dataesr/scientific-paragraphs-categorization huggingface dataset:
g. , Figs. 3  and 4 ). Parameters of the linear regression analysis of SBR as a function of age and their 95% CIs for both databases are presented in Table  5  for all striatal VOIs, irrespective of gender. Linear regression analysis revealed that measured SBRs in the striatum, for both genders combined, decreased by 30. 54% (Flash3D) and 33. 39% (FBP) within the considered age range  (16-88 years). This corresponds to a reduction rate in striatum SBR of 4. 24% (Flash3D) and 4. 64% (FBP) per decade. Women showed a steeper decline with advancing age compared to men in all striatal regions. For both men and women, posterior putamen showed the highest SBR decline while caudate SBR was the slowest to decline. The mean reduction rate of SBR was between 3. 80 and 5. 67% per decade for men and between 4.
47 and 5. 70% for women, depending on the used reconstruction method and on the striatal VOI. The calculated percentage declines of SBRs per decade are summarized in Table  6. We have compared regression parameters from the reconstructed Flash3D database to parameters generated from healthy volunteers by the ENC-DAT study using the  attenuation and scatter corrected (ACSC) and uncalibrated scans processed with BRASS analysis method  (Varrone et al. 2013). Corresponding results are shown in Table  7  and graphically displayed in Fig. 5. Using Eq. 3, we found no differences in r values between men and women for both databases. Similarly, no differences in r values were found between Flash3D database and the "uncalibrated ENC-DAT-ACSC" database according to gender in all striatal VOIs.
Asymmetries and caudate-to-putamen ratios Linear regression analysis performed on the box-cox transformed asymmetries and C/P ratios revealed an age effect only on the putamen asymmetry for the Flash3D database  (y = 0. 003 × x + 1. 19, r 2 = 0. 018, SE = 0. 37, p = 0. 037). When comparing these parameters between men and women, the differences were not statistically significant. The reference limit corresponding to each one of these parameters is estimated as the sample mean plus twice the sample standard deviation (i. e. , mean and SD of all corresponding reference values in the database). For instance, the reference limit corresponding to striatum asymmetry is 3. 02 + 2 × 2. 41 = 7. 84% (Flash3D) and 2. 44 + 2 × 1. 91 = 6. 26 (FBP). Sample means and SDs of the left and right C/P ratios and asymmetry values are summarized in Table  8  for both databases.
Comparison of new subjects to reconstructed databases Scans belonging to the 22 test subjects were compared to the generated databases using the syngo. via® software. For all abnormal cases (13/13), and independent of the reconstruction method, one or more SBR values fell below corresponding age-matched  reference limit confirming abnormality of the scans. For most of these cases, the C/P ratios and/or the asymmetry values were also greater than their corresponding reference limits. The majority of tested cases, including the nine normal ones, could easily be accurately classified based only on visual assessments of the corresponding parametric slab views (see examples on Fig. 8 )  (Buchert et al. 2016b ). However, for a normal case corresponding to a 63-year old male subject, the tracer uptake was uniformly reduced on the left side compared to the right side as can be clearly seen on the slab view on Fig.
Discussion In this study, we generated a large database of 123 I-FP-CIT reference values from a cohort of patients with normal 123 I-FP-CIT scans and no confirmed forms of degenerative parkinsonism at baseline nor after a follow-up ranging from 3 to 10 years. Our cohort was rigorously selected, in two separate stages, from a pool of patients' data collected over 8 years at the same center and acquired on the same SPECT-CT imaging system following the same acquisition and processing protocols. This helped overcome the inter-center variability and the challenge of recruiting a large enough cohort of healthy volunteers as in the previously published European (n = 139)  (Varrone et al. 2013)  and Japanese (n = 256)  (Matsuda et al. 2018)  databases. To the best of our knowledge, this is the largest cohort of patients with normal 123 I-FP-CIT SPECT, and a well-balanced gender distribution (50.
One originality of this study is that our "normal" data sets, as identified at the first stage of the patients' selection process, went through additional and independent quality and medical checks followed by analysis using a dedicated commercial software that allows quantification and improved visual assessment of 123 I-FP-CIT SPECT scans  (Buchert et al. 2016b). At this second selection stage, we excluded 19/256 patients, four of which had normal 123 I-FP-CIT scans and were diagnosed with MSA-C. These Fig. 6  Left and right putamen to caudate ratios for the Flash3D (upper row) and the FBP (bottom row) databases irrespective of gender. The solid blue line (y = mean + 2 × standard deviations of corresponding reference values) defines the reference limit above which a scan could be suspected as being positive SWEDD cases represent a negligible proportion of our cohort (1.
