An in-vivo study of BOLD laminar responses as a function of echo time and static magnetic field strength.

Layer specific functional MRI requires high spatial resolution data. To compensate the associated poor signal to noise ratio it is common to integrate the signal from voxels at a given cortical depth. If the region is sufficiently large then physiological noise will be the dominant noise source. In this work, activation profiles in response to the same visual stimulus are compared at 1.5 T, 3 T and 7 T using a multi-echo, gradient echo (GE) FLASH sequence, with a 0.75 mm isotropic voxel size and the cortical integration approach. The results show that after integrating over a cortical volume of 40, 60 and 100 mm3 (at 7 T, 3 T, and 1.5 T, respectively), the signal is in the physiological noise dominated regime. The activation profiles obtained are similar for equivalent echo times. BOLD-like noise is found to be the dominant source of physiological noise. Consequently, the functional contrast to noise ratio is not strongly echo-time or field-strength dependent. We conclude that laminar GE-BOLD fMRI at lower field strengths is feasible but that larger patches of cortex will need to be examined, and that the acquisition efficiency is reduced.

Laminar specific fMRI reveals directed interactions in distributed networks during language processing.

Interactions between top-down and bottom-up information streams are integral to brain function but challenging to measure noninvasively. Laminar resolution, functional MRI (lfMRI) is sensitive to depth-dependent properties of the blood oxygen level-dependent (BOLD) response, which can be potentially related to top-down and bottom-up signal contributions. In this work, we used lfMRI to dissociate the top-down and bottom-up signal contributions to the left occipitotemporal sulcus (LOTS) during word reading. We further demonstrate that laminar resolution measurements could be used to identify condition-specific distributed networks on the basis of whole-brain connectivity patterns specific to the depth-dependent BOLD signal. The networks corresponded to top-down and bottom-up signal pathways targeting the LOTS during word reading. We show that reading increased the top-down BOLD signal observed in the deep layers of the LOTS and that this signal uniquely related to the BOLD response in other language-critical regions. These results demonstrate that lfMRI can reveal important patterns of activation that are obscured at standard resolution. In addition to differences in activation strength as a function of depth, we also show meaningful differences in the interaction between signals originating from different depths both within a region and with the rest of the brain. We thus show that lfMRI allows the noninvasive measurement of directed interaction between brain regions and is capable of resolving different connectivity patterns at submillimeter resolution, something previously considered to be exclusively in the domain of invasive recordings.

Is visual activation associated with changes in cerebral high-energy phosphate levels?

Phosphorus magnetic resonance spectroscopy (31P MRS) has been employed before to assess phosphocreatine (PCr) and other high-energy phosphates in the visual cortex during visual stimulation with inconsistent results. We performed functional 31P MRS imaging in the visual cortex and control regions during a visual stimulation paradigm at an unprecedented sensitivity, exploiting a dedicated RF coil design at a 7 T MR system. Visual stimulation in a 3 min 24 s on-off paradigm in eight young healthy adults generated a clear BOLD effect with traditional 1H functional MRI in the visual cortex (average z score 9.9 ± 0.2). However, no significant event-related changes in any of the 31P metabolite concentrations, linewidths (7.9 ± 1.8 vs 7.8 ± 1.9 Hz) or tissue pH (7.07 ± 0.13 vs 7.06 ± 0.07) were detectable. Overall, our study of 31P MRSI in 15 cm3 voxels had a detection threshold for changes in PCr, Pi and γ-ATP between stimulation and rest of 5, 17 and 10%, respectively. In individual subjects, the mean coefficients of variance for PCr and Pi levels of control voxels were 6 ± 3 and 19 ± 8% (three time point average of 3 min 24 s). Altogether this indicates that energy supply for neuronal activation at this temporal resolution does not drain global PCr resources.

Oxidative capacity varies along the length of healthy human tibialis anterior.

