Thrombus Histology of Basilar Artery Occlusions : Are There Differences to the Anterior Circulation?

BACKGROUND: For patients with acute vessel occlusions of the anterior circulation histopathology of retrieved cerebral thrombi has been reported to be associated to stroke etiology. Due to the relatively small incidence of posterior circulation stroke, exclusive histopathologic analyses are missing for this subgroup. The aim of the study was to investigate thrombus histology for patients with basilar artery occlusions and uncover differences to anterior circulation clots with respect to underlying etiology. METHODS: A total of 59 basilar thrombi were collected during intracranial mechanical recanalization and quantitatively analyzed in terms of their relative fractions of the main constituents, e.g. fibrin/platelets (F/P), red (RBC) and white blood cells (WBC). Data were compared to histopathological analyses of 122 thrombi of the anterior circulation with respect to underlying pathogenesis. RESULTS: The composition of basilar thrombi differed significantly to thrombi of the anterior circulation with an overall higher RBC amount (median fraction in % (interquartile range):0.48 (0.37-0.69) vs. 0.37 (0.28-0.50), p < 0.001) and lower F/P count (0.45 (0.21-0.58) vs. 0.57 (0.44-0.66), p < 0.001). Basilar thrombi composition did not differ between the different etiological stroke subgroups. CONCLUSION: The results depict a differing thrombus composition of basilar thrombi in comparison to anterior circulation clots with an overall higher amount of RBC. This may reflect different pathophysiologic processes between anterior and posterior circulation thrombogenesis, e.g. a larger proportion of appositional thrombus growth in the posterior circulation.

A short history of thrombectomy - Procedure and success analysis of different endovascular stroke treatment techniques.

BACKGROUND: The historical development of interventional stroke treatment shows a wide variation of different techniques and materials used. Thus, the question of the present work is whether the technical and procedural differences of thrombectomy techniques lead to different technical and clinical results. METHODS AND RESULTS: Analysis of a mixed retrospective/prospective database of all endovascular treated patients with an occlusion of the Carotid-T or M1 segment of the MCA at a single comprehensive stroke center since 2008. Patients were classified regarding the technical approach used. Six hundred sixty-eight patients were available for the final analysis. Reperfusion rates ranged between 56% and 100% depending on the technical approach. The use of balloon guide catheters and most recently the establishment of combination techniques using balloon guide catheters, aspiration catheters and stent retrievers have shown a further significant increase in the rates of successful recanalization, full recanalization and first-pass recanalization. Additionally, the technical development of interventional techniques has led to a subsequent drop in complications, embolization into previously unaffected territories in particular. CONCLUSION: Technical success of MT has improved substantially over the past decade owing to improved materials and procedural innovations. Combination techniques including flow modulation have emerged to be the most effective approach and should be considered as a standard of care.Level of evidence: Level 3, retrospective study.

Basal Ganglia versus Peripheral Infarcts: Predictive Value of Early Fiber Alterations.

BACKGROUND AND PURPOSE: Impairment of fiber integrity of the corticospinal tract in the subacute and chronic phases after ischemic stroke has been linked to poor motor outcome. The aim of the study was an assessment of fiber integrity in the acute poststroke phase and an evaluation of its association with the clinical course dependent on the infarction pattern (subtypes: peripheral versus basal ganglia infarction). MATERIALS AND METHODS: All patients who underwent mechanical recanalization of a large-vessel occlusion in the anterior circulation and postinterventional DTI were included (n = 165). The fractional anisotropy index of the patient-specific corticospinal tract within the posterior limb of the internal capsule was correlated to clinical parameters (NIHSS scores/mRS at 90 days), and the interaction of stroke subtype (peripheral infarcts versus basal ganglia infarction) was tested in a moderation analysis. RESULTS: The fractional anisotropy index was reduced in the acute poststroke phase with a correlation to clinical presentation, especially in case of peripheral infarcts (eg, with the NIHSS motor subscore: r = -0.4, P < .001). This correlation was absent for basal ganglia infarction (r = -0.008, P > .05). There was a significant association between the fractional anisotropy index and clinical outcome (mRS after 90 days, P < .01), which is moderated by stroke subtype with significant effects only for peripheral infarcts. CONCLUSIONS: Corticospinal tract abnormalities can be observed in the early stage after mechanical recanalization and have prognostic capacity. This finding increases the clinical value of early DTI imaging parameters. Because the effects observed were limited to peripheral infarcts, further and longitudinal evaluation of fiber integrities within basal ganglia infarction is required.

Etiology of recurrent large vessel occlusions treated with repeated thrombectomy.

