parallel group study. The REAL group exhibited greater activation in the posterior insula and anterior cingulate cortex, reflecting the needling-specific components of acupuncture. We demonstrated that PHNT could be delivered credibly. Interestingly, the PHNT-credible group exhibited bilateral activation in SI/SII and also reported vicarious acupuncture sensations without needling stimulation. The PHNT group showed greater activation in the bilateral dorsolateral/ventrolateral prefrontal cortex (dlPFC/vlPFC). Moreover, the PHNT group exhibited significant pain reduction, with a significant correlation between the subjective fMRI signal in the right dlPFC/vlPFC and a score assessing belief in acupuncture effectiveness. These results support an expectation-related placebo analgesic effect on subjective pain intensity ratings, possibly mediated by right prefrontal cortex activity.

Functional topography of the primary motor cortex during motor execution and motor imagery as revealed by functional MRI.

Controversy exists regarding the involvement of the primary motor cortex (M1) during motor imagery (MI) and also regarding the differential somatotopic representation of motor execution (ME) and mental simulation of movement, that is, MI within M1. Although some research reported clear M1 involvement during MI without overt motor output, others did not. However, possible somatotopic representation between execution and imagery has not been clearly investigated to date. The aim of the present study was to aid in the resolution of this controversy by investigating the possible involvement of M1 during MI, and the differential, within M1, somatotopic representation between execution and imagery by quantitatively assessing different location markers such as activation peak and center of mass as well as intensity differences between the two tasks in case of with and without the overlap between the two representations. Forty-one healthy volunteers participated in two functional MRI runs of mouth-stretching ME and MI tasks. Our findings suggest the clear involvement of M1 (BA 4) during MI with lower signal intensity compared with ME, and further showed distinct centers for each representation along the y-axis (anteroposterior plane), with MI showing more involvement of the anterior sector of M1 (BA 4a), whereas ME recruited more of the posterior sector (BA 4p). These results parallel the pioneering findings of a functional distinction between BA 4a and BA 4p, where BA 4a is more involved in the cognitive aspects of MI, whereas BA 4p is more related to executive function, promoting the idea of distinctive somatotopic mapping between execution and imagery within M1 sectors.

Greater corticostriatal activation associated with facial motor imagery compared with motor execution: a functional MRI study.

Motor imagery (MI) relies on conscious mental simulation of a motor act without overt motor output and can promote motor skill acquisition and facilitate rehabilitation for patients with stroke or neurological conditions. Although a plethora of neuroimaging studies have investigated the neural network of MI regarding different body parts, exploration of the neural correlates to facial MI remains warranted. Here, we used functional MRI with a large cohort of 41 participants who underwent motor execution (ME) and MI runs of mouth-stretching tasks. Then, we carried out conjunction and contrast analyses to investigate the commonalities and differences between the two conditions. Conjunction analysis, representing the shared neural network between ME and MI, showed activation in the primary motor cortex, primary and secondary somatosensory cortices, premotor cortex, parietal lobe, anterior insula, supplementary motor area (SMA) and pre-SMA, thalamus, putamen, and caudate. Contrast analysis showed greater activation of primary motor cortex, primary and secondary somatosensory cortices, SMA, anterior insula, and the thalamus in response to ME than MI and greater activation of the premotor cortex, pre-SMA, putamen, and caudate in response to MI than ME. Interestingly, we found exclusive activation in the anterior cingulate cortex and left ventrolateral prefrontal cortex in response to MI, reflecting the motor inhibition network responsible for blocking the transmission of motor commands to peripheral effectors during mental rehearsal. Taken together, these findings show that, despite the neural overlap between ME and MI, there are different degrees of activation within this overlap, and that MI normally involves motor command inhibition possibly mediated by the anterior cingulate cortex and ventrolateral prefrontal cortex.

Brain correlates to facial motor imagery and its somatotopy in the primary motor cortex.

Motor imagery (MI) has attracted increased interest for motor rehabilitation as many studies have shown that MI shares the same neural networks as motor execution (ME). Nevertheless, MI in terms of facial movement has not been studied extensively; thus, in the present study, we investigated shared neural networks between facial motor imagery (FMI) and facial motor execution (FME). In addition, FMI somatotopy within-face was investigated between the forehead and the mouth. Functional MRI was used to examine 34 healthy individuals with ME and MI paradigms for the forehead and the mouth. The general linear model and a paired t-test were performed to define the facial area in the primary motor cortex (M1) and this area has been used to investigate somatotopy between the forehead and mouth FMI. FMI recruited similar brain motor areas as FME, but showed less neural activity in all activated regions. The facial areas in M1 were distinguishable from other body movements such as finger movement. Further investigation of this area showed that forehead and mouth imagery tended to lack a somatotopic representation for position on M1, and yet had distinct characteristics in terms of neural activity level. FMI showed different characteristics from general MI as the former exclusively activated facial processing areas. In addition, FME and FMI showed different characteristics in terms of BOLD signal level, while sharing the same neural areas. The results imply a potential usefulness of MI training for rehabilitation of facial motor disease considering that forehead and mouth somatotopy showed no clear position difference, and yet showed a significant BOLD signal intensity variation.

Evaluating validity of various acupuncture device types: a random sequence clinical trial.

BACKGROUND: Although various placebo acupuncture devices have been developed and used in acupuncture research, there is controversy concerning whether these devices really serve as appropriate placebos for control groups. METHODS/DESIGN: The proposed study is a single-center prospective random sequence participant- and assessor-blinded trial with two parallel arms. A total of 76 participants will be randomly assigned to Group 1 or Group 2 in a 1:1 ratio. Group 1 will consist of Sham Streitberger's needle, Real Streitberger's needle, and Phantom acupuncture session. Group 2 will consist of Park Sham device with real needle, Park Sham device with sham needle, and no treatment session. Participants will have a total of three acupuncture sessions in a day. The primary endpoint is blinding test questionnaire 1. Secondary endpoints are the Bang's blinding index, the Massachusetts General Hospital Acupuncture Sensation Scale index, and physiological data including heart rate, heart rate variability, and skin conductance response. DISCUSSION: This trial will evaluate the relevance of using placebo acupuncture devices as controls using a validation test procedure. TRIAL REGISTRATION: Clinical Research Information Service: KCT0001347 .