KEY POINTS: During exercise skeletal muscles use the energy buffer phosphocreatine. The post-exercise recovery of phosphocreatine is a measure of the oxidative capacity of muscles and is traditionally assessed by 31 P magnetic resonance spectroscopy of a large tissue region, assuming homogeneous energy metabolism. To test this assumption, we collected spatially resolved spectra along the length of human tibialis anterior using a home-built array of 31 P detection coils, and observed a striking gradient in the recovery rate of phosphocreatine, decreasing along the proximo-distal axis of the muscle. A similar gradient along this muscle was observed in signal changes recorded by 1 H muscle functional MRI. These findings identify intra-muscular variation in the physiology of muscles in action and highlight the importance of localized sampling for any methodology investigating oxidative metabolism of this, and potentially other muscles. ABSTRACT: The rate of phosphocreatine (PCr) recovery (kPCr ) after exercise, characterizing muscle oxidative capacity, is traditionally assessed with unlocalized 31 P magnetic resonance spectroscopy (MRS) using a single surface coil. However, because of intramuscular variation in fibre type and oxygen supply, kPCr may be non-uniform within muscles. We tested this along the length of the tibialis anterior (TA) muscle in 10 male volunteers. For this purpose, we employed a 3T MR system with a 31 P/1 H volume transmit coil combined with a home-built 31 P phased-array receive probe, consisting of five coil elements covering the TA muscle length. Mono-exponential kPCr was determined for all coil elements after 40 s of submaximal isometric dorsiflexion (SUBMAX) and incremental exercise to exhaustion (EXH). In addition, muscle functional MRI (1 H mfMRI) was performed using the volume coil after another 40 s of SUBMAX. A strong gradient in kPCr was observed along the TA (P < 0.001), being two times higher proximally vs. distally during SUBMAX and EXH. Statistical analysis showed that this gradient cannot be explained by pH variations. A similar gradient was seen in the slope of the initial post-exercise 1 H mfMRI signal change, which was higher proximally than distally in both the TA and the extensor digitorum longus (P < 0.001) and strongly correlated with kPCr . The pronounced differences along the TA in functional oxidative capacity identify regional variation in the physiological demand of this muscle during everyday activities and have implications for the bio-energetic assessment of interventions to modify its performance and of neuromuscular disorders involving the TA.

Selective Activation of the Deep Layers of the Human Primary Visual Cortex by Top-Down Feedback.

In addition to bottom-up input, the visual cortex receives large amounts of feedback from other cortical areas [1-3]. One compelling example of feedback activation of early visual neurons in the absence of bottom-up input occurs during the famous Kanizsa illusion, where a triangular shape is perceived, even in regions of the image where there is no bottom-up visual evidence for it. This illusion increases the firing activity of neurons in the primary visual cortex with a receptive field on the illusory contour [4]. Feedback signals are largely segregated from feedforward signals within each cortical area, with feedforward signals arriving in the middle layer, while top-down feedback avoids the middle layers and predominantly targets deep and superficial layers [1, 2, 5, 6]. Therefore, the feedback-mediated activity increase in V1 during the perception of illusory shapes should lead to a specific laminar activity profile that is distinct from the activity elicited by bottom-up stimulation. Here, we used fMRI at high field (7 T) to empirically test this hypothesis, by probing the cortical response to illusory figures in human V1 at different cortical depths [7-14]. We found that, whereas bottom-up stimulation activated all cortical layers, feedback activity induced by illusory figures led to a selective activation of the deep layers of V1. These results demonstrate the potential for non-invasive recordings of neural activity with laminar specificity in humans and elucidate the role of top-down signals during perceptual processing.

Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging.

