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In JoVE (2)
- Monitoring Acupuncture Effects on Human Brain by fMRI
- Bioluminescence Imaging of Heme Oxygenase-1 Upregulation in the Gua Sha Procedure
Other Publications (35)
- Ophthalmic Research
- Magnetic Resonance Imaging
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- NeuroImage
- Magnetic Resonance Imaging
- Human Brain Mapping
- Human Brain Mapping
- Journal of Applied Physiology (Bethesda, Md. : 1985)
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- NeuroImage
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Human Brain Mapping
- NeuroImage
- NeuroImage
- Human Brain Mapping
- Proceedings of the National Academy of Sciences of the United States of America
- Brain Research
- Neuroscience Letters
- Neuroscience Letters
- NeuroImage
- Brain Research
- NeuroImage
- Neuroscience Letters
- Brain Research
- Autonomic Neuroscience : Basic & Clinical
- NeuroImage
- NeuroImage
- NeuroImage
- Clinica Chimica Acta; International Journal of Clinical Chemistry
- NeuroImage
- Synapse (New York, N.Y.)
Articles by Kenneth K. Kwong in JoVE
JoVE General
Monitoring Acupuncture Effects on Human Brain by fMRI
1Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 2William Beaumont Hospital
FMRI and physiological monitoring is used to study the effects of Acupuncture on the central and peripheral nervous systems. Acupuncture mobilizes a limbic-paralimbic-neocortical network, with great overlap with the default mode network, to modulate neurological activity, possibly related to its autonomic effect in the peripheral nervous system.
JoVE General
Bioluminescence Imaging of Heme Oxygenase-1 Upregulation in the Gua Sha Procedure
1Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 3Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 4Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 5Center for biotechnology and Informatics, The Methodist Hospital Research Institute, 6Department of Radiology, The Methodist Hospital, Weill Cornell Medical College, 7Bejing University of Chinese Medicine, 8Department of Health Technology and Informatics, The Hong Kong Polytechnic University, 9Department of Radiology, Brigham and Women's Hospital, Harvard Medical School
Gua Sha, traditional Chinese therapeutic skin scraping, causes subcutaneous microvascular blood extravasation. We report a protocol of bioluminescence imaging of HO-1-luciferase transgenic mice to demonstrate that Gua Sha upregulates heme oxygenase-1 (HO-1) in multiple organs.
Other articles by Kenneth K. Kwong on PubMed
MRI of Blood Volume and Cellular Uptake of Superparamagnetic Iron in an Animal Model of Choroidal Melanoma
Functional magnetic resonance imaging (MRI), using monocrystalline iron oxide nanoparticles (MION) as a new intravascular contrast agent, was adapted for a rabbit model of pigmented choroidal melanoma. Three-dimensionally spoiled gradient recalled sequences were used for the quantitative assessment of blood volume and cellular uptake. In all ocular tissues studied, MION reduced the T(2)-weighted signal intensity within 0.5 h and at 24 h (both p < 0.05) after the injection. In individual tumors, MION reduced the T(2)-weighted signal intensity by 46-78% within 0.5 h and by 24-48% at 24 h. In addition, MION increased the T(1)-weighted signal intensity in all tissues. T(2) yielded a higher sensitivity than T(1)-weighted images. Functional MRI with MION is a noninvasive technique with regard to the eye, permitting measurement of blood volume and cellular uptake of the contrast agent. Further study is necessary to determine the feasibility of this technique for the tumor diagnosis and evaluation of tumor viability following treatments.
MRI of Blood Volume with MS 325 in Experimental Choroidal Melanoma
Functional magnetic resonance imaging (MRI) allows quantitative blood volume imaging in vivo at high tissue resolution. The purpose is to apply this technique for untreated and hyperthermia-treated experimental choroidal melanoma. MS 325 was used as new intravascular albumin-bound gadolinium-based contrast agent. Pigmented choroidal melanomas were established in albino rabbits. MRI was performed in 7 untreated eyes and 7 eyes treated with a Neodymium:Yttrium-Lanthanum-Fluoride-laser at 1047 nm. 3D-spoiled gradient echo pulse sequences were used to acquire T' weighted axial images. First, a set of images was collected without contrast agent. MS 325 was then injected i.v. and images were obtained within 12 min after injection. Signal intensities were measured within tumor, ciliary body, choroid, and iris and relative signal intensities were determined for these tissues in relation to vitreous. In untreated tumors, the relative signal intensity was higher after injection of MS 325 (5.61+0.70) than without MS 325 (2.90+0.33; p = 0.0002). In contrast, the relative signal intensity of treated tumors did not differ significantly before and after MS 325 (6.19+1.59 and 6.13+1.64). Histopathological sections indicated vascular occlusion in treated tumors. All other studied tissues of untreated and treated eyes showed a significant increase of relative signal intensities in the presence of MS 325. An animal model for the research on contrast agents in MRI is presented. Blood volume measurement with MS 325 was adapted for experimental choroidal melanomas. Reduced change of relative signal intensity indicates compromised blood volume after vascular occlusion in hyperthermia-treated melanoma. Further studies are needed to investigate whether this technique allows the evaluation of tumor viability following treatments.
