Carolin Gramsch

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.

Neural mechanisms mediating positive and negative treatment expectations in visceral pain: a functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers.

Summary The experience and neural processing of visceral pain can be increased or decreased using nocebo or placebo suggestions. Abstract To elucidate placebo and nocebo effects in visceral pain, we conducted a functional magnetic resonance imaging (fMRI) study to analyze effects of positive and negative treatment expectations in a rectal pain model. In 36 healthy volunteers, painful rectal distensions were delivered after intravenous application of an inert substance combined with either positive instructions of pain relief (placebo group) or negative instructions of pain increase (nocebo group), each compared to neutral instructions. Neural activation during cued‐pain anticipation and pain was analyzed along with expected and perceived pain intensity. Expected and perceived pain intensity were significantly increased in the nocebo group and significantly decreased in the placebo group. In the placebo group, positive expectations significantly reduced activation of the somatosensory cortex during anticipation and of the insula, somatosensory cortex, and amygdala during pain delivery when compared to neutral expectations. Within the nocebo group, negative expectations led to significantly increased insula activation during painful stimulation. Direct group contrasts during expectation modulation revealed significantly increased distension‐induced activation within the somatosensory cortex in the nocebo group. In conclusion, the experience and neural processing of visceral pain can be increased or decreased by drug‐specific expectations. This first brain imaging study on nocebo effects in visceral pain has implications for the pathophysiology and treatment of patients with chronic abdominal complaints such as irritable bowel syndrome.

Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers.

Despite the clinical relevance of nocebo effects, few studies have addressed their underlying neural mechanisms in clinically-relevant pain models. We aimed to address the contribution of nocebo effects and their underlying neural circuitry to central pain amplification in visceral pain, as it may develop over repeated painful experiences due to negative pain-related expectations. Healthy volunteers received verbal suggestions of pain sensitization (nocebo group, N=28) or neutral instructions (control group, N=16). fMRI was used to investigate changes in neural responses during cued pain anticipation and painful rectal distensions delivered in successive fMRI sessions. Pain intensity was rated trial-by-trial, and expected pain intensity, state anxiety and tension were assessed prior to each session. Behavioral analyses demonstrated significantly greater increases in both expected and perceived pain in the nocebo group. The fMRI analysis performed on nocebo-responders only (N=14) revealed that these behavioral changes were associated with increased activation within the secondary somatosensory cortex and amygdala during pain anticipation and within the thalamus, insula and amygdala during painful stimulation when compared to controls. A subsequent psycho-physiological interaction analysis of the pain phase showed increased functional connectivity between the anterior insula, which was set-up as seed region based on group results, and midcingulate cortex as a function of negative expectations. These findings support that negative pain-related expectations can play a crucial role in pain amplification of visceral pain, which is mediated, at least in part, by a neural up-regulation of pain-associated areas and their connectivity. These findings may have implications for the pathophysiology and treatment of chronic abdominal pain.

Association of aneurysms and variation of the A1 segment

Background and purpose Previous studies have described a correlation between variants of the circle of Willis and pathological findings, such as cerebrovascular diseases. Moreover, anatomic variations of the anterior cerebral artery (ACA) seem to correspond to the prevalence of aneurysms in the anterior communicating artery (ACoA). The aim of this study was to assess the prevalence of aneurysms in patients with anatomical/morphological variations of the circle of Willis. Methods We retrospectively analyzed 223 patients who underwent cerebral angiography between January 2002 and December 2010 for aneurysm of the ACoA. Diagnostic imaging was reviewed and statistically evaluated to detect circle of Willis anomalies, aneurysm size, and rupture. 204 patients with an unrelated diagnosis served as the control group. Results Variations of the A1 segment occurred significantly more frequently in the aneurysm group than in the control group. Mean aneurysm size in patients with grades I and III hypoplasia or aplasia was 6.58 mm whereas in patients with grade II hypoplasia it was 7.76 mm. Conclusions We found that variations in the A1 segment of the ACAs are correlated with a higher prevalence of ACoA aneurysms compared with patients with a symmetric circle of Willis.