PURPOSE: To prospectively assess the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging in the detection of pelvic lymph node metastases in patients with prostate and/or bladder cancer staged as N0 with preoperative cross-sectional imaging. MATERIALS AND METHODS: This study was approved by an independent ethics committee. Written informed consent was obtained from all patients. Patients with no enlarged lymph nodes on preoperative cross-sectional images who were scheduled for radical resection of the primary tumor and extended pelvic lymph node dissection were enrolled. All patients were examined with a 3-T MR unit, and examinations included conventional and DW MR imaging of the entire pelvis. Image analysis was performed by three independent readers blinded to any clinical information. Metastases were diagnosed on the basis of high signal intensity on high b value DW MR images and morphologic features (shape, border). Histopathologic examination served as the standard of reference. Sensitivity and specificity were calculated, and bias-corrected 95% confidence intervals (CIs) were obtained with the bootstrap method. The Fleiss and Cohen κ and median test were applied for statistical analyses. RESULTS: A total of 4846 lymph nodes were resected in 120 patients. Eighty-eight lymph node metastases were found in 33 of 120 patients (27.5%). Short-axis diameter of these metastases was less than or equal to 3 mm in 68, more than 3 mm to 5 mm in 13, more than 5 mm to 8 mm in five; and more than 8 mm in two. On a per-patient level, the three readers correctly detected metastases in 26 (79%; 95% CI: 64%, 91%), 21 (64%; 95% CI: 45%, 79%), and 25 (76%; 95% CI: 60%, 90%) of the 33 patients with metastases, with respective specificities of 85% (95% CI: 78%, 92%), 79% (95% CI: 70%, 88%), and 84% (95% CI: 76%, 92%). Analyzed according to hemipelvis, lymph node metastases were detected with histopathologic examination in 44 of 240 pelvic sides (18%); the three readers correctly detected these on DW MR images in 26 (59%; 95% CI: 45%, 73%), 19 (43%; 95% CI: 27%, 57%), and 28 (64%; 95% CI: 47%, 78%) of the 44 cases. CONCLUSION: DW MR imaging enables noninvasive detection of small lymph node metastases in normal-sized nodes in a substantial percentage of patients with prostate and bladder cancer diagnosed as N0 with conventional cross-sectional imaging techniques.

Diffusion-weighted magnetic resonance imaging detects significant prostate cancer with high probability.

PURPOSE: We prospectively assessed the diagnostic accuracy of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer. MATERIALS AND METHODS: We performed a prospective study of 111 consecutive men with prostate and/or bladder cancer who underwent 3 Tesla diffusion-weighted magnetic resonance imaging of the pelvis without an endorectal coil before radical prostatectomy (78) or cystoprostatectomy (33). Three independent readers blinded to clinical and pathological data assigned a prostate cancer suspicion grade based on qualitative imaging analysis. Final pathology results of prostates with and without cancer served as the reference standard. Primary outcomes were the sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer with significance defined as a largest diameter of the index lesion of 1 cm or greater, extraprostatic extension, or Gleason score 7 or greater on final pathology assessment. Secondary outcomes were interreader agreement assessed by the Fleiss κ coefficient and image reading time. RESULTS: Of the 111 patients 93 had prostate cancer, which was significant in 80 and insignificant in 13, and 18 had no prostate cancer on final pathology results. The sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant PCa was 89% to 91% and 77% to 81%, respectively, for the 3 readers. Interreader agreement was good (Fleiss κ 0.65 to 0.74). Median reading time was between 13 and 18 minutes. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging (3 Tesla) is a noninvasive technique that allows for the detection of significant prostate cancer with high probability without contrast medium or an endorectal coil, and with good interreader agreement and a short reading time. This technique should be further evaluated as a tool to stratify patients with prostate cancer for individualized treatment options.

Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer.

BACKGROUND: Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer patients. OBJECTIVE: To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Examinations with 3-Tesla MRI 24-36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO-DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed. RESULTS AND LIMITATIONS: At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17-68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3-26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis. CONCLUSIONS: Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time.

Ultrasmall superparamagnetic particles of iron oxide allow for the detection of metastases in normal sized pelvic lymph nodes of patients with bladder and/or prostate cancer.

AIM: Lymph node metastases influence prognosis and outcome in patients with bladder and prostate cancer. Cross sectional imaging criteria are limited in detecting metastases in normal sized lymph nodes. This prospective study assessed the diagnostic accuracy of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) for the detection of metastases in normal sized lymph nodes using extended pelvic lymph node dissection (ePLND) and histopathology as the reference standard. METHODS: Seventy-five patients (bladder cancer, n=19, prostate cancer n=48, both, n=8) were examined using 3T MR before and after USPIO-administration. A preoperative reading with two readers in consensus and a second postoperative reading with three independent blinded readers were performed. Results were correlated with histopathology and diagnostic accuracies were calculated for all readings. RESULTS: A total of 2993 lymph nodes were examined histopathologically. Fifty-four metastatic nodes were found in 20/75 patients (26.7%). The first reading had a sensitivity of 55.0%, specificity of 85.5%, positive predictive value (PPV) of 57.9%, negative predictive value (NPV) of 83.9%, and diagnostic accuracy (DA) of 77.3% on a per patient level. The second reading had a mean sensitivity of 58.3%, specificity of 83.0%, PPV of 58.0%, NPV of 84.4% and DA of 76.4% on a per patient level. The majority of missed metastases were smaller than 5mm in short axis diameter. CONCLUSIONS: USPIO-enhanced MRI in bladder and prostate cancer patients allows detection of metastases in normal sized lymph nodes and might guide the surgeon to remove suspicious lymph nodes not included in standard PLND.