BACKGROUND: Repeated mechanical thrombectomy for acute stroke treatment in individual patients has been proven feasible. However, less is known about the etiology of recurrent vessel occlusions after prior thrombectomy. We aimed to understand if the etiology of such recurrent events differs from the first stroke. METHODS: Retrospectively, we identified all patients at our center who received a repeated mechanical thrombectomy between 2007 and 2019. Clinical data were retrieved from medical records. Etiology of stroke was evaluated retrospectively, and angiographic studies were revisited. RESULTS: Twenty-three patients (1.5%) were identified. Median age was 68 years (IQR 56-77). Median NIHSS at first admission was 11 points (IQR 5-15). In nine cases (39.1%), the recurrent vessel occlusion was located exactly at the same position as the prior occlusion. Overall, five (21.7%) patients had a remarkable extracranial pathology as likely cause of stroke recurrence. In 16 patients (69.6%), the etiology of the first stroke and its recurrence was considered as likely being the same, mostly of cardioembolic or unknown origin. In the seven remaining patients (30.4%), the cause of stroke possibly differed from the first event, with five patients (21.7%) having a postinterventional intracranial intimal lesion as possible cause of stroke. CONCLUSION: Incidence of repeated thrombectomy was low. However, the high number of patients with known origin of stroke etiology raises the question how their monitoring may be optimized. The number of patients with remarkable extracranial pathologies or intracranial endothelial lesions supports current clinical practice to pay attention to final angiographic series.

Microstructural Integrity of Salvaged Penumbra after Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: There are sparse data on the microstructural integrity of salvaged penumbral tissue after mechanical thrombectomy of large-vessel occlusions. The aim of the study was to analyze possible microstructural alteration in the penumbra and their association with clinical symptoms as well as angiographic reperfusion success in patients undergoing mechanical thrombectomy. MATERIALS AND METHODS: All patients who underwent mechanical thrombectomy for large-vessel occlusions in the anterior circulation and who received an admission CT perfusion together with postinterventional DTIs were included (n = 65). Angiographic reperfusion success by means of modified Thrombolysis in Cerebral Infarction (mTICI) scale and clinical outcome were recorded. Microstructural integrity was assessed by DTI evaluating the mean diffusivity index within the salvaged gray matter of the former penumbra. RESULTS: The mean diffusivity index was higher in completely recanalized patients (mTICI 3: -0.001 ± 0.034 versus mTICI <3: -0.030 ± 0.055, P = .03). There was a positive correlation between the mean diffusivity index and NIHSS score improvement (r = 0.49, P = .003) and the mean diffusivity index was associated with midterm functional outcome (r = -0.37, P = .04) after adjustment for confounders. In mediation analysis, the mean diffusivity index and infarction growth mediated the association between reperfusion success and clinical outcomes. CONCLUSIONS: The macroscopic salvaged penumbra included areas of microstructural integrity changes, most likely related to the initial hypoperfusion. These abnormalities were found early after mechanical thrombectomy, were dependent on angiographic results, and correlated with the clinical outcome. When confirmed, these findings prompt the evaluation of therapies for protection of the penumbral tissue integrity.

Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer.

BACKGROUND: Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers. MATERIAL AND METHODS: 138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis. RESULTS: CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group. The opposite was found for RARB (p<0.001). RASSF1 methylation increased with tumor type and grade (p<0.001) with strongest methylation in neuroendocrine tumors (NET). CONCLUSION: Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade. RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET. L1RE1 in combination with either RARB or RASSF1 could function as biomarkers for separating lung cancer and non-cancerous tissue and could be useful for samples of limited size such as biopsies.

Aspiration thrombectomy in clinical routine interventional stroke treatment : Is this the end of the stent retriever era?

PURPOSE: The aim of our study was the technical evaluation of a first pass approach of primary thrombus aspiration (AST) in patients with emergency large intracerebral vessel occlusions (ELVO) under routine clinical conditions. MATERIALS AND METHODS: We collected procedural and clinical data of 104 patients who underwent mechanical thrombectomy due to ELVO between June 2014 and January 2016 with intentional first-line thrombus aspiration. Procedures were conducted due to occlusions of the distal internal carotid artery, middle cerebral artery, anterior cerebral artery, basilar artery and posterior cerebral artery and were performed with the patient under either conscious sedation or general anesthesia. If the AST technique failed completely or to some extent, stent retriever-based thrombectomy (SRT) was performed. RESULTS: As a stand-alone method AST was successful in achieving TICI (Thrombolysis in Cerebral Infarction) score 2b or 3 results in 29 cases (27.8%). After additional use of SRT successful recanalization was achieved in a total of 95 cases (91.3%, p = 0.048). If AST was performed exclusively, median procedure time until TICI 2b/3 was 15 min, in cases of combined procedures 35 min (p = 0.001). Subarachnoid hemorrhage (SAH) after thrombectomy appeared only if additional SRT was performed (12.0%) and not in cases of AST maneuvers alone (p = 0.09). CONCLUSION: When used as a first pass attempt AST is a fast and safe approach for patients suffering from stroke due to ELVO. Nonetheless, early conversion to SRT is needed in most cases and leads to overall excellent procedural results with low complication rates.

