Liver Iron Content Determination Using a Volumetric Breath-Hold Gradient-Echo Sequence With In-Line R2 * Calculation.

BACKGROUND: Liver iron overload is a serious condition occurring in patients requiring blood transfusions (eg, in thalassemia and different forms of anemia) or with dysfunctional iron resorption, since there is no physiological mechanism to excrete iron. Above a certain level of iron concentration, chelation therapy is indicated. To monitor therapy success, liver iron content should be assessed regularly. A noninvasive method is important for patient management. Existing MRI methods suffer from long acquisition times and cost. PURPOSE: To study the correlation of liver iron content (LIC) reference values to liver R2 * determined using a 3D breath-hold multigradient echo (GRE) MRI sequence, employing accelerated acquisition by parallel imaging and in-line R2 * calculation. STUDY TYPE: Prospective. POPULATION: In all, 117 patients (22.1 ± 14.1 years, 66 men) suspected of iron overload. SEQUENCE: GRE. FIELD STRENGTH: 1.5T. ASSESSMENT: For comparison, a regulatory-approved method with a considerably longer scan time was used, providing LIC reference values. Participants were divided into a calibration group (65 participants), analyzed independently by two observers, and a validation group (52 participants). STATISTICAL TESTS: Linear correlation parameters were evaluated for R2 * values with LIC reference values, and for LIC determined from R2 * for validation group participants with LIC reference values. Sensitivity/specificity for clinical relevant LIC thresholds were analyzed. Interobserver variability was determined by intraclass correlation coefficient (ICC). RESULTS: Interobserver agreement was excellent, with an ICC of 0.99, P < 0.001. Good correlation (R2 = 0.89) and congruence of LIC values obtained with our method to LIC reference values was found, and almost identical diagnostic accuracy. Sensitivity/specificity were 0.98/0.67 for the diagnostic relevant LIC threshold of 4.5 mg/g and 1.0/0.95 for the threshold of 7 mg/g. DATA CONCLUSION: MRI acquisition times for determination of LIC can be significantly reduced by the use of comprehensive in-line R2 * map generation without compromising diagnostic accuracy. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Frequency and Diagnostic Implications of Image Artifacts by Eye-Lens Shielding in Head CT.

OBJECTIVE: The eye lens is one of the most radiosensitive organs, and medical radiation is one of the main causes of cataracts. To protect the lens during head CT examinations, protectors have been developed; however, they can lead to image artifacts, which is a major disadvantage of their use. This study retrospectively evaluates the frequency and extent of artifacts caused by these protectors related to three anatomic regions (eye, brain, and bone) and their dependence on protector positioning. MATERIALS AND METHODS: Datasets from 261 consecutive head CT examinations obtained during 3.5 months of routine clinical imaging were assessed. Diagnostic quality of the images was evaluated by objective measuring and subjective scoring on a 5-point Likert scale. Furthermore, the position of the lens protector in correlation to the eye lens and the intensity and frequency of artifacts were analyzed. RESULTS: Only 4.6% of all analyzed examinations were completely free from artifacts; 95.4% showed artifacts at least in the orbital cavity. Although the brain was affected in 27.8% of cases, in only 5.8% of cases was there a risk of misinterpretation, such as suspected intracranial bleeding. In 24.9% of cases, the lens was not properly covered by the protector. A too cranial position of the protector was identified as the main risk factor for cerebral artifacts. CONCLUSION: Eye shielding for brain CT examinations often leads to artifacts. However, in only a small percentage of cases do these artifacts affect tissue depiction in regions beyond the eye (i.e., brain or bones). Correct positioning is mandatory to minimize artifacts.

Quantification of inflammatory activity in patients with Crohn's disease using diffusion weighted imaging (DWI) in MR enteroclysis and MR enterography.