Therapy response with diffusion MRI: an update.

The efficiency of an oncological treatment regimen is often assessed by morphological criteria such as tumour size evaluated by cross-sectional imaging, or by laboratory measurements of plasma biomarkers. Because these types of measures typically allow for assessment of treatment response several weeks or even months after the start of therapy, earlier response assessment that provides insight into tumour function is needed. This is particularly urgent for the evaluation of newer targeted therapies and for fractionated therapies that are delivered over a period of weeks to allow for a change of treatment in non-responding patients. Diffusion-weighted MRI (DW-MRI) is a non-invasive imaging tool that does not involve radiation or contrast media, and is sensitive to tissue microstructure and function on a cellular level. DW-MRI parameters have shown sensitivity to treatment response in a growing number of tumour types and organ sites, with additional potential as predictive parameters for treatment outcome. A brief overview of DW-MRI principles is provided here, followed by a review of recent literature in which DW-MRI has been used to monitor and predict tumour response to various therapeutic regimens.

Tracer kinetic analysis of dynamic contrast-enhanced MRI and CT bladder cancer data: A preliminary comparison to assess the magnitude of water exchange effects.

The purpose of this study was to determine the impact of water exchange on tracer kinetic parameter estimates derived from T(1)-weighted dynamic contrast-enhanced (DCE)-MRI data using a direct quantitative comparison with DCE-CT. Data were acquired from 12 patients with bladder cancer who underwent DCE-CT followed by DCE-MRI within a week. A two-compartment tracer kinetic model was fitted to the CT data, and two versions of the same model with modifications to account for the fast exchange and no exchange limits of water exchange were fitted to the MR data. The two-compartment tracer kinetic model provided estimates of the fractional plasma volume (v(p)), the extravascular extracellular space fraction (v(e)), plasma perfusion (F(p)), and the microvascular permeability surface area product. Our findings suggest that DCE-CT is an appropriate reference for DCE-MRI in bladder cancers as the only significant difference found between CT and MR parameter estimates were the no exchange limit estimates of v(p) (P = 0.002). These results suggest that although water exchange between the intracellular and extravascular-extracellular space has a negligible effect on DCE-MRI, vascular-extravascular-extracellular space water exchange may be more important.

Detecting vascular-targeting effects of the hypoxic cytotoxin tirapazamine in tumor xenografts using magnetic resonance imaging.

PURPOSE: To determine whether vascular-targeting effects can be detected in vivo using magnetic resonance imaging (MRI). METHODS AND MATERIALS: MR images of HCT-116 xenograft-bearing mice were acquired at 7 Tesla before and 24 hours after intraperitoneal injections of tirapazamine. Quantitative dynamic contrast-enhanced MRI analyses were performed to evaluate changes in tumor perfusion using two biomarkers: the volume transfer constant (K(trans)) and the initial area under the concentration-time curve (IAUC). We used novel implanted fiducial markers to obtain cryosections that corresponded to MR image planes from excised tumors; quantitative immunohistochemical mapping of tumor vasculature, perfusion, and necrosis enabled correlative analysis between these and MR images. RESULTS: Conventional histological analysis showed lower vascular perfusion or greater amounts of necrosis in the central regions of five of eight tirapazamine-treated tumors, with three treated tumors showing no vascular dysfunction response. MRI data reflected this result, and a striking decrease in both K(trans) and IAUC values was seen with the responsive tumors. Retrospective evaluation of pretreatment MRI parameters revealed that those tumors that did not respond to the vascular-targeting effects of tirapazamine had significantly higher pretreatment K(trans) and IAUC values. CONCLUSIONS: MRI-derived parameter maps showed good agreement with histological tumor mapping. MRI was found to be an effective tool for noninvasively monitoring and predicting tirapazamine-mediated central vascular dysfunction.