Accelerated brain ageing in sepsis survivors with cognitive long-term impairment.

In the last years, cognitive impairment was emphasized to be a prominent long-term sequelae of sepsis. The level of cognitive impairment is comparable with that in mild cognitive impairment (MCI) patients. Whether sepsis survivors also show a comparable brain atrophy is still unclear. For the analysis of brain atrophy, a novel method named brain age gap estimation (BrainAGE) was used. In this analysis approach, an algorithm identifies age-specific atrophy across the whole brain and calculates a BrainAGE score in years. In case of accelerated brain atrophy, the BrainAGE score is increased in comparison to the healthy age reference group, indicating a difference in estimated chronological age. 20 survivors of severe sepsis (longer than 2 years post sepsis) with persistent cognitive deficits were investigated with a battery of neuropsychological tests. Their MRI images were compared to an age- and sex-matched control group. Sepsis survivors showed a significant higher BrainAGE score of 4.5 years compared to healthy controls. We also found a close relationship between the BrainAGE score and severity of cognitive impairment (a higher BrainAGE score was associated with more severe cognitive impairment). Consequently, sepsis survivors with persistent cognitive impairment showed an accelerated brain ageing, which was closely associated with the severity of cognitive impairment (similar to MCI patients).

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.

OBJECTIVES: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. METHODS: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. RESULTS: Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. CONCLUSION: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.

Attention modulates topology and dynamics of auditory sensory gating.

This work challenges the widely accepted model of sensory gating as a preattention inhibitory process by investigating whether attention directed at the second tone (S2) within a paired-click paradigm could affect gating at the cortical level. We utilized magnetoencephalography, magnetic resonance imaging and spatio-temporal source localization to compare the cortical dynamics underlying gating responses across two conditions (passive and attention) in 19 healthy subjects. Source localization results reaffirmed the existence of a fast processing pathway between the prefrontal cortex (PFC) and bilateral superior temporal gyri (STG) that underlies the auditory gating process. STG source dynamics comprised two gating sub-components, Mb1 and Mb2, both of which showed significant gating suppression (>51%). The attention directed to the S2 tone changed the gating network topology by switching the prefrontal generator from a dorsolateral location, which was active in the passive condition (18/19), to a medial location, active in the attention condition (19/19). Enhanced responses to the attended stimulus caused a significant reduction in gating suppression in both STG gating components (>50%). Our results demonstrate that attention not only modulates sensory gating dynamics, but also exerts topological rerouting of information processing within the PFC. The present data, suggesting that the cortical levels of early sensory processing are subject to top-down influences, change the current view of gating as a purely automatic bottom-up process.

Growth rates of malignant and benign thyroid nodules in an ultrasound follow-up study: a retrospective cohort study.

BACKGROUND: Thyroid nodules are frequently detected by cervical ultrasound examinations. In follow-up studies, malignant as well as benign nodules may exhibit an increase in size. The objective of our investigation was to test whether histologically determined malignant and benign thyroid nodules show differences in growth rates above a defined significance level. METHODS: A retrospective ultrasound cohort follow-up study from 4 to 132 months included 26 patients with differentiated carcinomas and 26 patients with adenomas of the thyroid gland. Significance levels were determined by intra- and interobserver variations of volumetric measurements in 25 individuals. RESULTS: Intra- and interobserver volumetric measurements were highly correlated (r = 0.99 and r = 0.98, respectively), with variations of 28 and 40%, respectively. The growth rates of malignant and benign nodules did not show differences with respect to two sonographic measurements (d = - 0.04, 95%CI(P): 0.41-0.85, P = 0.83). Using shorter increments and multiple measurements, growth rates of malignant nodules revealed significantly higher values (d = 0.16, 95%CI(P): 0.02-0.04, P = 0.039). CONCLUSIONS: The growth rates of benign and malignant thyroid nodules do not appear to differ using two sonographic volumetric measurements. However, due to temporal changes in cellular proliferation and arrest, malignant nodules may exhibit higher growth rates with multiple assessments and shorter increments.

The Influence of Eye Closure on Somatosensory Discrimination: A Trade-off Between Simple Perception and Discrimination.