Background Individual studies have demonstrated the potential of diffusion-weighted magnetic resonance imaging (DWI-MRI) for identifying inflamed bowel segments. However, these studies were conducted with rather small patient cohorts and in most cases by means of MR enterography only. Purpose To demonstrate the feasibility of detecting inflamed bowel segments in a large collective of patients with Crohn's disease using DWI in MR enteroclysis and MR enterography and to compare the results of both techniques, also considering clinical parameters by means of the Harvey-Bradshaw Index (HBI). Material and Methods Ninety-six patients underwent MRI enteroclysis and 35 patients MR enterography, both with additional DWI. The HBI as well as apparent diffusion coefficients (ADC) in areas of inflamed and normal bowel wall were determined. Thus resulting in 208 bowel segments that were visualized and subsequently statistically analyzed. Results There were no significant differences in ADC values in MR enteroclysis and MR enterography ( P = 0.383 in inflammation, P = 0.223 in normal wall). Areas of inflammation showed statistically highly significant lower ADC values than areas of normal bowel wall ( P < 0.001). An ADC threshold of 1.56 × 10-3 mm2/s can distinguish between normal and inflamed bowel segments with a sensitivity of 97.4% and a specificity of 99.2%. A highly significant correlation could be shown between ADC and HBI values ( P = 0.001). Conclusion DWI-MRI facilitates recognition of inflamed bowel segments in patients with Crohn's disease and the ADC values show an excellent correlation to the HBI. There were no significant differences in ADC values in MR enteroclysis and MR enterography. An ADC threshold of 1.56 × 10-3 mm2/s differentiates between normal and inflamed bowel wall.

Noninvasive liver iron quantification by MRI using refocused gradient-echo (bSSFP): preliminary results.

PURPOSE: To evaluate the feasibility of using a balanced steady-state free precession sequence (bSSFP) to determine liver iron content (LIC). METHOD: Thirty-five consecutive patients with liver iron overload were examined with bSSFP. Signal intensity ratios of liver parenchyma to paraspinal muscles were retrospectively correlated with LIC values obtained by FerriScan, which was used as the reference method. Combinations of bSSFP protocols were also evaluated. The best combination was utilized to calculate LIC from bSSFP data. The sensitivity and specificity for the therapeutically relevant LIC threshold of 80 µmol/g (4.5 mg/g) were determined. RESULTS: LIC values ranged from 24 to 756 µmol/g. The best SIR-to-LIC correlation of a single protocol was obtained with a 3.5-ms repetition time (TR) and 17° excitation flip angle (FA). A combination of protocols with TRs of 3.5, 5, and 6.5 ms, each at 17° FA, yielded a superior correlation. LIC values calculated using this combination resulted in a sensitivity/specificity of 0.91/0.85. CONCLUSION: bSSFP is basically suitable to determine LIC. Its advantages are high SNR efficiency and the ability to acquire the entire liver in a breath hold without acceleration techniques. KEY POINTS: · The bSSFP sequence is suited to quantify liver iron overload.. · bSSFP has a high scanning efficiency and potential for LIC screening.. · Despite susceptibility artifacts, the LIC determined from bSSFP data showed high accuracy.. CITATION FORMAT: · Wunderlich AP, Cario H, Götz M et al. Noninvasive liver iron quantification by MRI using refocused gradient-echo (bSSFP): preliminary results. Fortschr Röntgenstr 2023; 195: 804 - 808.

Volumetric Evaluation of 3D Multi-Gradient-Echo MRI Data to Assess Whole Liver Iron Distribution by Segmental R2* Analysis: First Experience.

PURPOSE: MR transverse relaxation rate R2* has been shown to be useful for monitoring liver iron overload. A sequence enabling acquisition of the whole liver in a single breath hold is now available, thus allowing volumetric hepatic R2* distribution studies. We evaluated the feasibility of computer-assisted whole liver segmentation of 3 D multi-gradient-echo MRI data, and compared whole liver R2* determination to analyzing only a single slice. Also, segmental R2* differences were studied. MATERIALS AND METHODS: The liver of 44 patients, investigated by multi-gradient echo MRI at 1.5 T, was segmented and divided into nine segments. Segmental R2* values were examined for all patients together and with respect to two criteria: average R2* values, and reason for iron overload. Correlation of single-slice and volumetric data was tested with Spearman's rank test, segmental and group differences were evaluated by analysis of variance. RESULTS: Whole-liver R2* values correlated excellent to single slice data (p < 0.001). The lowest R2* occurred in segment 1 (S1), differences of S1 with regard to other segments were significant in five cases and highly significant in two cases. Patients with high average R2* showed significant differences between S1 and segments 2, 6, and 7. Disease-related differences with respect to S1 were significant in segments 3 to 5 and 7. CONCLUSION: Our results suggest inhomogeneous hepatic iron distribution. Low R2* in S1 may be explained by its special vascularization. KEY POINTS: · Hepatic R2* distribution is not as homogeneous as previously thought.. · Liver segments might have a functional relevance.. · Segmental and total liver R2* values coincide best in segment 8.. CITATION FORMAT: · Wunderlich AP, Cario H, Kannengießer S et al. Volumetric Evaluation of 3D Multi-Gradient-Echo MRI Data to Assess Whole Liver Iron Distribution by Segmental R2* Analysis: First Experience. Fortschr Röntgenstr 2023; 195: 224 - 233.

