Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.

BACKGROUND: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. METHODS: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. RESULTS: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. CONCLUSIONS: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. CLINICAL TRIAL REGISTRATION: NCT0061015.

A comparison of 31P magnetic resonance spectroscopy and microbubble-enhanced ultrasound for characterizing hepatitis c-related liver disease.

We compared in vivo hepatic (31) P magnetic resonance spectroscopy ((31) P MRS) and hepatic vein transit times (HVTT) using contrast-enhanced ultrasound with a microbubble agent to assess the severity of hepatitis C virus (HCV)-related liver disease. Forty-six patients with biopsy-proven HCV-related liver disease and nine healthy volunteers had (31) P MRS and HVTT performed on the same day. (31) P MR spectra were obtained at 1.5 T. Peak areas were calculated for metabolites, including phosphomonoesters (PME) and phosphodiesters (PDE). Patients also had the microbubble ultrasound contrast agent, Levovist (2 g), injected into an antecubital vein, and time-intensity Doppler ultrasound signals of the right and middle hepatic veins were measured. The HVTT was calculated as the time from injection to a sustained rise in Doppler signal 10% greater than baseline. The shortest times were used for analysis. Based on Ishak histological scoring, there were 15 patients with mild hepatitis, 20 with moderate/severe hepatitis and 11 with cirrhosis. With increasing severity of disease, the PME/PDE ratio was steadily elevated, while the HVTT showed a monotonic decrease. Both imaging modalities could separate patients with cirrhosis from the mild and moderate/severe hepatitis groups. No statistical difference was observed in the accuracy of each test to denote mild, moderate/severe hepatitis and cirrhosis (Fisher's exact test P =1.00). (31) P MRS and HVTT show much promise as noninvasive imaging tests for assessing the severity of chronic liver disease. Both are equally effective and highly sensitive in detecting cirrhosis.

Optimal combinations of ultrasound-based and serum markers of disease severity in patients with chronic hepatitis C.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.

Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans.

Simultaneous recording of event-related electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) responses has the potential to provide information on how the human brain reacts to an external stimulus with unique spatial and temporal resolution. However, in most studies combining the two techniques, the acquisition of functional MR images has been interleaved with the recording of evoked potentials. In this study we investigated the feasibility of recording pain-related evoked potentials during continuous and simultaneous collection of blood oxygen level-dependent (BOLD) functional MR images at 3 T. Brain potentials were elicited by selective stimulation of cutaneous Adelta and C nociceptors using brief radiant laser pulses (laser-evoked potentials, LEPs). MR-induced artifacts on EEG data were removed using a novel algorithm. Latencies, amplitudes, and scalp distribution of LEPs recorded during fMRI were not significantly different from those recorded in a control session outside of the MR scanner using the same equipment and experimental design. Stability tests confirmed that MR-image quality was not impaired by the evoked potential recording, beyond signal loss related to magnetic susceptibility differences local to the electrodes. fMRI results were consistent with our previous studies of brain activity in response to nociceptive stimulation. These results demonstrate the feasibility of recording reliable pain-related LEPs and fMRI responses simultaneously. Because LEPs collected during fMRI and those collected in a control session show remarkable similarity, for many experimental designs the integration of LEP and fMRI data collected in separate, single-modality acquisitions may be appropriate. Truly simultaneous recording of LEPs and fMRI is still desirable in specific experimental conditions, such as single-trial, learning, and pharmacological studies.

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Magnetic resonance imaging of rheumatoid arthritis in metacarpophalangeal joints.

OBJECTIVE: To report the development of high-resolution targeted magnetic-resonance imaging (MRI) techniques (not using injections of contrast media) to investigate and monitor rheumatoid arthritis (RA) in the metacarpophalangeal (MCP) joints. DESIGN AND PATIENTS: A total of 25 RA patients (age range 30-68 years) with varying degrees of disease severity ranging from early onset through active disease to the burnt-out stage, were imaged. (One patient subsequently underwent surgery and histological data was obtained.) A series of 10 control subjects were also studied--two for each 10-year age range. All the RA subjects were assessed for disease activity using standard clinical criteria and radiography as part of normal procedures. MRI was carried out using a targeted system and novel radiofrequency coil. Images of the MCP were performed at very high resolution with 1.5 mm slice thickness and in-plane resolution 130 microns. Standard gradient-echo (GE) sequences were used for anatomical imaging, multiple-echo GE sequences used to produce effective spin-spin relaxation time (T2*) maps and optimised binomialpulse presaturation used in conjunction with a GE sequence to generate magnetization-transfer (MT) ratio maps. RESULTS: High-quality high-resolution images of the MCP joints were obtained which highlighted normal anatomy and key features characterising the disease state (e.g. pannus, bone erosions, vascularity). Accurate measurements of T2* and MT with variations of +/- 4% and +/- 2% respectively were achieved. In active disease, variations in T2* and MT could be determined throughout areas of pannus, clearly demonstrating the heterogeneity of this erosive tissue. Pannus in MCP joints with active destruction was found to have high values of T2* varying from 25 ms to 40 ms with pockets up to 100 ms, whereas pannus present in chronic destruction, or burnt-out disease, had T2* values ranging from 21 to 29 ms. MT-active tissue was uniformly distributed in burnt-out disease, which was confirmed histologically in one case, compared with a more heterogeneous distribution in active disease. CONCLUSION: The MRI sequences and targeted system developed allow high-resolution studies of RA disease progression and activity. The data confirm the variable pattern of the disease and, in particular, heterogeneity of pannus.