Degenerate Mode Birdcage Volume Coil for Sensitivity-encoded Imaging
A volume birdcage coil for accelerated image encoding with parallel acquisition methods such as SENSE is demonstrated. The coil is degenerately tuned with both the standard homogeneous mode and the first gradient mode of the birdcage coil resonant at the Larmor frequency. Conventional and antisymmetric coupling structures allow imaging from each of these modes simultaneously. The coil for SENSE-type reconstruction with acceleration factors of up to 2-fold is demonstrated. The spatial distribution of the added noise from the SENSE reconstruction (g-factor map) due to geometrical arrangement of the two-channel system is estimated. The spatially averaged g-factors were found to be 1.21, 1.36, and 1.55 for 1.3, 1.6, and 2-fold accelerations, respectively. The system was demonstrated in vivo using accelerated and nonaccelerated anatomical brain images at 1.5 T. The maximal 2-fold acceleration in this dual-mode degenerate birdcage coil offers the potential to extend SENSE-type image reconstruction methods to applications demanding uniform whole brain coverage.
In Vivo Study of Microbubbles As an MR Susceptibility Contrast Agent
The potential application of gas microbubbles as a unique intravascular susceptibility contrast agent for MRI has not been fully explored. In this study, the MR susceptibility effect of an ultrasound microbubble contrast agent, Optison, was studied with rat liver imaging at 7 T. Optison suspension in two different doses (0.15 mL/kg and 0.4 mL/kg) was injected into rats, and induced transverse relaxation rate increases (deltaR2*) of 29.1 +/- 1.6 s(-1) (N = 2) and 61.5 +/- 12.9 s(-1) (N = 6), respectively, in liver tissue. Liver uptake of intact albumin microbubbles was observed 10 min after injection. Eight of the 16 rats studied showed no susceptibility enhancement. This is probably attributable to the intravascular microbubble growth due to transmural CO2 supersaturation in the cecum and colon in small animals that causes microbubble aggregation and trapping in the inferior vena cava (IVC). In vitro deltaR2* measurements of Optison suspension at different concentrations are also reported.
Parallel Imaging Reconstruction Using Automatic Regularization
Increased spatiotemporal resolution in MRI can be achieved by the use of parallel acquisition strategies, which simultaneously sample reduced k-space data using the information from multiple receivers to reconstruct full-FOV images. The price for the increased spatiotemporal resolution in parallel MRI is the degradation of the signal-to-noise ratio (SNR) in the final reconstructed images. Part of the SNR reduction results when the spatially correlated nature of the information from the multiple receivers destabilizes the matrix inversion used in the reconstruction of the full-FOV image. In this work, a reconstruction algorithm based on Tikhonov regularization is presented that reduces the SNR loss due to geometric correlations in the spatial information from the array coil elements. Reference scans are utilized as a priori information about the final reconstructed image to provide regularized estimates for the reconstruction using the L-curve technique. This automatic regularization method reduces the average g-factors in phantom images from a two-channel array from 1.47 to 0.80 in twofold sensitivity encoding (SENSE) acceleration. In vivo anatomical images from an eight-channel system show an averaged g-factor reduction of 1.22 to 0.84 in 2.67-fold acceleration.
Neuroanatomy of Adult Strabismus: a Voxel-based Morphometric Analysis of Magnetic Resonance Structural Scans
Cerebral deficit has been implicated in the genesis of strabismus and in the mechanisms adopted to compensate for the visual disorder. Voxel-based morphometry (VBM) was applied to magnetic resonance images of strabismic adults to detect any abnormal brain anatomy, which could not be easily identified by simple inspection. The gray matter volume in strabismic adults was smaller than that in normal subjects at the areas consistent with the occipital eye field (OEF) and parietal eye field (PEF). However, greater gray matter volume was found in strabismic adults relative to normal controls at the areas consistent with the frontal eye field (FEF), the supplementary eye field (SEF), the prefrontal cortex (PFC), and subcortical regions such as the thalamus and the basal ganglia. These opposite gray matter changes in the visual and the oculomotor processing areas are compatible with a hypothesis of plasticity in the oculomotor regions to compensate for the cortical deficits in the visual processing areas.
MRI of Blood Volume with Superparamagnetic Iron in Choroidal Melanoma Treated with Thermotherapy
Functional magnetic resonance imaging (MRI) with a new intravascular contrast agent, monocrystalline iron oxide nanoparticles (MION), was applied to assess the effect of transpupillary thermotherapy in a rabbit model of choroidal melanoma. 3D-spoiled gradient recalled sequences were used for quantitative assessment of blood volume. The MRI-parameters were 5/22/35 degrees (time of repetition (TR)/echo delay (TE)/flip angle (FA)) for T(1)- and 50/61/10 degrees for T(2)-weighted sequences. Images were collected before and at different times after MION injection. In all untreated tissues studied, MION reduced the T(2)-weighted signal intensity within 0.5 h and at 24 h (all p <== 0.012), whereas no significant changes were detected in treated tumors. T(1)-weighted images also revealed differences of MION-related signal changes between treated tumors and other tissues, yet at lower sensitivity and specificity than T(2). The change of T(2)-weighted MRI signal caused by intravascular MION allows early distinction of laser-treated experimental melanomas from untreated tissues. Further study is necessary to determine whether MRI can localize areas of tumor regrowth within tumors treated incompletely.