Segmental quantification of hepatic lipid content based on volumetric MRI data in patients with suspected iron overload.

PURPOSE: To investigate the segmental distribution of hepatic fat fraction, determined with MRI (MR proton density fat fraction, short MR-PDFF) in patients suspected of having liver iron overload. METHODS: The liver of 44 patients examined with MRI using a 3D multi-echo gradient-echo sequence was segmented semiautomatically and subdivided into nine segments (segment 4 divided in 4a and 4b). Segmental fat content was determined on MR-PDFF maps. Whole-liver steatosis grades were compared to those found in individual segments. Segmental MR-PDFF differences were tested for statistical significance. RESULTS: The most common diseases were thalassemia, various forms of anemia, and hereditary hemochromatosis. No patients suffered from fat metabolism disease. Iron overload was present in 37/44 (84 %) patients. For the whole liver, 22 patients showed a steatosis grade of 0, 21 patients were graded S1, and one patient had a steatosis grade of 2. The grade of steatosis was underestimated in 5 of 21 patients (24 %) in segment 8 and in 8 of 21 patients (38 %) in segment 7. Highly significant segmental MR-PDFF differences were detected with p < 0.00 001, e. g., comparing segment 2 to 5. Segments 1 to 3 had the highest fat content, segments 7 and 8 had the lowest. CONCLUSION: Our results suggest that the storage of fat in the liver is inhomogeneous, so that segment-wise differing fat concentrations were found. Fat distribution in patients with suspected hepatic iron overload was similar to living liver donors. However, it showed significant differences compared with the values published for NAFLD patients, which were less pronounced in the group with high average hepatic MR-PDFF values than in the group with normal lipid content. In patients suspected of having iron overload, segment 8, which is mainly targeted for biopsy, and segment 7 may underestimate steatosis grade. KEY POINTS: · A volumetric analysis of 3D MRI data of patients with suspected hepatic iron overload yielded a markedly elevated MR proton density fat fraction (MR-PDFF) in hepatic segments 1 to 3.. · This hepatic fat distribution, observed for the whole patient cohort, is similar to healthy living liver donors.. · The subgroup of patients with a high average MR-PDFF ≥ 6.5 % shows this effect with lower segmental deviations.. · In patients without fat metabolic disorders, the steatosis grade may be underestimated when taking biopsies in segment 8 or 7..

Substantial and reversible brain gray matter reduction but no acute brain lesions in ultramarathon runners: experience from the TransEurope-FootRace Project.

BACKGROUND: During the extremely challenging 4,487 km ultramarathon TransEurope-FootRace 2009, runners showed considerable reduction of body weight. The effects of this endurance run on brain volume changes but also possible formation of brain edema or new lesions were explored by repeated magnetic resonance imaging (MRI) studies. METHODS: A total of 15 runners signed an informed consent to participate in this study of planned brain scans before, twice during, and about 8 months after the race. Because of dropouts, global gray matter volume analysis could only be performed in ten runners covering three timepoints, and in seven runners who also had a follow-up scan. Scanning was performed on three identical 1.5 T Siemens MAGNETOM Avanto scanners, two of them located at our university. The third MRI scanner with identical sequence parameters was a mobile MRI unit escorting the runners. Volumetric 3D datasets were acquired using a magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Additionally, diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) imaging was performed. RESULTS: Average global gray matter volume as well as body weight significantly decreased by 6% during the race. After 8 months, gray matter volume returned to baseline as well as body weight. No new brain lesions were detected by DWI or FLAIR imaging. CONCLUSIONS: Physiological brain volume reduction during aging is less than 0.2% per year. Therefore a volume reduction of about 6% during the 2 months of extreme running appears to be substantial. The reconstitution in global volume measures after 8 months shows the process to be reversible. As possible mechanisms we discuss loss of protein, hypercortisolism and hyponatremia to account for both substantiality and reversibility of gray matter volume reductions. Reversible brain volume reduction during an ultramarathon suggests that extreme running might serve as a model to investigate possible mechanisms of transient brain volume changes. However, despite massive metabolic load, we found no new lesions in trained athletes participating in a multistage ultramarathon.See related commentary http://www.biomedcentral.com/1741-7015/10/171.