Risk of Thrombus Fragmentation during Endovascular Stroke Treatment.

BACKGROUND AND PURPOSE: Periprocedural thrombus fragmentation is a relevant risk in endovascular stroke treatment. Because factors influencing its occurrence are largely unknown, this study addresses a potential relationship between thrombus histology and clot stability. MATERIALS AND METHODS: Eighty-five patients with anterior circulation stroke treated with thrombectomy were included in this retrospective study. The number and location of emboli after retrieving the primary thrombus, the number of maneuvers, and TICI scores were evaluated. H&E and neutrophil elastase staining of retrieved clots was performed, and semiquantitative measurements of thrombus components were correlated with procedural parameters. RESULTS: An inverse correlation between maneuvers required for thrombus retrieval and the number of distal and intermediate emboli was observed (Spearman r, -0.23; P = .032). Younger patients were at higher risk for periprocedural thrombus fragmentation (Spearman r, -0.23; P = .032). Bridging thrombolysis tended to be associated with fewer maneuvers (2 vs 3, P = .054) but more emboli (1 vs 0, P = .067). While no consistent correlation between procedural parameters and red/white blood cells and fibrin-/platelet fractions could be found, higher amounts of neutrophil elastase-positive cells within the thrombus were independently associated with the occurrence of multiple emboli (adjusted OR, 4.6; 95% CI, 1.1-19.7; P = .041) and lower rates of complete recanalization (adjusted OR, 0.3; 95% CI, 0.1-0.9; P = .050). CONCLUSIONS: Younger age, easy-to-retrieve thrombi, and bridging thrombolysis may be risk factors for periprocedural thrombus fragmentation. Findings from standard histologic stains did not provide insight into thrombectomy-relevant thrombus stability. However, higher neutrophil levels in the thrombus tissue were related to an increased risk of periprocedural thrombus fragmentation. This observation aligns with the proposed thrombolytic capacity of neutrophil elastase and points to its potential clinical relevance in the context of stroke thrombectomy.

Reliability of Semi-Automated Segmentations in Glioblastoma.

PURPOSE: In glioblastoma, quantitative volumetric measurements of contrast-enhancing or fluid-attenuated inversion recovery (FLAIR) hyperintense tumor compartments are needed for an objective assessment of therapy response. The aim of this study was to evaluate the reliability of a semi-automated, region-growing segmentation tool for determining tumor volume in patients with glioblastoma among different users of the software. METHODS: A total of 320 segmentations of tumor-associated FLAIR changes and contrast-enhancing tumor tissue were performed by different raters (neuroradiologists, medical students, and volunteers). All patients underwent high-resolution magnetic resonance imaging including a 3D-FLAIR and a 3D-MPRage sequence. Segmentations were done using a semi-automated, region-growing segmentation tool. Intra- and inter-rater-reliability were addressed by intra-class-correlation (ICC). Root-mean-square error (RMSE) was used to determine the precision error. Dice score was calculated to measure the overlap between segmentations. RESULTS: Semi-automated segmentation showed a high ICC (> 0.985) for all groups indicating an excellent intra- and inter-rater-reliability. Significant smaller precision errors and higher Dice scores were observed for FLAIR segmentations compared with segmentations of contrast-enhancement. Single rater segmentations showed the lowest RMSE for FLAIR of 3.3 % (MPRage: 8.2 %). Both, single raters and neuroradiologists had the lowest precision error for longitudinal evaluation of FLAIR changes. CONCLUSIONS: Semi-automated volumetry of glioblastoma was reliably performed by all groups of raters, even without neuroradiologic expertise. Interestingly, segmentations of tumor-associated FLAIR changes were more reliable than segmentations of contrast enhancement. In longitudinal evaluations, an experienced rater can detect progressive FLAIR changes of less than 15 % reliably in a quantitative way which could help to detect progressive disease earlier.

Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging.