Effects of Electroacupuncture Versus Manual Acupuncture on the Human Brain As Measured by FMRI
The goal of this functional magnetic resonance imaging (fMRI) study was to compare the central effects of electroacupuncture at different frequencies with traditional Chinese manual acupuncture. Although not as time-tested as manual acupuncture, electroacupuncture does have the advantage of setting stimulation frequency and intensity objectively and quantifiably. Manual acupuncture, electroacupuncture at 2 Hz and 100 Hz, and tactile control stimulation were carried out at acupoint ST-36. Overall, electroacupuncture (particularly at low frequency) produced more widespread fMRI signal increase than manual acupuncture did, and all acupuncture stimulations produced more widespread responses than did our placebo-like tactile control stimulation. Acupuncture produced hemodynamic signal increase in the anterior insula, and decrease in limbic and paralimbic structures including the amygdala, anterior hippocampus, and the cortices of the subgenual and retrosplenial cingulate, ventromedial prefrontal cortex, frontal, and temporal poles, results not seen for tactile control stimulation. Only electroacupuncture produced significant signal increase in the anterior middle cingulate cortex, whereas 2-Hz electroacupuncture produced signal increase in the pontine raphe area. All forms of stimulation (acupuncture and control) produced signal increase in SII. These findings support a hypothesis that the limbic system is central to acupuncture effect regardless of specific acupuncture modality, although some differences do exist in the underlying neurobiologic mechanisms for these modalities, and may aid in optimizing their future usage in clinical applications.
Voxel-based Analysis of MRI Detects Abnormal Visual Cortex in Children and Adults with Amblyopia
Amblyopia, sometimes called "lazy eye," is a relatively common developmental visual disorder well characterized behaviorally; however, the neural substrates associated with amblyopia in humans remain unclear. We hypothesized that abnormalities in the cerebral cortex of subjects with amblyopia exist, possibly as a result of experience-dependent neuronal plasticity. Anatomic magnetic resonance imaging (MRI) and psychophysical vision testing was carried out on 74 subjects divided into two age ranges, 7-12 years and 18-35 years, and three diagnoses, strabismic amblyopia, anisometropic amblyopia, and normal vision. We report a behavioral impairment in contrast sensitivity for subjects with amblyopia, consistent with previous reports. When the high-resolution MRI brain images were analyzed quantitatively with optimized voxel-based morphometry, results indicated that adults and children with amblyopia have decreased gray matter volume in visual cortical regions, including the calcarine sulcus, known to contain primary visual cortex. This finding was confirmed with a separate region-of-interest analysis. For the children with amblyopia, additional gray matter reductions in parietal-occipital areas and ventral temporal cortex were detected, consistent with recent reports that amblyopia can result in spatial location and object processing deficits. These data are the first to provide possible neuroanatomic bases for the loss of binocularity and visual sensitivity in children and adults with amblyopia.
Functional Imaging of Working Memory in Obstructive Sleep-disordered Breathing
Functional magnetic resonance imaging was used to map cerebral activation in 16 patients with obstructive sleep-disordered breathing (OSDB) and 16 healthy subjects, during the performance of a 2-back verbal working memory task. Six patients with OSDB were reimaged after a minimum period of 8 wk of treatment with positive airway pressure. Working memory speed in OSDB was significantly slower than in healthy subjects, and a group average map showed absence of dorsolateral prefrontal activation, regardless of nocturnal hypoxia. After treatment, resolution of subjective sleepiness contrasted with no significant change in behavioral performance, persistent lack of prefrontal activation, and partial recovery of posterior parietal activation. These findings suggest that working memory may be impaired in OSDB and that this impairment is associated with disproportionate impairment of function in the dorsolateral prefrontal cortex. Nocturnal hypoxia may not be a necessary determinant of cognitive dysfunction, and sleep fragmentation may be sufficient. There may be dissociations between respiratory vs. cortical recovery and objective vs. subjective recovery. Hypofrontality may provide a plausible biological mechanism for a clinical overlap with disorders of mood and attention.
Functional MRI Using Regularized Parallel Imaging Acquisition
Parallel MRI techniques reconstruct full-FOV images from undersampled k-space data by using the uncorrelated information from RF array coil elements. One disadvantage of parallel MRI is that the image signal-to-noise ratio (SNR) is degraded because of the reduced data samples and the spatially correlated nature of multiple RF receivers. Regularization has been proposed to mitigate the SNR loss originating due to the latter reason. Since it is necessary to utilize static prior to regularization, the dynamic contrast-to-noise ratio (CNR) in parallel MRI will be affected. In this paper we investigate the CNR of regularized sensitivity encoding (SENSE) acquisitions. We propose to implement regularized parallel MRI acquisitions in functional MRI (fMRI) experiments by incorporating the prior from combined segmented echo-planar imaging (EPI) acquisition into SENSE reconstructions. We investigated the impact of regularization on the CNR by performing parametric simulations at various BOLD contrasts, acceleration rates, and sizes of the active brain areas. As quantified by receiver operating characteristic (ROC) analysis, the simulations suggest that the detection power of SENSE fMRI can be improved by regularized reconstructions, compared to unregularized reconstructions. Human motor and visual fMRI data acquired at different field strengths and array coils also demonstrate that regularized SENSE improves the detection of functionally active brain regions.