Diagnostic value of 3D fluid attenuated inversion recovery sequence in multiple sclerosis

Background Magnetic resonance imaging (MRI) is an indispensable tool in the diagnostic work-up of multiple sclerosis (MS). To date, guidelines suggest MRI protocols containing axial dual-echo, unenhanced and post-contrast T1-weighted sequences. Especially the usage of dual-echo sequences has markedly improved the ability of MRI to detect cortical and infratentorial lesions. Newer 3D FLAIR sequences are supposed to provide even more positive imaging features such as improved detection of white matter lesions and a better resolution due to smaller slice thickness. Purpose To evaluate the diagnostic impact of 3D FLAIR sequences in comparison to conventional T2 and PD sequences. Material and Methods Examinations of 20 MS patients (10 women, 10 men) were reviewed retrospectively. All patients received MRI standard protocol containing PD and T2 sequences and a mid-sagittal T2 sequence. Additionally an isotropic 3D FLAIR sequence was performed. Whole-brain lesion load and number of lesions in juxtacortical, infratentorial, and midcallosal localizations were assessed by two observers independently and compared. Results Whole lesion load and the count of detectable lesions at the 3D FLAIR sequence were significantly higher in the juxtacortical and infratentorial regions compared to the PD/T2 sequence. Detection rate of midcallosal lesions did not differ significantly in sagittal T2 and 3D FLAIR sequence. Conclusion 3D FLAIR sequences can improve the detection of brain lesions in patients with MS and are even more sensitive in depicting lesions in cortical and infratentorial locations than current dual-echo sequences. The sequence can replace both PD/T2 sequences and mid-sagittal T2 sequences of the corpus callosum.

Intracranial hemorrhage detection over time using susceptibility-weighted magnetic resonance imaging

Background The reliable detection of intracranial hemorrhages is important, but just 1 year after the hemorrhage onset it might be missed using T2-weighted spin-echo and gradient-echo sequences. Susceptibility-weighted imaging (SWI) is a new magnetic resonance imaging sequence that is extremely sensitive in hemorrhage detection and that might improve the detection of hemorrhages over time. Purpose To investigate whether the detectability of intracranial blood and its degradation products is independent of the time span after intracranial hemorrhage using SWI. Material and Methods Sixty-six consecutive patients (28 men, 38 women) with definitely known time point of intracranial hemorrhage and available SWI sequence (1.5 or 3 T) were analyzed retrospectively. Twenty-one patients had a SWI follow-up. All SWI images were assessed by two radiologists in consensus regarding hemorrhage visibility using a 5-point scale. Statistical analysis was performed using Spearman’s correlation test. Results Median time interval between hemorrhage and first available SWI measurement was 819 days (range, 0 days to 13.2 years). Nine of 66 patients had an isolated subarachnoid hemorrhage (iSAH) and were therefore analyzed separately. In eight of these nine patients the hemorrhage could clearly be detected, the remaining one had minor iSAH. Spearman analysis showed no significant correlation between time span and visibility (P = 0.660). In the remaining 57 patients (no iSAH) the hemorrhage was always visible achieving at least 3/5 points on the 5-point scale, and Spearman’s analysis revealed only a weak correlation between time span and visibility (r = 0.493, P < 0.001). Conclusion The detectability of blood and its degradation products using SWI is reliably possible over a long period after intracranial hemorrhage.

Value of DSA in the diagnostic workup of pulsatile tinnitus.

Objectives Pulsatile tinnitus (PT) is a rare complaint, but can be a symptom of life-threatening disease. It is often caused by vascular pathologies, e.g. dural arteriovenous fistula (dAVF), arteriovenous malformation (AVM) or vascularized tumors. The current diagnostic pathway includes clinical examination, cranial MRI and additional DSA. The aim of this study was to evaluate the diagnostic impact of DSA in the diagnostic workup of patients with PT in comparison to MRI alone. Methods Retrospectively, 54 consecutive patients with pulsatile tinnitus were evaluated. All patients had a diagnostic workup including cranial MRI and DSA. MRI examinations were blinded to the results of DSA and retrospectively analyzed in consensus by two experienced neuroradiologists. The MR-examinations were evaluated for each performed sequence separately: time-of-flight-angiography, ce-MRA, T2, ce-T1-sequence and ce-T1-sequence with fat saturation. Results 37 of the 54 patients revealed a pathology explaining PT on MRI, which was detected by the readers in 100% and proofed by means of DSA. 24 dAVF, four paraganglioma, two AVM and seven more pathologies were described. All patients without pathology on MRI did also not show any pathology in DSA. Conclusions MR imaging is sufficient to exclude pathology in patients with pulsatile tinnitus.

Nigrosome 1 visibility at susceptibility weighted 7T MRI—A dependable diagnostic marker for Parkinson's disease or merely an inconsistent, age-dependent imaging finding?