Graded cutaneous electrical vs thermal stimulation in humans shows different insular and cingulate cortex activation.

Pain can result from various sensory input modalities. To elucidate the differences of cortical responses to graded electrical and thermal stimulation, functional magnetic resonance imaging (fMRI) results of two studies using the same stimulation paradigms but different modalities with 15 healthy subjects each are compared. During painful electrical stimulation contralateral dorsal posterior insula and ventral posterior anterior cingulate cortex (ACC) activated more. During thermal stimulation, there was more activation in ipsilateral primary motor area (MI)/primary sensory area (SI) complex and premotor areas as well as dorsal posterior ACC. Thus electrostimulation preferably activates structures of the lateral pain projection system resulting in contralateral dorsal posterior insula and ventral posterior ACC activation. During thermal stimulation, more dorsal areas of the posterior ACC activated. The activation of ipsilateral MI/SI complex and premotor areas may be attributed to the slower perception of thermal stimuli and resulting re-evaluation. This has to be taken into account in the interpretation of other cross-modality studies as well.

Variability in memory performance in aged healthy individuals: an fMRI study.

Episodic memory performance varies in older subjects but underlying biological correlates remain as yet ambiguous. We investigated episodic memory in healthy older individuals (n=24; mean age: 64.4+/-6.7 years) without subjective memory complaints or objective cognitive impairment. Episodic memory was assessed with repetitive learning and recall of abstract geometric patterns during fMRI. Group analysis of brain activity during initial learning and maximum recall revealed hippocampal activation. Correlation analysis of brain activation and task performance demonstrated significant hippocampal activity during initial learning and maximum recall in a success-dependent manner. Neither age nor gray matter densities correlated with hippocampal activation. Functional imaging of episodic memory thus permits to detect objectively variability in hippocampal recruitment in healthy aged individuals without subjective memory complaints. Correlation analysis of brain activation and performance during an episodic memory task may be used to determine and follow-up hippocampal malfunction in a very sensitive manner.

No hypofrontality, but absence of prefrontal lateralization comparing verbal and spatial working memory in schizophrenia.

Hypofrontality and decreased lateralization have been two major, albeit controversial, results from functional neuroimaging studies of schizophrenia. We used fMRI to study cortical activation during a verbal and spatial working memory (WM) task (2-back) in 15 inpatients acutely ill with schizophrenia and 15 matched control subjects. We hypothesized (i) hypofrontality in patients in both tasks and (ii) decreased lateralization of prefrontal activation in patients under the assumption that, in controls, left prefrontal cortex (PFC) is engaged preferentially in the verbal task (verbal domain dominance) and the right prefrontal cortex is engaged preferentially in the spatial task (spatial domain dominance). Our results showed no significant differences in frontal activation between controls and patients, i.e. no hypofrontality in patients, even at a very liberal threshold (p<0.01). This may be explained by the fact that nearly all patients studied received atypical neuroleptics. Nonetheless, we found evidence for more subtle, domain-related prefrontal dysfunction. Whereas controls showed verbal WM domain dominance in left inferior frontal cortex and spatial WM domain dominance in right prefrontal cortex, these domain dominance effects were absent in the patient group, i.e. there were no lateralization effects. Finally, only patients showed an inverse correlation between performance and right prefrontal activation in verbal WM. We conclude that the finding of hypofrontality may depend on the medication of the patients and that there is prefrontal dysfunction even in the absence of hypofrontality.

Cultural objects modulate reward circuitry.

Using event-related fMRI we investigated the rewarding properties of cultural objects (cars) signaling wealth and social dominance. It has been shown recently that reward mechanisms are involved in the regulation of social relations like dominance and social rank. Based on evolutionary considerations we hypothesized that sports cars in contrast to other categories of cars, e.g. limousines and small cars, are strong social reinforcers and would modulate the dopaminergic reward circuitry. Twelve healthy male subjects were studied with fMRI while viewing photographs of different car classes followed by an attractivity rating. Behaviorally sports cars were rated significantly more attractive than limousines and small cars. Our fMRI results revealed significantly more activation in ventral striatum, orbitofrontal cortex, anterior cingulate and occipital regions for sports cars in contrast to other categories of cars. We could thus demonstrate that artificial cultural objects associated with wealth and social dominance elicit activation in reward-related brain areas.