The Integrated Response of the Human Cerebro-cerebellar and Limbic Systems to Acupuncture Stimulation at ST 36 As Evidenced by FMRI
Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system, but the specific effects of acupuncture on the human brain remain unclear. Even less is known about its effects on the cerebellum. This fMRI study demonstrated that manual acupuncture at ST 36 (Stomach 36, Zusanli), a main acupoint on the leg, modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems. The pattern of hemodynamic response depended on the psychophysical response to needle manipulation. Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine. The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon, diencephalon, brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi. When deqi was mixed with sharp pain, the hemodynamic response was mixed, showing a predominance of signal increases instead. Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions. The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response.
PROPELLER EPI: an MRI Technique Suitable for Diffusion Tensor Imaging at High Field Strength with Reduced Geometric Distortions
A technique suitable for diffusion tensor imaging (DTI) at high field strengths is presented in this work. The method is based on a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) k-space trajectory using EPI as the signal readout module, and hence is dubbed PROPELLER EPI. The implementation of PROPELLER EPI included a series of correction schemes to reduce possible errors associated with the intrinsically higher sensitivity of EPI to off-resonance effects. Experimental results on a 3.0 Tesla MR system showed that the PROPELLER EPI images exhibit substantially reduced geometric distortions compared with single-shot EPI, at a much lower RF specific absorption rate (SAR) than the original version of the PROPELLER fast spin-echo (FSE) technique. For DTI, the self-navigated phase-correction capability of the PROPELLER EPI sequence was shown to be effective for in vivo imaging. A higher signal-to-noise ratio (SNR) compared to single-shot EPI at an identical total scan time was achieved, which is advantageous for routine DTI applications in clinical practice.
Dynamic Magnetic Resonance Inverse Imaging of Human Brain Function
MRI is widely used for noninvasive hemodynamic-based functional brain imaging. In traditional spatial encoding, however, gradient switching limits the temporal resolution, which makes it difficult to unambiguously identify possible fast nonhemodynamic changes. In this paper we propose a novel reconstruction approach, called dynamic inverse imaging (InI), that is capable of providing millisecond temporal resolution when highly parallel detection is used. To achieve an order-of-magnitude speedup in generating time-resolved contrast estimates and dynamic statistical parametric maps (dSPMs), the spatial information is derived from an array of detectors rather than by time-consuming gradient-encoding methods. The InI approach was inspired by electroencephalography (EEG) and magnetoencephalography (MEG) source localization techniques. Dynamic MR InI was evaluated by means of numerical simulations. InI was also applied to measure BOLD hemodynamic time curves at 20-ms temporal resolution in a visual stimulation experiment using a 90-channel head array. InI is expected to improve the time resolution of MRI and provide increased flexibility in the trade-off between spatial and temporal resolution for studies of dynamic activation patterns in the human brain.
PROPELLER-EPI with Parallel Imaging Using a Circularly Symmetric Phased-array RF Coil at 3.0 T: Application to High-resolution Diffusion Tensor Imaging
A technique integrating multishot periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) and parallel imaging is presented for diffusion echo-planar imaging (EPI) at high spatial resolution. The method combines the advantages of parallel imaging to achieve accelerated sampling along the phase-encoding direction, and PROPELLER acquisition to further decrease the echo train length (ETL) in EPI. With an eight-element circularly symmetric RF coil, a parallel acceleration factor of 4 was applied such that, when combined with PROPELLER acquisition, a reduction of geometric distortions by a factor substantially greater than 4 was achieved. The resulting phantom and human brain images acquired with a 256 x 256 matrix and an ETL of only 16 were visually identical in shape to those acquired using the fast spin-echo (FSE) technique, even without field-map corrections. It is concluded that parallel PROPELLER-EPI is an effective technique that can substantially reduce susceptibility-induced geometric distortions at high field strength.
Using FMRI to Dissociate Sensory Encoding from Cognitive Evaluation of Heat Pain Intensity
Neuroimaging studies of painful stimuli in humans have identified a network of brain regions that is more extensive than identified previously in electrophysiological and anatomical studies of nociceptive pathways. This extensive network has been described as a pain matrix of brain regions that mediate the many interrelated aspects of conscious processing of nociceptive input such as perception, evaluation, affective response, and emotional memory. We used functional magnetic resonance imaging in healthy human subjects to distinguish brain regions required for pain sensory encoding from those required for cognitive evaluation of pain intensity. The results suggest that conscious cognitive evaluation of pain intensity in the absence of any sensory stimulation activates a network that includes bilateral anterior insular cortex/frontal operculum, dorsal lateral prefrontal cortex, bilateral medial prefrontal cortex/anterior cingulate cortex, right superior parietal cortex, inferior parietal lobule, orbital prefrontal cortex, and left occipital cortex. Increased activity common to both encoding and evaluation was observed in bilateral anterior insula/frontal operculum and medial prefrontal cortex/anterior cingulate cortex. We hypothesize that these two regions play a crucial role in bridging the encoding of pain sensation and the cognitive processing of sensory input.