6%), in agreement with the findings by  Nicastro et al. in their prospective study  (Nicastro et al. 2018)  where they showed that 3/155 (2. 1%) subjects with suspected degenerative parkinsonism (1 corticobasal syndrome, 1 MSA-C, and 1 PD) and 1/53 (1. 9%) with DLB had a normal visual 123 I-FP-CIT SPECT. Using a dedicated Striatal Analysis software (syngo. via®), we generated two different versions of the database corresponding to two reconstruction methods often used in clinical routine, and we investigated the effects of gender and age on all measured outcomes. Our results showed a significant linear effect of age on SBR values in all striatal Fig. 7  Asymmetry values (%) corresponding to caudate, putamen, and striatum (from top to bottom) and for the Flash3D (left) and FBP (right) databases.
2000; van Dyck et al. 1995; van Dyck et al. 2002). In particular, the ENC-DAT study  (Varrone et al. 2013 ) reported an average age-related decline in DAT availability of 5. 5% per decade for both genders in good agreement with our measured decline. These results clearly validate our approach of using normal 123 I-FP-CIT SPECT uptake values obtained in non-healthy subjects but without dopaminergic degeneration to generate a normal and age-stratified 123 I-FP-CIT database. Several factors, including image reconstruction and correction as well as quantitative analysis, may have contributed to the variability in the estimated decline rate of DAT availability seen between different published studies. We also found that regardless of gender and irrespective of the reconstruction method, the rate of SBR decline was faster for putamen compared to that for caudate, and even more so in the posterior region of the putamen compared to that in the anterior region.
81%. A new scan acquired and reconstructed using the same protocols as scans in one of the generated databases should raise the possibility of alteration of the presynaptic dopaminergic system when its left or right C/P ratio, or one of its interhemispheric asymmetries, is two SDs above corresponding sample mean. For example, our results suggest that a normal 123 I-FP-CIT scan is associated with a striatum asymmetry that is lower than 7. 84% (Flash3D) or than 6. 26% (FBP). In general, normal 123 I-FP-CIT scans should be associated with low asymmetry values and with C/P ratios that are closer to unity, irrespective of age and gender. Contrary to results reported in  (Matsuda et al. 2018) , our results revealed a slight but not statistically significant increase of asymmetry values with advancing age, except for the putamen asymmetry for the Flash3D database.
016 × 65 + 4. 028) -0. 8 = 2. 19 (see Table  5 ). Regarding the effect of gender, we found that women had higher uptake than men in all striatal VOIs, in agreement with some previous studies  (Varrone et al. 2013; Matsuda et al. 2018; Eusebio et al. 2012; Kaasinen et al. 2015; Lavalaye et al. 2000). However, we found that this difference was only significant for the Flash3D database. The lack of such statistical significance for the FBP database may either be due to the fact that there is no correlation between gender and DAT availability or that such gender difference exists but was not statistically significant due to inaccuracies in the Chang attenuation correction method which uses a simpler approximation to individual head geometry and assumes a uniform attenuation inside the head. This may have led to more statistical noise and then to higher p values compared to using CT-based attenuation correction for the Flash3D database.
Other factors differentiating the two databases, such as scatter correction, may have led to the discrepancy seen in gender effect. Some published studies have reported higher DAT availability in women compared to men  (Lavalaye et al. 2000; Staley et al. 2001; Mozley et al. 2001) , whereas others did not report any gender-related difference  (Ryding et al. 2004; van Dyck et al. 1995; van Dyck et al. 2002). Various hypotheses were put forward as to why women exhibit higher striatal uptake than men, related either to higher DAT density in women compared to men, or to the differences in the striatal volume between genders  (Varrone et al. 2013; Eusebio et al. 2012). In this study, we observed a greater separation between regression lines of men and women SBR data at earlier decades and even more so for the Flash3D database.
For both databases, we have established reference values identical for men and women. In comparison with the ENC-DAT study  (Varrone et al. 2013) , we found that Flash3D reference values are comparable to those generated by the BRASS method from uncalibrated and ACSC data in the ENC-DAT study for both men and women. For example, the 95% CI mean slope for striatum in men is -0. 015 (range -0. 019 to -0. 011) in the Flash3D database versus -0. 015 (range -0. 021 to -0. 09) in the ENC-DAT study. For women, we found a mean slope of -0. 018 (range -0. 024 to -0. 013) in the Flash3D database versus -0. 018 (range -0. 025 to -0. 011) in the ENC-DAT database. Slight differences between regression parameters in the two databases may be attributed in part to the difference in attenuation correction methods used in both studies.