We often close our eyes to improve perception. Recent results have shown a decrease of perception thresholds accompanied by an increase in somatosensory activity after eye closure. However, does somatosensory spatial discrimination also benefit from eye closure? We previously showed that spatial discrimination is accompanied by a reduction of somatosensory activity. Using magnetoencephalography, we analyzed the magnitude of primary somatosensory (somatosensory P50m) and primary auditory activity (auditory P50m) during a one-back discrimination task in 21 healthy volunteers. In complete darkness, participants were requested to pay attention to either the somatosensory or auditory stimulation and asked to open or close their eyes every 6.5 min. Somatosensory P50m was reduced during a task requiring the distinguishing of stimulus location changes at the distal phalanges of different fingers. The somatosensory P50m was further reduced and detection performance was higher during eyes open. A similar reduction was found for the auditory P50m during a task requiring the distinguishing of changing tones. The function of eye closure is more than controlling visual input. It might be advantageous for perception because it is an effective way to reduce interference from other modalities, but disadvantageous for spatial discrimination because it requires at least one top-down processing stage.

Somatosensory Functions in Survivors of Critical Illness.

OBJECTIVES: There is growing evidence for increased levels of pain and reduced health-related quality of life in survivors of critical illness. Recent studies showed marked small nerve fiber pathology in critically ill patients, which may contribute to chronic pain states and reduced physical recovery after ICU discharge. Primary objective of this study was the comparison of somatosensory functions between survivors of critical illness 6 months after ICU discharge and controls. In post hoc analyses, we aimed to identify associations between small fiber deficits, pain, health-related quality of life, and clinical data. DESIGN: Cross-sectional study. SETTING: Study in critical illness survivors. PATIENTS: Critical illness survivors (n = 84) and controls (n = 44). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Somatosensory functions were assessed with validated quantitative sensory testing. Pain and pain-related disability were assessed with the chronic pain grade questionnaire. Health-related quality of life was assessed by means of the Short Form-36. Compared with controls, former patients showed significantly increased thermal detection thresholds and more abnormal values in thermal testing, indicating reduced small fiber functioning. In addition, compared to patients without significant small fiber deficits (n = 46, 54.8%), patients with significant small fiber deficits (n = 38, 45.2%) reported higher average pain intensity, pain-related disability, and reduced physical health-related quality of life in the SF-36. CONCLUSIONS: A large portion of former critically ill patients show small fiber deficits which seem to be associated with increased pain and reduced physical health-related quality of life. Screening of somatosensory functions in the (post-) acute setting could possibly help to identify patients at risk of long-term impairments.

Modality-independent reduction mechanisms of primary sensory evoked fields in a one-back task.

Attentional modulation of early, primary sensory components is still a topic of debate, as studies have produced conflicting results concerning the existence of a modulation within the primary somatosensory cortex and its direction. We previously showed that attention to tactile stimuli in a stream with visual stimuli leads to a reduction of primary somatosensory components when discrimination of different stimulus locations is requested. The question arises whether this effect is universal and independent from the distracting or attended modality. To test this, we compared the magnitude of primary somatosensory evoked fields (somatosensory P50m) in a one-back task after tactile finger stimulation during attention to tactile stimuli vs. auditory distraction in 28 volunteers. In comparison to acoustic distraction, we found a significantly decreased primary somatosensory activity when attending to tactile stimuli. Strikingly, similar results were produced within the auditory modality: when attention was focused on acoustic targets, primary auditory (auditory P50m) fields were lower as compared to the situation when attention was directed to the tactile stimulation. Our results clearly indicate that the type of task, independent from the modality, is actually the crucial factor for the direction of modulation of early sensory components by attention. Therefore, our finding of reduced primary sensory components in a discrimination task represents a universal effect independent from the distracting or attended modality.

Prevalence and Characteristics of Chronic Intensive Care-Related Pain: The Role of Severe Sepsis and Septic Shock.

OBJECTIVE: There is only limited knowledge about chronic pain conditions resulting from critical care. Experimental and clinical data suggest a close relationship between inflammation and pain perception. Since sepsis is the most severe form of systemic inflammation, the primary objective was to evaluate chronic pain states and functional impairment of septic and nonseptic patients 6 months after discharge from ICU. Second, we aimed to obtain the total prevalence and characteristics of chronic ICU-related pain. DESIGN: Case-control study. SETTING: Observational study in long-term survivors of mixed surgical and medical ICUs. PATIENTS: Septic and nonseptic survivors of critical care (n = 207) and healthy controls (n = 46). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected comprehensive information on patients' past and present pain 6 months after ICU discharge by means of the German pain questionnaire. Pain intensity levels and pain interference ratings were compared between septic and nonseptic patients and healthy controls. We found no differences in prevalence, severity, and interference of pain between septic and nonseptic patients. However, both patient groups differed significantly from controls. In secondary analysis, a third of all patients reported chronic clinically relevant pain associated with the ICU stay 6 months after ICU discharge. Half of these patients experienced chronic pain conditions before ICU admission and reported additional sources of pain. Most important, 16% of all patients had no preexisting pain condition and now experience chronic ICU-related pain. The majority of patients with chronic ICU-related pain reported a high degree of disabling pain, limiting daily activities. CONCLUSIONS: A high percentage of former ICU patients develop chronic pain conditions associated with critical care. These patients differ significantly from control data in terms of pain intensity and show high levels of interference with pain. The presence of sepsis per se seems to play a marginal role for the development of chronic ICU-related pain.