Somatosensory Cortical Plasticity in Carpal Tunnel Syndrome--a Cross-sectional FMRI Evaluation
Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the median nerve characterized by paresthesias and pain in the first, second, and third digits. We hypothesize that aberrant afferent input in CTS will lead to cortical plasticity. Functional MRI (fMRI) and neurophysiological testing were performed on CTS patients and healthy adults. Median nerve innervated digit 2 (D2), and digit 3 (D3) and ulnar nerve innervated digit 5 (D5) were stimulated during fMRI. Surface-based and ROI-based analyses consistently demonstrated more extensive and stronger contralateral sensorimotor cortical representations of D2 and D3 for CTS patients as compared to healthy adults (P < 0.05). Differences were less profound for D5. Moreover, D3 fMRI activation in both the contralateral SI and motor cortex correlated positively with the D3 sensory conduction latency. Analysis of somatotopy suggested that contralateral SI representations for D2 and D3 were less separated for CTS patients (3.8 +/- 1.0 mm) than for healthy adults (7.5 +/- 1.2 mm). Furthermore, the D3/D2 separation distance correlated negatively with D2 sensory conduction latency-the greater the latency, the closer the D2/D3 cortical representations (r = -0.79, P < 0.05). Coupled with a greater extent of SI representation for these CTS affected digits, the closer cortical representations can be interpreted as a blurred somatotopic arrangement for CTS affected digits. These findings provide further evidence that CTS is not manifest in the periphery alone. Our results are consistent with Hebbian plasticity mechanisms, as our cohort of CTS patients had predominant paresthesias, which produce more temporally coherent afferent signaling from affected digits.
Strategies for Improving the Detection of FMRI Activation in Trigeminal Pathways with Cardiac Gating
Functional magnetic resonance imaging (fMRI) has become a powerful tool for studying the normal and diseased human brain. The application of fMRI in detecting neuronal signals in the trigeminal system, however, has been hindered by low detection sensitivity due to activation artifacts caused by cardiac pulse-induced brain and brainstem movement. A variety of cardiac gating techniques have been proposed to overcome this issue, typically by phase locking the sampling to a particular time point during each cardiac cycle. We sought to compare different cardiac gating strategies for trigeminal system fMRI. In the present study, we used tactile stimuli to elicit brainstem and thalamus activation and compared the fMRI results obtained without cardiac gating and with three different cardiac gating strategies: single-echo with TR of 3 or 9 heartbeats (HBs) and dual-echo T2*-mapping EPI (TR = 2 HBs, TE = 21/55 ms). The dual-echo T2* mapping and the single-echo with TR of 2 and 3 HBs cardiac-gated fMRI techniques both increased detection rate of fMRI activation in brainstem. Activation in the brainstem and the thalamus was best detected by cardiac-gated dual-echo EPI.
Somatosensory Cortical Plasticity in Carpal Tunnel Syndrome Treated by Acupuncture
Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the median nerve characterized by paresthesias and pain in the first through fourth digits. We hypothesize that aberrant afferent input from CTS will lead to maladaptive cortical plasticity, which may be corrected by appropriate therapy. Functional MRI (fMRI) scanning and clinical testing was performed on CTS patients at baseline and after 5 weeks of acupuncture treatment. As a control, healthy adults were also tested 5 weeks apart. During fMRI, sensory stimulation was performed for median nerve innervated digit 2 (D2) and digit 3 (D3), and ulnar nerve innervated digit 5 (D5). Surface-based and region of interest (ROI)-based analyses demonstrated that while the extent of fMRI activity in contralateral Brodmann Area 1 (BA 1) and BA 4 was increased in CTS compared to healthy adults, after acupuncture there was a significant decrease in contralateral BA 1 (P < 0.005) and BA 4 (P < 0.05) activity during D3 sensory stimulation. Healthy adults demonstrated no significant test-retest differences for any digit tested. While D3/D2 separation was contracted or blurred in CTS patients compared to healthy adults, the D2 SI representation shifted laterally after acupuncture treatment, leading to increased D3/D2 separation. Increasing D3/D2 separation correlated with decreasing paresthesias in CTS patients (P < 0.05). As CTS-induced paresthesias constitute diffuse, synchronized, multidigit symptomatology, our results for maladaptive change and correction are consistent with Hebbian plasticity mechanisms. Acupuncture, a somatosensory conditioning stimulus, shows promise in inducing beneficial cortical plasticity manifested by more focused digital representations.
Visual Word Processing and Experiential Origins of Functional Selectivity in Human Extrastriate Cortex
How do category-selective regions arise in human extrastriate cortex? Visually presented words provide an ideal test of the role of experience: Although individuals have extensive experience with visual words, our species has only been reading for a few thousand years, a period not thought to be long enough for natural selection to produce a genetically specified mechanism dedicated to visual word recognition per se. Using relatively high-resolution functional magnetic resonance imaging (1.4 x 1.4 x 2-mm voxels), we identified a small region of extrastriate cortex in most participants that responds selectively to both visually presented words and consonant strings, compared with line drawings, digit strings, and Chinese characters. Critically, we show that this pattern of selectivity is dependent on experience with specific orthographies: The same region responds more strongly to Hebrew words in Hebrew readers than in nonreaders of Hebrew. These results indicate that extensive experience with a given visual category can produce strong selectivity for that category in discrete cortical regions.
The Role of the Basal Ganglia in Bimanual Coordination
The functional anatomical role of the basal ganglia in bimanual coordination is unknown. Utilizing functional MRI (fMRI) at 3 T, we analyzed brain activity during three different typing tasks. The first task consisted of typing with parallel finger movements (moving left to right with four fingers on both hands). The second task was mirror movements (moving little finger to index finger on both hands), and the third task compared a resting condition with right-handed unimanual typing (moving little finger to index finger). Task dependent BOLD activity in the supplementary motor area (SMA) and dorsolateral premotor areas was observed. In addition, activation patterns were present in the cerebellar vermis during bimanual coordination tasks, with greater activation in the parallel than in the mirror condition. Finally, we also identified activity in the putamen during the tasks described above. Interestingly, putaminal activity was greatest during the period of motor task initiation, and activity during this period was greatest in the parallel condition. Our results suggest a critical role of the basal ganglia in the neural control of bimanual coordination.