Optimum setting of binomial pulses for magnetization transfer contrast.

Investigation of the cause of image artifacts generated by a magnetization transfer (MT) sequence using binomial-pulse trains led to findings of imperfections in the pulses. These imperfections caused anomalous direct saturation of the free water, which was localized due to the static magnetic field inhomogeneity. In the case of single binomial pulses a loss of overall MT response across the field of view results. Two methods of correcting the imperfections and removing the artifact have been established using interactive adjustment of sub-pulse lobes and phase swapping of pulse trains. These imperfections may be present in many systems and may have led to erroneous judgements of the value of binomial pulses for MT imaging. A technique for interrogating the frequency spectrum of the binomial-pulse train has been utilized, allowing its optimization. The use of accurate and optimized binomial pulses may yet prove to be preferable to pulsed off-resonance methods for quantitative, clinical MT imaging.

Measurement of acoustic streaming using magnetic resonance.

Magnetic resonance imaging (MRI) has been used to explore acoustic streaming caused in water under ultrasonic exposure conditions similar to those used for diagnostic applications. Streaming was established in an enclosed tube with acoustically transparent end windows, using a pulsed, weakly-focused transducer of acoustic frequency 3.5 MHz. Phase-detection MRI was used to image and quantify streaming profiles in the region of the acoustic focus. Acoustic powers in the range 0.4 mW to 100 mW were used. The sensitivity of the technique enabled streaming velocities down to 0. 1 mm s(-1) to be measured, generated by acoustic power less than 1 mW. In addition, acoustic streaming generated within open meshes with minimum pore dimensions of 3.0 mm and 2.0 mm was measured. The flow velocity in the coarser mesh reached 0.9 mm s(-1) at 95 mW total acoustic power. These observations demonstrate that acoustic streaming is probably a much more general phenomenon in diagnostic ultrasound (ultrasound) than previously recognised. The combination of magnetic resonance and ultrasound shows promise as a diagnostic method for the differentiation of cystic lesions in vivo, and for their characterisation, with sensitivity significantly greater than using ultrasound alone.

Magnetic resonance imaging techniques demonstrate soft tissue damage in the diabetic foot.

AIMS: Our objective was to assess the qualitative soft tissue changes which occur in the diabetic neuropathic foot, which may predispose to ulceration, using a specific magnetic resonance imaging (MRI) contrast sequence, magnetization transfer (MT) which produces contrast based on exchange between water bound to macromolecules (e.g. collagen) and free water (e.g. extracellular fluid). METHODS: The first metatarsal head of 19 diabetic neuropathic subjects and 11 diabetic non-neuropathic controls was studied using a 'targeted' radiofrequency coil. Neuropathy was classified using vibration perception threshold (VPT) (< or > 25 V), cold threshold (< 1 degree C or > 4 degrees C) and Michigan neuropathy score (< 5 or > 15). Peripheral vascular disease was excluded. Results were expressed as percentage of tissue MT activity in a cross-sectional area. At autopsy full thickness biopsies were taken from the plantar fat pad of 10 unrelated subjects with diabetic neuropathy. RESULTS: Healthy muscle displays high MT activity, whereas adipose tissue induces little activity. Muscle MT activity was considerably reduced (75+/-20%, 30+/-24%, P<0.001) and fat pad MT activity was considerably increased in subjects with neuropathy (37+/-17% 68+/-21%, P<0.001). Muscle fibre atrophy decreases MT activity, whereas fibrous infiltration of the fat pad increases MT activity, fibro-atrophic post-mortem histological changes were found in the plantar fat pads of all neuropathic subjects examined (n = 10). CONCLUSIONS: Changes in MT activity reflect qualitative structural changes which this study reveals are extensive in the diabetic neuropathic foot. Fibrotic atrophy of the plantar fat pad may affect its ability to dissipate the increased weight-bearing forces associated with diabetic neuropathy.

Automatic realignment of time-separated MR images by genetic algorithm.

A simple yet highly efficient artificial intelligence technique utilizing a genetic algorithm is used to register time-separated pairs of MRI data sets. To encourage others to try the approach, the algorithm is presented by way of a simple example to a 2-D data set; it is equally applicable to 3-D data. The technique is reliably found to reduce mismatch in images of the distal-interphalangeal joint from the order of several mm to just 200 microm (one pixel). The method and transformation are general and would be suitable for locating physical changes between any image data sets. We believe the technique to be of use in functional imaging, measurement of disease progression with time (e.g., degradation of cartilage in arthritic disease) and pre/post-surgical studies.