Parallel processing of somatosensory information: Evidence from dynamic causal modeling of MEG data.

The advent of methods to investigate network dynamics has led to discussion of whether somatosensory inputs are processed in serial or in parallel. Both hypotheses are supported by DCM analyses of fMRI studies. In the present study, we revisited this controversy using DCM on magnetoencephalographic (MEG) data during somatosensory stimulation. Bayesian model comparison was used to allow for direct inference on the processing stream. Additionally we varied the duration of the time-window of analyzed data after the somatosensory stimulus. This approach allowed us to explore time dependent changes in the processing stream of somatosensory information and to evaluate the consistency of results. We found that models favoring a parallel processing route best describe neural activities elicited by somatosensory stimuli. This result was consistent for different time-windows. Although it is assumed that the majority of somatosensory information is delivered to the SI, the current results indicate that at least a small part of somatosensory information is delivered in parallel to the SII. These findings emphasize the importance of data analysis with high temporal resolution.

Cortical reorganization after macroreplantation at the upper extremity: a magnetoencephalographic study.

With the development of microsurgical techniques, replantation has become a feasible alternative to stump treatment after the amputation of an extremity. It is known that amputation often induces phantom limb pain and cortical reorganization within the corresponding somatosensory areas. However, whether replantation reduces the risk of comparable persisting pain phenomena as well as reorganization of the primary somatosensory cortex is still widely unknown. Therefore, the present study aimed to investigate the potential development of persistent pain and cortical reorganization of the hand and lip areas within the sensory cortex by means of magnetoencephalographic dipole analyses after replantation of a traumatically amputated upper limb proximal to the radiocarpal joint. Cortical reorganization was investigated in 13 patients with limb replantation using air puff stimulation of the phalanges of both thumbs and both corners of the lower lip. Displacement of the centre of gravity of lip and thumb representations and increased cortical activity were found in the limb and face areas of the primary somatosensory cortex contralateral to the replanted arm when compared to the ipsilateral hemisphere. Thus, cortical reorganization in the primary somatosensory cortex also occurs after replantation of the upper extremity. Patients' reports of pain in the replanted body part were negatively correlated with the amount of cortical reorganization, i.e. the more pain the patients reported, the less reorganization of the subjects' hand representation within the primary somatosensory cortex was observed. Longitudinal studies in patients after macroreplantation are necessary to assess whether the observed reorganization in the primary somatosensory cortex is a result of changes within the representation of the replanted arm and/or neighbouring representations and to assess the relationship between the development of persistent pain and reorganization.

Long-term sequelae of severe sepsis: cognitive impairment and structural brain alterations - an MRI study (LossCog MRI).

BACKGROUND: The number of patients with cognitive impairment after sepsis or septic shock is high. However, the underlying neurophysiological basis of sepsis induced cognitive impairment is not fully understood. METHODS/DESIGN: This is a prospective, controlled observational study. We are in the process of recruiting 25 survivors of severe sepsis or septic shock who will be investigated with functional MRI (fMRI), T1-weighted MRI und Diffusion Tensor Imaging (DTI) as well as Magnetoencephalography (MEG). Furthermore, patients will undergo neuropsychological evaluation using the DemTect and the clock drawing tests. In addition, verbal and declarative memory is assessed by the Verbal Learning and Memory Test. The primary aim is to determine the volumetry of the amygdala and the hippocampus. The secondary aim is to analyze the relationship between cognitive tests and MEG, and the (f)MRI results. Moreover, a between-group comparison will be evaluated to an age-matched group of healthy controls. DISCUSSION: In a previous MEG study, we observed a significant slowing of the prominent background activity in sepsis survivors and hepatic encephalopathy patients in particular shortly after discharge from the ICU. Intriguingly, the rhythmic brain activity after visual flickering stimulation was altered in sepsis survivors in comparison to age-matched healthy volunteers. We propose that this desynchronization is based on affected underlying neuronal responses between various interconnected brain regions. The current project will analyze whether the modifications are related to a damage of the fibers connecting different brain regions or to a disturbance of the functional interaction between different brain regions or even due to an atrophy of certain brain regions. TRIAL REGISTRATION: "Langzeitfolgen nach schwerer Sepsis: Kognitive Beeinträchtigungen und strukturelle Veränderungen am Gehirn, eine MRT Studie"; German Clinical Trials Register (DRKS00005484).