Inhibition of Stimulated Dopamine Release and Hemodynamic Response in the Brain Through Electrical Stimulation of Rat Forepaw
The subcortical response to peripheral somatosensory stimulation is not well studied. Prior literature suggests that somatosensory stimulation can affect dopaminergic tone. We studied the effects of electrical stimulation near the median nerve on the response to an amphetamine-induced increase in synaptic dopamine. We applied the electrical stimulation close to the median nerve 20 min after administration of 3mg/kg amphetamine. We used fMRI and microdialysis to measure markers of dopamine (DA) release, together with the release of associated neurotransmitters of striatal glutamate (Glu) and gamma-aminobutyric acid (GABA). Changes in cerebral blood volume (CBV), a marker used in fMRI, indicate that electrical stimulation significantly attenuated increased DA release (due to AMPH) in the striatum, thalamus, medial prefrontal and cingulate cortices. Microdialysis showed that electrical stimulation increased Glu and GABA release and attenuated the AMPH-enhanced DA release. The striatal DA dynamics correlated with the CBV response. These results demonstrate that electrical stimulation near the median nerve activates Glu/GABA release, which subsequently attenuate excess striatal DA release. These data provide evidence for physiologic modulation caused by electroacupuncture at points near the median nerve.
Electrical Stimulation Modulates the Amphetamine-induced Hemodynamic Changes: an FMRI Study to Compare the Effect of Stimulating Locations and Frequencies on Rats
Our previous fMRI and microdialysis measurements showed that electroacupuncture (EA) at LI4 was effective in alleviating excessive cerebral dopamine release induced by d-amphetamine (AMPH) in rats. We now compare the effect of EA in adjusting excess dopamine release at two stimulating frequencies (2 Hz versus 100 Hz at LI4) and at two acupoints (forepaw (LI4) versus hindpaw (ST36), at 2 Hz). fMRI measurements of relative cerebral blood volume (rCBV) were used to monitor the brain activity of "rest", followed by AMPH challenge, 10 min "rest", and then 20 min of EA. Results: EA at LI4 and ST36 significantly attenuated the AMPH-induced rCBV increases in the striatum, S1 cortex, and thalamus. Frequency: EA at 100 Hz induced greater attenuation of rCBV than EA at 2 Hz in the S1, insula, anterior cingulate cortices, dorsolateral striatum, and thalamus. Acupoints: EA at LI4 modulated a broader area in the medial anterior striatum while EA at ST36 modulated a more site-specific area in the dorsolateral striatum. In the thalamus, EA at LI4 showed greater attenuating effect than EA at ST36 did. However, in the insular cortex, EA at ST36 showed stronger attenuation. Conclusion: EA at both LI4 and ST36 was effective in restoring dopamine homeostasis from an excess state, with the most effective response at LI4 with 100 Hz, while the responses to 2Hz EA at LI4 and ST36 showed slightly different spatial distribution of MR signal. This therefore provided insight into the neurophysiological basis of electroacupuncture effects in cortical and subcortical circuits.
Time-variant FMRI Activity in the Brainstem and Higher Structures in Response to Acupuncture
Acupuncture modulation of activity in the human brainstem is not well known. This structure is plagued by physiological artifact in neuroimaging experiments. In addition, most studies have used short (<15 min) block designs, which miss delayed responses following longer duration stimulation. We used brainstem-focused cardiac-gated fMRI and evaluated time-variant brain response to longer duration (>30 min) stimulation with verum (VA, electro-stimulation at acupoint ST-36) or sham point (SPA, non-acupoint electro-stimulation) acupuncture. Our results provide evidence that acupuncture modulates brainstem nuclei important to endogenous monoaminergic and opioidergic systems. Specifically, VA modulated activity in the substantia nigra (SN), nucleus raphe magnus, locus ceruleus, nucleus cuneiformis, and periaqueductal gray (PAG). Activation in the ventrolateral PAG was greater for VA compared to SPA. Linearly decreasing time-variant activation, suggesting classical habituation, was found in response to both VA and SPA in sensorimotor (SII, posterior insula, premotor cortex) brain regions. However, VA also produced linearly time-variant activity in limbic regions (amygdala, hippocampus, and SN), which was bimodal and not likely habituation--consisting of activation in early blocks, and deactivation by the end of the run. Thus, acupuncture induces different brain response early, compared to 20-30 min after stimulation. We attribute the fMRI differences between VA and SPA to more varied and stronger psychophysical response induced by VA. Our study demonstrates that acupuncture modulation of brainstem structures can be studied non-invasively in humans, allowing for comparison to animal studies. Our protocol also demonstrates a fMRI approach to study habituation and other time-variant phenomena over longer time durations.