Spatial congruence of neuronavigated transcranial magnetic stimulation and functional neuroimaging.

OBJECTIVES: Transcranial magnetic stimulation (TMS) is progressively gaining relevance as a tool in cognitive neuroscience and clinical research. However, most studies in this field do not consider individual anatomy. Neuronavigational devices allow to guide the coil to a specific cortical area, predetermined by functional magnetic resonance imaging (fMRI). Therefore, it is crucial to know whether the area of a certain function as identified by fMRI corresponds to the area where the TMS should be placed in order to influence this function. METHODS: We investigated the spatial relation between the cortical area activated by a motor task in fMRI and the area of magnetically evoked motor potentials (MEP) in 8 subjects, using a spacing of 5x5 mm. A neuronavigational system was adapted for coil positioning and for the registration of the stimulation coordinates. RESULTS: A spatial divergence of the centers of gravity from fMRI and MEP was found with a mean distance of about 10 mm, with the MEP centers being, by a mean derivation of 7.5 mm, consistently anterior to the center of fMRI activation. However, regarding MEP areas and fMRI activities, a large overlap was found for stimulation intensities of both 110 and 120% motor threshold. CONCLUSIONS: The combination of fMRI and neuronavigated TMS is useful for non-invasive investigation of individual cortical functions predetermined by fMRI. Whereas both are spatially by and large congruent, discrepencies in the exact spatial relation between MEP and fMRI areas should be considered and further studied.

Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex.

Neuroimaging studies in humans have shown that different working memory (WM) tasks recruit a common bilateral fronto-parietal cortical network. Animal studies as well as neuroimaging studies in humans have suggested that this network, in particular the prefrontal cortex, is preferentially recruited when material from different domains (e.g. spatial information or verbal/object information) has to be memorized. Early imaging studies have suggested qualitative dissociations in the prefrontal cortex for spatial and object/verbal WM, either in a left-right or a ventral-dorsal dimension. However, results from different studies are inconsistent. Moreover, recent fMRI studies have failed to find evidence for domain dependent dissociations of WM-related activity in prefrontal cortex. Here we present evidence from two independent fMRI studies using physically identical stimuli in a verbal and spatial WM task showing that domain dominance for WM does indeed exist, although only in the form of quantitative differences in activation and not in the form of a dissociation with different prefrontal regions showing mutually exclusive activation in different domains. Our results support a mixed dimension model of domain dominance for WM within the prefrontal cortex, with left ventral prefrontal cortex (PFC) supporting preferentially verbal WM and right dorsal PFC supporting preferentially spatial WM. The concept of domain dominance is discussed in the light of recent theories of prefrontal cortex function.

Regionally accentuated reversible brain grey matter reduction in ultra marathon runners detected by voxel-based morphometry.

BACKGROUND: During the 4,487 km ultra marathon TransEurope-FootRace 2009 (TEFR09), runners showed catabolism with considerable reduction of body weight as well as reversible brain volume reduction. We hypothesized that ultra marathon athletes might have developed changes to grey matter (GM) brain morphology due to the burden of extreme physical training. Using voxel-based morphometry (VBM) we undertook a cross sectional study and two longitudinal studies. METHODS: Prior to the start of the race 13 runners volunteered to participate in this study of planned brain scans before, twice during, and 8 months after the race. A group of matched controls was recruited for comparison. Twelve runners were able to participate in the scan before the start of the race and were taken into account for comparison with control persons. Because of drop-outs during the race, VBM could be performed in 10 runners covering the first 3 time points, and in 7 runners who also had the follow-up scan after 8 months. Volumetric 3D datasets were acquired using an MPRAGE sequence. A level of p < 0.05, family-wise corrected for multiple comparisons was the a priori set statistical threshold to infer significant effects from VBM. RESULTS: Baseline comparison of TEFR09 participants and controls revealed no significant differences regarding GM brain volume. During the race however, VBM revealed GM volume decreases in regionally distributed brain regions. These included the bilateral posterior temporal and occipitoparietal cortices as well as the anterior cingulate and caudate nucleus. After eight months, GM normalized. CONCLUSION: Contrary to our hypothesis, we did not observe significant differences between TEFR09 athletes and controls at baseline. If this missing difference is not due to small sample size, extreme physical training obviously does not chronically alter GM.However, during the race GM volume decreased in brain regions normally associated with visuospatial and language tasks. The reduction of the energy intensive default mode network as a means to conserve energy during catabolism is discussed. The changes were reversible after 8 months.Despite substantial changes to brain composition during the catabolic stress of an ultra marathon, the observed differences seem to be reversible and adaptive.