Background Visualisation of nigrosome 1, a substructure of the healthy substantia nigra, was restricted in susceptibility weighted MR imaging in almost all patients with Parkinsons disease studied so far. The purpose of this study was to determine the degree of visibility of this substructure in subjects without Parkinson’s disease and to examine the potential link between increasing brain iron accumulation with age and its detectability. Methods In 46 subjects (21 women, 25 men; 19 to 75 y; mean age: 44.5; SD: 15.6) examined with susceptibility weighted MR imaging at 7T visibility of nigrosome 1 was rated and classified. We assessed differences related to age and to signal intensities in the substantia nigra, red nucleus and putamen as correlates of the individual iron concentration. Results In 93% nigrosome 1was at least unilaterally clearly present. In 24% at least one-sided limited visibility was observed. Using predefined classification criteria the specificity of the visibility across all age groups reached approximately 94%. We found no correlation with increasing iron concentrations with age. Conclusion Aging with a related increase in iron concentration probably does not affect the visibility of nigrosome 1 at 7T SWI MRI. Our results support the role of this feature as a future differential diagnostic tool but further large-scale prospective studies are needed to better define the extent of a “limited visibility” to which an individual can be considered healthy.

Diagnostic impact of integrated 18F-FDG PET/MRI in cerebral staging of patients with non-small cell lung cancer

Background Integrated positron emission tomography/magnetic resonance imaging (PET/MRI) systems are increasingly being available and used for staging examinations. Brain metastases (BM) are frequent in patients with non-small cell lung cancer (NSCLC) and decisive for treatment strategy. Purpose To assess the diagnostic value of integrated 18F-2-fluoro-2-deoxy-D glucose (18F-FDG) PET/MRI in initial staging in patients with NSCLC for BM in comparison to MRI alone. Material and Methods Eighty-three patients were prospectively enrolled for an integrated 18F-FDG PET/MRI examination. The 3 T MRI protocol included a fluid-attenuated inversion-recovery sequence (FLAIR) and a contrast-enhanced three-dimensional magnetization prepared rapid acquisition GRE sequence (MPRAGE). Two neuroradiologists evaluated the datasets in consensus regarding: (i) present lesions; (ii) size of lesions; and (iii) number of lesions detected in MRI alone, compared to the PET component when reading the 18F-FDG PET/MRI. Results Based on MRI alone, BM were detected in 15 out of the 83 patients, comprising a total of 39 metastases. Based on PET alone, six patients out of the 83 patients were rated positive for metastatic disease, revealing a total of 15 metastases. PET detected no additional BM. The size of the BM correlated positively with sensitivity of detection in PET. Conclusion The sensitivity of PET in detection of BM depends on their size. 18F-FDG PET/MRI does not lead to an improvement in diagnostic accuracy in cerebral staging of NSCLC patients, as MRI alone remains the gold standard.

Can we now dispense with DSA in the evaluation of aneurysm occlusion even in the most crucial first follow-up after endovascular treatment?

OBJECTIVES Catheter angiography (DSA) as gold standard for the evaluation of aneurysmal occlusion after coiling has now been largely replaced by MRI or CTA in long term observations. However, the first year after treatment is crucial because most recurrences occur in this time. Until now no guidelines exist concerning the imaging modality to adopt in this period. Aim of the study was to determine whether DSA could also be omitted in the first follow-up examination after coiling due to MRI results. PATIENTS AND METHODS 489 consecutive half-year follow-up examinations consisting of DSA, CE-MRA and TOF-MRA at 1.5 or 3T were reviewed retrospectively. Visualization of residual or recurrent aneurysms in both MRA-techniques was compared to DSA by two experienced readers. RESULTS Remnants/recurrences could be visualized in at least one of the three techniques in 190 (38.9%) aneurysms. Remnants/recurrences requiring retreatment (n=52) were detectable with at least one of the two MRI-techniques. In three cases (0.6%) remnants/recurrences were only visible on DSA but neither on CE-MRA nor on TOF-MRA. However, they were small (<2mm) and therapy concept did not change. In one case (0.2%) they were only visible on the CE-MRA and TOF-MRA but not on the DSA, in five cases (1%) visible on DSA and TOF-MRA but not on the CE-MRA and in four cases (0.8%) not visible on the TOF-MRA but on both of the other imaging modalities. CONCLUSION The combination of CE-MRA und TOF-MRA is also an appropriate alternative to DSA concerning the evaluation of residual or recurrent aneurysms in the crucial first follow-up.