Acupuncture Mobilizes the Brain's Default Mode and Its Anti-correlated Network in Healthy Subjects
Previous work has shown that acupuncture stimulation evokes deactivation of a limbic-paralimbic-neocortical network (LPNN) as well as activation of somatosensory brain regions. This study explores the activity and functional connectivity of these regions during acupuncture vs. tactile stimulation and vs. acupuncture associated with inadvertent sharp pain. Acupuncture during 201 scans and tactile stimulation during 74 scans for comparison at acupoints LI4, ST36 and LV3 was monitored with fMRI and psychophysical response in 48 healthy subjects. Clusters of deactivated regions in the medial prefrontal, medial parietal and medial temporal lobes as well as activated regions in the sensorimotor and a few paralimbic structures can be identified during acupuncture by general linear model analysis and seed-based cross correlation analysis. Importantly, these clusters showed virtual identity with the default mode network and the anti-correlated task-positive network in response to stimulation. In addition, the amygdala and hypothalamus, structures not routinely reported in the default mode literature, were frequently involved in acupuncture. When acupuncture induced sharp pain, the deactivation was attenuated or became activated instead. Tactile stimulation induced greater activation of the somatosensory regions but less extensive deactivation of the LPNN. These results indicate that the deactivation of the LPNN during acupuncture cannot be completely explained by the demand of attention that is commonly proposed in the default mode literature. Our results suggest that acupuncture mobilizes the anti-correlated functional networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response.
Hierarchical Coding of Characters in the Ventral and Dorsal Visual Streams of Chinese Language Processing
Functional and spatial hierarchical organization of increasingly language-like word forms has been proposed for alphabetic languages at the occipitotemporal cortex for visual word recognition. In the logographic Chinese language system, similar functional and spatial hierarchical presentations of brain responses to sublexical orthographic structure are beginning to be explored. In this study, we used whole-brain fMRI to show that a hierarchical coding of increasingly language-like character type is present in multiple Chinese language processing areas. Fluent Chinese readers were presented with Chinese synonyms/non-synonym pairs, identical/non-identical non-pronounceable pseudo-character pairs constructed with Chinese radicals, and identical/non-identical Korean character pairs. We observed the presence of a spatial gradient for increasing language-like character types in the ventral and dorsal visual streams of the cortex. At the left occipitotemporal cortex of the ventral visual stream, we observed a posterior-to-anterior gradient of character type selectivity with the anterior fusiform region being more selective for real Chinese characters and the posterior fusiform region being more selective for Korean characters. At the left and right intraparietal sulci of the dorsal visual stream, a medial-to-lateral gradient of character type selectivity was observed, with the lateral edge being more selective for real Chinese characters, the medial edge being more selective for pseudo-characters, and with less activation attributable to Korean characters. Spatial gradients of selecting character type were also identified in prefrontal cortex, dorsal striatum and lateral temporal cortex. The results suggest that the left occipitotemporal cortex and both left and right intraparietal sulci are tuned with a functional and spatial hierarchical sensitivity to the presence of semantic elements as well as different orthographic structures.
Can Cantonese Rhymes Be Used in the Assessment of Hemispheric Dominance for Language?
English vowels had been proposed in previous studies to be used as a simple tool for the brain mapping of language. A proper fMRI study of Cantonese rhymes, each of which being a required and fundamental unit of a Cantonese syllable, remains to be carried out. Using an auditory task with Cantonese rhymes which carry no semantic meaning, we observed a minimal amount of positive BOLD signal at the caudate nucleus when Cantonese rhymes were contrasted with their corresponding filtered sounds. Typical language activating regions of the prefrontal cortex, the medial prefrontal cortex and the lateral temporal cortex on both left and right sides were not activated by Cantonese rhymes. Based on the absence of brain activation at the typical language areas in the contrast of Cantonese rhymes relative to filtered sounds, the auditory task with Cantonese rhymes may not be a robust tool for the individual clinical assessment of hemispheric dominance for language.
Transcranial Doppler Study of Cerebrovascular Reactivity: Are Migraineurs More Sensitive to Breath-hold Challenge?
Transcranial Doppler sonography (TCD) of cerebrovascular reactivity has been used to study migraine interictally. However, the previous TCD findings had been quite varied at the post breath-hold period. Autonomic responses were usually studied with cardiac information. The aim of this study was to use TCD as a tool to examine difference in cerebrovascular reactivity between migraineurs and non-headache controls by measuring interictally the whole time course of cerebral blood flow velocity (CBFV) during and after a breath-hold challenge. The percentage change of CBFV was derived in the left and right middle cerebral arteries in 10 migraineurs and 10 controls during and after a 20 s breath-hold. Three phases of CBFV change were identified with an initial positive phase above baseline, a middle negative phase during breath-hold, and a late positive phase which started before the cessation of breath-hold and continued for a period after. In addition to CBFV, we also extracted and utilized the information of the cardiac cycle duration (CC) derived from the time course of CBFV. The percentage change of CC was derived from time intervals between every two points of inflexion in CBFV. Two undershoots of CC change were shown at the transitions of breathing motions. We found evidence that migraineurs had significant difference of CBFV change at the middle negative phase during breath-hold and the pronounced undershoots of CC change compared to non-headache controls.