Purpose: Brain metastases are a common complication of cancer and occur in about 15 - 40 % of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Materials and Methods: Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Results: Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADClymphoma 0.92 [0.83 - 1.07] vs. ADCno_lymphoma 1.35 [1.10 - 1.64] P = 0.001). Further differentiation between types of metastases was not possible using FA and ADC. Conclusion: There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis. Key Points: • Histopathological subtypes of brain metastases/CNS lymphomas show different morphologic features on MRI• Primary CNS lymphomas show significantly reduced ADC values• DTI is not a reliable tool for differentiation between brain metastases Citation Format: • Bette S, Wiestler B, Delbridge C et al. Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging. Fortschr Röntgenstr 2016; 188: 1134 - 1143.

Task-free MRI predicts individual differences in brain activity during task performance.

When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects.

Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories.

Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.

The Impact of Histological Clot Composition in Embolic Stroke.

PURPOSE: Thrombus composition has been suggested to have a decisive impact on the outcome of patients treated by mechanical thrombectomy because of embolic stroke. The recent development of stent retrievers allows collection and, hence, histopathological analysis of fresh thrombus material. Against this background, the aim of this prospective study was to assess the impact of thrombus composition on mechanical recanalization, clinical outcome and stroke etiology. METHODS: Thirty-four patients suffering from acute ischemic stroke due to occlusion of the distal internal carotid artery/carotid-T, anterior cerebral artery, or middle cerebral arteries were mechanically recanalized, and thrombus material was obtained. Histological thrombus composition was compared with imaging, clinical, and neurointerventional data. RESULTS: The main findings were that a higher percentage of white blood cells (WBCs) in the thrombus was associated with (i) cardioembolic etiology, (ii) extended mechanical recanalization time, and (iii) less favorable recanalization (Thrombolysis in Cerebral Infarction score) and clinical outcome (National Institute of Health Stroke Scale). CONCLUSION: Our results suggest that thrombi with a high WBC fraction are related to more organized thrombi of cardioembolic origin associated with less favorable recanalization and clinical outcome in acute ischemic anterior circulation stroke. WBC-mediated immunological and coagulatory processes may play a key role in thrombus formation and pathogenesis of stroke warranting further investigation.

The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression.

Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60-positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon.

MHC associations with clinical and autoantibody manifestations in European SLE.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.

Biomarker research with prospective study designs for the early detection of cancer.

This article describes the principles of marker research with prospective studies along with examples for diagnostic tumor markers. A plethora of biomarkers have been claimed as useful for the early detection of cancer. However, disappointingly few biomarkers were approved for the detection of unrecognized disease, and even approved markers may lack a sound validation phase. Prospective studies aimed at the early detection of cancer are costly and long-lasting and therefore the bottleneck in marker research. They enroll a large number of clinically asymptomatic subjects and follow-up on incident cases. As invasive procedures cannot be applied to collect tissue samples from the target organ, biomarkers can only be determined in easily accessible body fluids. Marker levels increase during cancer development, with samples collected closer to the occurrence of symptoms or a clinical diagnosis being more informative than earlier samples. Only prospective designs allow the serial collection of pre-diagnostic samples. Their storage in a biobank upgrades cohort studies to serve for both, marker discovery and validation. Population-based cohort studies, which may collect a wealth of data, are commonly conducted with just one baseline investigation lacking serial samples. However, they can provide valuable information about factors that influence the marker level. Screening programs can be employed to archive serial samples but require significant efforts to collect samples and auxiliary data for marker research. Randomized controlled trials have the highest level of evidence in assessing a biomarker's benefit against usual care and present the most stringent design for the validation of promising markers as well as for the discovery of new markers. In summary, all kinds of prospective studies can benefit from a biobank as they can serve as a platform for biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

A practical guide to epidemiological practice and standards in the identification and validation of diagnostic markers using a bladder cancer example.

Technical advances to analyze biological markers have generated a plethora of promising new marker candidates for early detection of cancer. However, in subsequent analyses only few could be successfully validated as being predictive, clinically useful, or effective. This failure is partially due to rapid publication of results that were detected in early stages of biomarker research. Methodological considerations are a major concern when carrying out molecular epidemiological studies of diagnostic markers to avoid errors that increase the potential for bias. Although guidelines for conducting studies and reporting of results have been published to improve the quality of marker studies, their planning and execution still need to be improved. We will discuss different sources of bias in study design, handling of specimens, and statistical analysis to illustrate possible pitfalls associated with marker research, and present legal, ethical, and technical considerations associated with storage and handling of specimens. This article presents a guide to epidemiological standards in marker research using bladder cancer as an example. Because of the possibility to detect early cancer stages due to leakage of molecular markers from the target organ or exfoliation of tumor cells into the urine, bladder cancer is particularly useful to study diagnostic markers. To improve the overall quality of marker research, future developments should focus on networks of studies and tissue banks according to uniform legal, ethical, methodological, and technical standards. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan.