A programmable eddy-current compensation system for MRI and localized spectroscopy.

A programmable preemphasis system has been developed for eddy-current compensation in gradient sets with or without active screening. Preemphasis parameters are nonvolatile but can be changed rapidly when working with interchangeable gradient sets. The design allows easy retrofit to existing systems. A method for setting the preemphasis is presented, together with specimen results.

A three-dimensional NMR imaging scheme utilizing doubly resonant gradient coils.

A 3DFT gradient-echo technique has been developed which, in conjunction with series-resonant gradient-coil circuits, can produce three-dimensional NMR images with an echo time of less than 100 microseconds. The method involves a read-gradient waveform composed of two sinusoids of different frequencies. This is an improvement on previous imaging sequences using a single sinusoid where only half of k space was sampled and where the second half was calculated using conjugate symmetry. The inaccuracies involved in the necessary "cut and paste" of k space inevitably lead to artifacts in the final image. The important features of the new method are that with suitable phase encoding all octants of k space are sampled, the RF pulse is applied when the gradients are all zero, and the echo forms when the gradient is essentially constant. This method will allow more extensive application of solid imaging techniques to biological samples in vivo.

Magnetic resonance imaging reveals micro-haemorrhage in the feet of diabetic patients with a history of ulceration.

Soft tissue haemorrhage in the foot is a possible precursor of ulceration in patients with diabetic peripheral neuropathy. High resolution 'targetted' magnetic resonance imaging was used to scan the forefoot. Neuropathic patients with and without previous ulceration were matched for degree of neuropathy, mean vibration perception threshold 33.5 +/- 4.2 V (previous ulcer) vs 31.0 +/- 6.9 V (no ulcer), age, sex, and duration of diabetes against non-neuropathic controls. There were nine patients in each category. Paramagnetic materials, e.g. iron compounds, cause a signal void ('drop-out') on gradient-echo images which disappear on spin-echo images. Evidence of haemorrhage was seen in 6 patients with previous ulceration, and none in the other groups (p = 0.009, chi square test). Autologous injection of 20 microliters of blood into the foot of a healthy volunteer produced similar images, a 'drop-out' 1 cm across being visible on magnetic resonance scanning 3 days later. Peak vertical forefoot pressures were not significantly different in the neuropathic groups 0.67 +/- 0.20 vs 0.60 +/- 0.13 Pa but were lower in the non-neuropathic group, 0.43 +/- 0.11 Pa (p = 0.0004, Mann-Whitney), and do not explain the appearance of these haemorrhages. Magnetic resonance imaging provides a sensitive way of detecting micro-haemorrhage and its presence may predict an increased risk of foot ulceration.

Osteoarthritis and magnetic resonance imaging: potential and problems.

To date, MRI has primarily been used to study anatomical changes, and at a resolution that makes detailed analysis of focal change difficult. This is primarily because cost limits the development and use of tailor made research systems. The detailed analysis of soft tissue, cartilage, and bone marrow images should provide a fruitful non-invasive method to study OA. However, the development of MRI methods to study movement, diffusion and perfusion, and the spatial localisation of spectroscopic information, promises a revolution in the study of the living joint in man.

Modified birdcage coils for targeted imaging.

The design of a radiofrequency coil of U-shaped geometry, specifically intended to image individual knuckle joints of the hand, has been investigated. The coil geometry is that of a "split and opened" birdcage coil. The optimum leg positions for such a U-shaped coil have been theoretically predicted using a novel technique that considers both the signal-to-noise ratio and the homogeneity of the field-of-view. Two particular coils of this type have been constructed, each optimum for a different size of image space and assuming a different source of image noise (sample-dominated or coil-dominated). The experimentally determined radiofrequency fields produced by the coils correspond well to theory. Either coil can be used to obtain good-quality, high-resolution (130 microns x 130 microns in-plane) images in vivo of the first, second, or fifth metacarpophalangeal joints of the hand, sites of particular interest in the study of arthritis.

Water diffusion coefficient measurements in the finger by magnetic resonance imaging.

Diffusion coefficients of water have been measured in the fingers of humans by magnetic resonance imaging. It was found that the measured diffusion coefficients increased with subject age in certain regions of the finger but that these regions differed between males and females. The observation of an increased diffusion coefficient with age appears to be inconsistent with a direct-hydration model and possible explanations are given using other models. It is conjectured that the measured diffusion coefficient of water increases with age as a result of structural changes to proteins.

Magnetic resonance imaging manifestations of idiopathic haemochromatosis in the wrist.

The magnetic resonance imaging features of the wrist of a patient suffering from the arthropathy of haemochromatosis are presented. It is apparent that the deposition of iron within the bone marrow is focal in origin and may be associated with cyst formation. In addition, changes in serum ferritin levels with treatment suggest that the deposition is irreversible. Studies of two other patients with haemochromatosis without cyst formation in the wrists did not yield similar artefacts, in spite of having high ferritin levels and arthritis.