Empty nose syndrome: limbic system activation observed by functional magnetic resonance imaging.

OBJECTIVES/HYPOTHESIS: Empty nose syndrome (ENS) patients have a persistent sense of impaired nasal patency despite radical resection of nasal turbinates. The aim of this study was to elucidate differences in cerebral activation during free breathing and after inhalation of a fragrance (lemonene) and a pseudodecongestant (menthol) over a nasofacial mask. Our hypothesis was that menthol would be perceived as beneficial and that cerebral activation would show differences in areas corresponding to emotional suffering and air hunger in ENS patients. STUDY DESIGN: Prospective, controlled intervention with lemonene and menthol during functional magnetic resonance imaging (f-MRI) experiment. METHODS: Ten right-handed ENS patients were compared to 15 controls using f-MRI and fully automated data analysis with SPM software. Nasal patency was measured with rhinomanometry and rated on a four-point scale. RESULTS: Despite similar objective nasal flow, ENS patients rated nasal patency significantly worse than did controls. Menthol was perceived to increase nasal patency. In patients, f-MRI data showed different activation of temporal cortex areas after inhalation of menthol. The comparison of patients and controls showed ENS-specific activation of temporal and cerebellar areas and amygdala during the rating task itself. CONCLUSIONS: Our experiments showed different cerebral processing of the feeling of nasal patency in ENS patients with prominent activation of areas belonging to the limbic system. The beneficial effect of menthol seems to correspond to activation differences in the temporal pole. These results demonstrate a neuronal substrate for both symptoms and their relief in ENS patients.

Caudate nucleus and insular activation during a pain suppression paradigm comparing thermal and electrical stimulation.

Pain modulation is an integral function of the nervous system. It is needed to adapt to chronic stimuli. To gain insights into pain suppression mechanisms, two studies concerning the suppression of the feeling of pain with different stimulation modalities (heat vs. electrical stimuli) but using the same stimulation paradigms were compared: 15 subjects each had been stimulated on both hands under the instruction to suppress the feeling of pain. Anterior insula and DLPFC activation was seen in both single modality studies and seems to be a common feature of pain suppression, as it is absent in the interaction analyses presented here. During the task to suppress the feeling of pain, there were no consistent activations stronger under thermostimulation. But during electrostimulation, there was significantly stronger activation than during thermal stimulation in the caudate nucleus bilaterally and in the contralateral posterior insula. This may be attributed to the higher sensory-discriminative content and more demand on subjective rating and suppression of the painful electrical stimulus, compared to thermostimulation. The caudate nucleus seems to play an important role not only in the motor system but also in the modulation of the pain experience.

The role of periaqueductal gray and cingulate cortex during suppression of pain in complex regional pain syndrome.

OBJECTIVE: Complex regional pain syndrome I (CRPS I) is a frequent and debilitating condition with unclear etiology. Hypothesizing that maladaptive central processes play a crucial role in CRPS, the current study set out to explore cerebral activation during a task to suppress the feeling of pain under constant painful stimulation. METHODS: Ten individuals with CRPS I with symptoms on their left hand were subjected to electrical stimulation of both index fingers subsequently in a functional magnetic resonance imaging experiment. Their data were compared with 15 healthy controls. RESULTS: Concerning psychophysical measures, patients succeeded similarly as healthy controls in suppressing the feeling of pain. However, during constant painful stimulation and with the task to suppress the feeling of pain, there were significant differences in the interaction analyses of the corresponding cortical activation. DISCUSSION: Patients differ from healthy controls by the activation pattern of cerebral areas that belong to the descending opioid pain suppression pathway: PAG and cingulate cortex are activated significantly less during suppression of pain, regardless of whether the symptomatic or asymptomatic hand was stimulated. Thus, there is a generalized functional change in individuals with CRPS I. However, it cannot be deducted whether the abnormality is causative or merely an effect, possibly maladaptive.