Shifts in reinforcement signalling while playing slot-machines as a function of prior experience and impulsivity.

Electronic gaming machines (EGMs) offer significant revenue streams for mercantile gambling. However, limited clinical and experimental evidence suggests that EGMs are associated with heightened risks of clinically problematic patterns of play. Little is known about the neural structures that might mediate the transition from exploratory EGM play to the 'addictive' play seen in problem gamblers; neither is it known how personality traits associated with gambling activity (and gambling problems) influence reinforcement processing while playing EGMs. Using functional magnetic resonance imaging in healthy participants, we show that a single episode of slot-machine play is subsequently associated with reduced amplitudes of blood-oxygenation level-dependent signals within reinforcement-related structures, such as the ventral striatum and caudate nucleus, following winning game outcomes; but increased amplitudes of anticipatory signals within the ventral striatum and amygdala while watching the game reels spin. Trait impulsivity enhanced positive signals within the ventral striatum and amygdala following the delivery of winning outcomes but diminished positive signals following the experience of almost-winning ('near-misses'). These results indicate that a single episode of slot-machine play engages the well-characterised reinforcement-learning mechanisms mediated by ascending dopamine mesolimbic and mesostriatal pathways, to shift reward value of EGMs away from game outcomes towards anticipatory states. Impulsivity, itself linked to problem gambling and heightened vulnerability to other addictive disorders, is associated with divergent coding of winning outcomes and almost-winning experiences within the ventral striatum and amygdala, potentially enhancing the reward value of successful slot-machine game outcomes but, at the same time,modulating the aversive motivational consequences of near-miss outcomes.

Effects of image reconstruction on fiber orientation mapping from multichannel diffusion MRI: reducing the noise floor using SENSE.

PURPOSE: To examine the effects of the reconstruction algorithm of magnitude images from multichannel diffusion MRI on fiber orientation estimation. THEORY AND METHODS: It is well established that the method used to combine signals from different coil elements in multichannel MRI can have an impact on the properties of the reconstructed magnitude image. Using a root-sum-of-squares approach results in a magnitude signal that follows an effective noncentral-χ distribution. As a result, the noise floor, the minimum measurable in the absence of any true signal, is elevated. This is particularly relevant for diffusion-weighted MRI, where the signal attenuation is of interest. RESULTS: In this study, we illustrate problems that such image reconstruction characteristics may cause in the estimation of fiber orientations, both for model-based and model-free approaches, when modern 32-channel coils are used. We further propose an alternative image reconstruction method that is based on sensitivity encoding (SENSE) and preserves the Rician nature of the single-channel, magnitude MR signal. We show that for the same k-space data, root-sum-of-squares can cause excessive overfitting and reduced precision in orientation estimation compared with the SENSE-based approach. CONCLUSION: These results highlight the importance of choosing the appropriate image reconstruction method for tractography studies that use multichannel receiver coils for diffusion MRI acquisition.

Shifts in reinforcement signalling while playing slot-machines as a function of prior experience and impulsivity.

Electronic gaming machines (EGMs) offer significant revenue streams for mercantile gambling. However, limited clinical and experimental evidence suggests that EGMs are associated with heightened risks of clinically problematic patterns of play. Little is known about the neural structures that might mediate the transition from exploratory EGM play to the 'addictive' play seen in problem gamblers; neither is it known how personality traits associated with gambling activity (and gambling problems) influence reinforcement processing while playing EGMs. Using functional magnetic resonance imaging in healthy participants, we show that a single episode of slot-machine play is subsequently associated with reduced amplitudes of blood-oxygenation-level-dependent signals within reinforcement-related structures, such as the ventral striatum and caudate nucleus, following winning game outcomes; but increased amplitudes of anticipatory signals within the ventral striatum and amygdala while watching the game reels spin. Trait impulsivity enhanced positive signals within the ventral striatum and amygdala following the delivery of winning outcomes but diminished positive signals following the experience of almost-winning ('near-misses'). These results indicate that a single episode of slot-machine play engages the well-characterised reinforcement-learning mechanisms mediated by ascending dopamine mesolimbic and mesostriatal pathways, to shift reward value of EGMs away from game outcomes towards anticipatory states. Impulsivity, itself linked to problem gambling and heightened vulnerability to other addictive disorders, is associated with divergent coding of winning outcomes and almost-winning experiences within the ventral striatum and amygdala, potentially enhancing the reward value of successful slot-machine game outcomes but, at the same time, modulating the aversive motivational consequences of near-miss outcomes.