Bone flap necrosis after decompressive hemicraniectomy for malignant middle cerebral artery infarction.

BACKGROUND: Autologous bone flap reinsertion follows as a second surgical intervention after decompressive craniectomy in patients with malignant middle cerebral artery (MCA) infarction. In addition to surgery-related short-term complications, aseptic resorption of the reimplanted bone flap is a possible long-term problem which has not yet been sufficiently elucidated in these patients. METHODS: A total of 109 patients who had undergone decompressive hemicraniectomy for malignant MCA infarction in our institution between September 1994 and December 2011 were included in the study. Clinical and radiological findings were retrieved retrospectively. Aseptic bone necrosis was classified into two categories based on computer tomographic features. RESULTS: A total of 76 patients received their own cryoconserved bone flap (mean age 54.34 ± 10.73 years; 49 males). The overall short-term complication rate was 9.2 %. Bone flap necrosis occurred in 26 patients (22.8 %) with 7 flaps showing signs of surgically relevant type II necrosis after a median time of 14 months (interquartile range [IQR] 4-22). CONCLUSIONS: There is a noticeable complication rate in patients undergoing bone flap reinsertion after hemicraniectomy due to malignant MCA infarction. Aseptic bone necrosis represents a significant complication during long-term follow-up. The pathophysiological mechanisms remain unclear and more efforts should be undertaken to understand and possibly prevent this complication in these patients.

Fetal development of complex autonomic control evaluated from multiscale heart rate patterns.

Development of the fetal autonomic nervous system's integrative capacity in relation to gestational age and emerging behavioral pattern is reflected in fetal heart rate patterns. Conventional indices of vagal and sympathetic rhythms cannot sufficiently reflect their complex interrelationship. Universal behavioral indices of developing complex systems may provide additional information regarding the maturating complex autonomic control. We investigated fetal magnetocardiographic recordings undertaken at 10-min intervals in active (n = 248) and quiet (n = 111) states between 22 and 39 wk gestational age. Standard deviation of heartbeat intervals, skewness, contribution of particular rhythms to the total power, and multiscale entropy were analyzed. The multiscale entropy methodology was validated for 10-min data sets. Age dependence was analyzed by linear regression. In the quiet state, contribution of sympathovagal rhythms and their complexity over a range of corresponding short scales increased with rising age, and skewness shifted from negative to positive values. In the active state, age dependencies were weaker. Skewness as the strongest parameter shifted in the same direction. Fluctuation amplitude and the complexity of scales associated with sympathovagal rhythms increased. We conclude that in the quiet state, stable complex organized rhythms develop. In the active state, however, increasing behavioral variability due to multiple internal coordinations, such as movement-related heart rate accelerations, and external influences develop. Hence, the state-selective assessment in association with developmental indices used herein may substantially improve evaluation of maturation age and early detection and interpretation of developmental problems in prenatal diagnosis.

Adverse events unlikely after fine-needle aspiration biopsies of thyroid nodules in patients on low-dose aspirin: a prospective controlled systematic single center analysis.

AIM: Our aim was to test the assertion that in terms of rate or severity level, adverse events (AEs) after fine-needle aspiration biopsies (FNABs) of thyroid nodules are unfazed by daily low-dose (100 mg) aspirin (acetylsalicylic acid, ASA) intake. METHODS: We selected 268 patients for study, grouped as ASA-treated (PASA, n=78) or control (PCtrl, n=190) subjects. Controls received no antithrombotic medication. AE rates and severities were then analyzed based on patient- and nodule-related factors. We also compared group rates of non-diagnostic cytology results. RESULTS: AEs arising after FNABs (PASA, 5%; PCtrl, 8%) did not differ significantly by group in rate (p=0.4873) or severity level (p=0.3399). All were classifiable as minor incidents, none warranting any intervention. CONCLUSIONS: The data from the present study suggest, AEs after FNABs of thyroid nodules seldom occur and qualify as minor incidents. Such procedures may be safely conducted in patients taking daily low-dose ASA. There is no evidence to support preemptive therapeutic withdrawal.