Acupuncture, the Limbic System, and the Anticorrelated Networks of the Brain
The study of the mechanism of acupuncture action was revolutionized by the use of functional magnetic resonance imaging (fMRI). Over the past decade, our fMRI studies of healthy subjects have contributed substantially to elucidating the central effect of acupuncture on the human brain. These studies have shown that acupuncture stimulation, when associated with sensations comprising deqi, evokes deactivation of a limbic-paralimbic-neocortical network, which encompasses the limbic system, as well as activation of somatosensory brain regions. These networks closely match the default mode network and the anti-correlated task-positive network described in the literature. We have also shown that the effect of acupuncture on the brain is integrated at multiple levels, down to the brainstem and cerebellum. Our studies support the hypothesis that the effect of acupuncture on the brain goes beyond the effect of attention on the default mode network or the somatosensory stimulation of acupuncture needling. The amygdala and hypothalamus, in particular, show decreased activation during acupuncture stimulation that is not commonly associated with default mode network activity. At the same time, our research shows that acupuncture stimulation needs to be done carefully, limiting stimulation when the resulting sensations are very strong or when sharp pain is elicited. When acupuncture induced sharp pain, our studies show that the deactivation was attenuated or reversed in direction. Our results suggest that acupuncture mobilizes the functionally anti-correlated networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response. In this work we also discuss multiple avenues of future research, including the role of neurotransmitters, the effect of different acupuncture techniques, and the potential clinical application of our research findings to disease states including chronic pain, major depression, schizophrenia, autism, and Alzheimer's disease.
Early Time Points Perfusion Imaging
The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.
Early Time Points Perfusion Imaging: Theoretical Analysis of Correction Factors for Relative Cerebral Blood Flow Estimation Given Local Arterial Input Function
If local arterial input function (AIF) could be identified, we present a theoretical approach to generate a correction factor based on local AIF for the estimation of relative cerebral blood flow (rCBF) under the framework of early time points perfusion imaging (ET). If C(t), the contrast agent bolus concentration signal time course, is used for rCBF estimation in ET, the correction factor for C(t) is the integral of its local AIF. The recipe to apply the correction factor is to divide C(t) by the integral of its local AIF to obtain the correct rCBF. By similar analysis, the correction factor for the maximum derivative (MD1) of C(t) is the maximum signal of AIF and the correction factor for the maximum second derivative (MD2) of C(t) is the maximum derivative of AIF. In the specific case of using normalized gamma-variate function as a model for AIF, the correction factor for C(t) (but not for MD1) at the time to reach the maximum derivative is relatively insensitive to the shape of the local AIF.
Early Time Points Perfusion Imaging: Relative Time of Arrival, Maximum Derivatives and Fractional Derivatives
Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.
Guasha-induced Hepatoprotection in Chronic Active Hepatitis B: a Case Study
Heme oxygenase-1 (HO-1) has demonstrated hepatoprotective effect in animal hepatitis models. HO-1 was also reported to be upregulated with Guasha, an ancient therapeutic technique which applies instrument assisted press-stroking to treat many disorders.
Record of a Single FMRI Experiment in May of 1991
The discovery of BOLD fMRI at MGH in May 1991 was 1) built on the ongoing effort to develop new MR techniques for perfusion measurement with intrinsic blood contrast, 2) supported by the critical MGH expertise and experience on magnetic susceptibility and deoxyhemoglobin research, 3) inspired by the breakthrough in brain fMRI using dynamic susceptibility contrast (DSC) of the external contrast agent Gd-DTPA, 4) facilitated by the flow-BOLD insight of a hypoxia experiment, and 5) made possible by the availability of clinical echo planar imaging (EPI). The simultaneous demonstration of flow-weighted fMRI derived its intellectual origin from work on steady state arterial spin labeling (ASL). The free-wheeling and fertile intellectual environment structured by Dr. Thomas Brady and Dr. Bruce Rosen at the MGH-NMR Center provided the indispensable support for highly risky ideas to roam and succeed. The paper offers a first person account of the steps that led to the May experiment and its aftermath.
Restoring Cerebral Dopamine Homeostasis by Electrical Forepaw Stimulation: An FMRI Study
Deviation of dopamine homeostasis is known to be associated with disorders like drug addiction and Parkinson's disease. As dopamine function is tightly regulated within the basal ganglia circuitry, cortical perturbation would lead to modulation of dopaminergic activity in the striatum. We proposed and tested if somatosensory activity such as forepaw stimulation could modulate dopaminergic function. Specifically, we tested in rats if electrical forepaw stimulation (EFS) could attenuate dopamine release in the brain if dopamine is excessive, and boost dopamine release if dopamine is deficient. We had previously demonstrated that EFS effectively attenuated excessive DA concentration in the striatum. We now show in this manuscript with fMRI that EFS boosted DA release on two DA deficient conditions: (1) with quinpirole challenge, and (2) partial Parkinsonism model (PD). Quinpirole alone decreased dopamine release and thus the cerebral blood volume (CBV) that was restored by EFS. EFS also succeeded in increasing CBV in the basal-ganglia circuitry of the PD rats, but not in the controls. Context-dependent connectivity analysis showed increased connectivity during the basal state in the PD rats, compared with the controls. This "enhanced" yet abnormal connectivity of PD rats was reduced post-EFS. Our results suggest that EFS resets the deficient DA system by partially increasing DA release, in the meanwhile lessening the need for recruiting extra functional network in the basal ganglia circuitry. This study shows not only the capacity of peripheral stimulation to perturb neurotransmitter function, but also the potential of peripheral stimulation to restore neurotransmitter homeostasis. Synapse, 2012. © 2011 Wiley Periodicals, Inc.