Ultrasound characteristics of follicular and parafollicular thyroid neoplasms: diagnostic performance of artificial neural network.

BACKGROUND: Ultrasound is the first-line imaging modality for detection and classification of thyroid nodules. Certain features observable by ultrasound have recently been equated with potential malignancy. This retrospective cohort study was conducted to test the hypothesis that radiomics of the four categorical divisions (medullary [MTC], papillary [PTC], or follicular [FTC] carcinoma and follicular thyroid adenoma [FTA]) demonstrate distinctive sonographic characteristics. Using an artificial neural network model for proof of concept, these sonographic features served as input. METHODS: A total of 148 patients were enrolled for study, all with confirmed thyroid pathology in one of the four named categories. Preoperative ultrasound profiles were obtained via standardized protocols. The neural network consisted of seven input neurons; three hidden layers with 50, 250, and 100 neurons, respectively; and one output layer. RESULTS: Radiomics of contour, structure, and calcifications differed significantly according to nodule type (p = 0.025, p = 0.032, and p = 0.0002, respectively). Levels of accuracy shown by artificial neural network analysis in discriminating among categories ranged from 0.59 to 0.98 (95% confidence interval [CI]: 0.57-0.99), with positive and negative predictive ranges of 0.41-0.99 and 0.78-0.97, respectively. CONCLUSIONS: Our data indicate that some MTCs, PTCs, FTCs, and FTAs have distinctive sonographic characteristics. However, a significant overlap of these characteristics may impede an explicit classification. Further prospective investigations involving larger patient and nodule numbers and multicenter access should be pursued to determine if neural networks of this sort are beneficial, helping to classify neoplasms of the thyroid gland.

Fibroblast Activation Protein Inhibitor Imaging in Nonmalignant Diseases: A New Perspective for Molecular Imaging.

Fibroblast activation protein-α (FAP-α) is a type II transmembrane glycoprotein that is overexpressed in activated fibroblasts such as those in the stroma of tumors or in the fibrotic processes accompanying various benign diseases. The recent development and clinical implementation of radiolabeled quinolone-based tracers suitable for PET that act as FAP inhibitors (FAPIs) have opened a new perspective in molecular imaging. Although multiple studies have investigated the use of FAPI imaging in cancer, evidence concerning its use in nonmalignant diseases is still scarce. Herein, we provide a comprehensive review of FAPI imaging in nonmalignant diseases to clarify the current and potential role of this class of molecules in nuclear medicine.

Dose voxel kernel prediction with neural networks for radiation dose estimation.

BACKGROUND: Currently there is an ever increasing interest in Lu-177 targeted radionuclide therapies, which target neuro-endocrine and prostate tumours. For a patient-specific treatment, an individual dosimetry based on SPECT/CT imaging is necessary. The aim of this study is to introduce a dosimetry method, where dose voxel kernels (DVK) are predicted by a neural network. METHODS: Kidneys are considered one of the most critical organs in any radionuclide therapy. Hence we chose kidneys of 26 patients, who underwent Lu-177-DOTATOC or PSMA therapy, as target organs for our dosimetric method. First of all, density kernels with a size of 9×9×9 voxels were considered, and the corresponding DVKs were calculated by Monte Carlo simulations. These kernels were used to train a neural network (NN), which received a density kernel as input and predicted a DVK at the output. To predict the dose distribution of an entire kidney, the organ had to be partitioned into a large number of density kernels. Afterwards the DVKs were predicted by a trained NN, and employed to reconstruct the whole-organ dose distribution by convolution with the activity distribution. This method was compared to the standard method where the activity distribution is convolved with a DVK based on a homogeneous soft tissue kernel. RESULTS: The number of training kernels amounted to 52,274 density kernels with corresponding MC-derived DVKs. The results serve as proof of principle of the newly proposed method and showed that the NN approach yielded superior results compared to the standard method with no additional computational effort. CONCLUSION: The NN approach is an accurate and highly competitive dosimetric method to precisely estimate absorbed radiation dose in critical organs like kidneys in clinical routine. To further improve the results, a larger number of DVKs needs to be computed by Monte Carlo simulations. An extension of the method to other organs is easily conceivable.

Advanced thyroid carcinomas: neural network analysis of ultrasonographic characteristics.

BACKGROUND: Ultrasound is the first-line imaging modality for detection and classification of thyroid nodules. Certain characteristics observable by ultrasound have recently been identified that may indicate malignancy. This retrospective cohort study was conducted to test the hypothesis that advanced thyroid carcinomas show distinctive clinical and sonographic characteristics. Using a neural network model as proof of concept, nine clinical/sonographic features served as input. METHODS: All 96 study enrollees had histologically confirmed thyroid carcinomas, categorized (n = 32, each) as follows: group 1, advanced carcinoma (ADV) marked by local invasion or distant metastasis; group 2, non-advanced papillary carcinoma (PTC); or group 3, non-advanced follicular carcinoma (FTC). Preoperative ultrasound profiles were obtained via standardized protocols. The neural network had nine input neurons and one hidden layer. RESULTS: Mean age and the number of male patients in group 1 were significantly higher compared with groups 2 (p = 0.005) or 3 (p <  0.001). On ultrasound, tumors of larger volume and irregular shape were observed significantly more often in group 1 compared with groups 2 (p <  0.001) or 3 (p ≤ 0.01). Network accuracy in discriminating advanced vs. non-advanced tumors was 84.4% (95% confidence interval [CI]: 75.5-91), with positive and negative predictive values of 87.1% (95% CI: 70.2-96.4) and 92.3% (95% CI: 83.0-97.5), respectively. CONCLUSIONS: Our study has shown some evidence that advanced thyroid tumors demonstrate distinctive clinical and sonographic characteristics. Further prospective investigations with larger numbers of patients and multicenter design should be carried out to show whether a neural network incorporating these features may be an asset, helping to classify malignancies of the thyroid gland.

Automated emotion classification in the early stages of cortical processing: An MEG study.

PURPOSE: Here we aimed to automatically classify human emotion earlier than is typically attempted. There is increasing evidence that the human brain differentiates emotional categories within 100-300 ms after stimulus onset. Therefore, here we evaluate the possibility of automatically classifying human emotions within the first 300 ms after the stimulus and identify the time-interval of the highest classification performance. METHODS: To address this issue, MEG signals of 17 healthy volunteers were recorded in response to three different picture stimuli (pleasant, unpleasant, and neutral pictures). Six Linear Discriminant Analysis (LDA) classifiers were used based on two binary comparisons (pleasant versus neutral and unpleasant versus neutral) and three different time-intervals (100-150 ms, 150-200 ms, and 200-300 ms post-stimulus). The selection of the feature subsets was performed by Genetic Algorithm and LDA. RESULTS: We demonstrated significant classification performances in both comparisons. The best classification performance was achieved with a median AUC of 0.83 (95 %- CI [0.71; 0.87]) classifying brain responses evoked by unpleasant and neutral stimuli within 100-150 ms, which is at least 850 ms earlier than attempted by other studies. CONCLUSION: Our results indicate that using the proposed algorithm, brain emotional responses can be significantly classified at very early stages of cortical processing (within 300 ms). Moreover, our results suggest that emotional processing in the human brain occurs within the first 100-150 ms.

68Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study.

BACKGROUND: Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a 68Ga-labelled selective inhibitor of prolyl endopeptidase FAP (68Ga-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. METHODS: Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline 68Ga-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up 68Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6-10 months) to assess change over time. FINDINGS: 68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0·80 (IQR 0·60-2·10) in the systemic sclerosis-ILD group and 0·50 (0·40-0·50) in the control group (p<0·0001) and a mean whole lung maximal SUV of 4·40 (range 3·05-5·20) in the systemic sclerosis-ILD group compared with 0·70 (0·65-0·70) in the control group (p<0·0001). Whole-lung FAPI metabolic active volume (wlFAPI-MAV) and whole-lung total lesion FAPI (wlTL-FAPI) were not measurable in control participants, because no 68Ga-FAPI-04 uptake above background level was observed. In the systemic sclerosis-ILD group the median wlFAPI-MAV was 254·00 cm3 (IQR 163·40-442·30), and the median wlTL-FAPI was 183·60 cm3 (98·04-960·70). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression, or high EUSTAR activity scores than in those with with limited disease, previously stable ILD, or low EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04 PET-CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic drug nintedanib. INTERPRETATION: Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that 68Ga-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. FUNDING: German Research Foundation, Erlangen Anschubs-und Nachwuchsfinanzierung, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, Deutsche Stiftung Systemische Sklerose, Wilhelm-Sander-Foundation, Else-Kröner-Fresenius-Foundation, European Research Council, Ernst-Jung-Foundation, and Clinician Scientist Program Erlangen.