In addition, our mean C/P ratios are uniform across genders and less variable compared to those from the ENC-DAT uncalibrated ACSC data. Note that the comparisons between our study and the ENC-DAT study may be affected by several factors, including methodological differences in acquisition of scans; their reconstruction, correction, and quantification; and most importantly by the differences between the two considered cohorts. However, using data from patients with normal 123 I-FP-CIT scans who were adequately followed to confirm that they have not developed any form of degenerative parkinsonism, and scanned at a single site following the same protocol, we were able to generate reference values comparable to those generated from healthy volunteers. Equally important is that our mean values for caudate and putamen SBRs in men and women were similar if not identical to those from the ENC-DAT study using BRASS analysis of uncalibrated ACSC data.
Our data also showed that comorbidities (e. g. , diabetes, hypertension) did not seem to increase the variance in outcomes when compared to healthy subjects, making it possible for clinicians to build their own normal 123 I-FP-CIT databases from scans acquired during routine clinical practice. In comparison with a published database generated from patients with normal 123 I-FP-CIT scans and no degenerative conditions  (Nicastro et al. 2017; Nicastro et al. 2016) , we have used a larger cohort (237 vs. 182) with a well-balanced gender distribution and a wider age range, including a relatively very young subset of participants. We also had longer follow-ups for all of our subjects who were included through a stringent two-phase selection process. This may have contributed to generating reference values and limits comparable to those of healthy volunteers.
There are some limitations to this study. First, the diagnoses were mainly based on clinical criteria without autopsy confirmation. However, the non-degenerative nature of parkinsonism was assessed by the clinical evolution for 3 to 10 years (4. 8 ± 1. 3 years), which represents the gold standard to establish a diagnosis in routine clinical practice. Second, our approach for normative data definition was monocentric, which may limit the ability to extend our references to other groups and centers. Effort is underway to generalize the use of the reconstructed databases for other imaging systems and/or other reconstruction/correction methods. This warrants a thorough investigation on how the reconstruction and scanner characterization impact the performance of our reference values in assessing clinical scan normality.
An evaluation of the generated reference values against a large sample of degenerative cases is also warranted but is beyond the scope of this paper. Third, we have found that differences in SBRs between genders were only statistically significant for the Flash3D database. We have postulated that the lack of such significance for the FBP database is mainly due to inaccuracies in Chang attenuation correction method which has been shown to be a challenging and often inconsistent task with DAT imaging due to low tracer binding in cortical areas  (Barnden et al. 2006). This deserves further investigation. The use of CTAC for the Flash3D database, although it comes at the expense of exposing patients to additional radiation (~2 mSv), has the advantage of providing more accurate attenuation correction.
Conclusion This study provides a large database of 123 I-FP-CIT reference parameters from a cohort of patients with normal SPECT scans and no degenerative parkinsonism, scanned at the same center on the same imaging system and following the same protocol. The generated age-matched SBRs as well as C/P and asymmetry reference values and limits compared favorably to parameters from a normal database of healthy volunteers. Our results could be used to assess new scans acquired and processed in an equivalent manner as one of the reconstructed databases. Generalization to assess scans acquired with other imaging systems and processed with other reconstruction/correction methods is currently under way.
30 (3. 95, 4. 64) 4. 01 (3. 62, 4. 40) Slope -0. 017 -0. 016 -0. 02 -0. 017 (-0. 022, -0. 013) (-0. 022, -0. 009) (-0. 025, -0. 015) (-0. 024, -0. 010) r 2 0. 38 0. 28 0. 33 0. 29 ACSC attenuation correction and scatter correction, ENC-DAT European Normal Control Database of DaTscan.
Microscopy. Micrographs were obtained with an Eclipse 80i Nikon microscope equipped with a Hamamatsu digital camera (Life Sciences, Japan), and with a nanozoomer S60 (Hamamatsu). Pictures were adjusted for brightness and contrast in Adobe Photoshop. cell counting. For analyzing constitutive neurogenesis, proliferative activity was determined by quantification of PCNA-positive from 2 to 3 cryostat consecutive sections (12 µm thickness/section) by region of interest. Images were analyzed for detection of PCNA positive nuclei using ImageJ software (National Institutes of Health, Bethesda, MD; RRID: SCR_003070) by adjusting parameters (threshold, binary, and watershed). Briefly, the parameters were set up as follows for each picture: threshold 65, 255, particle size 200-infinity. Minor modifications in these parameters could be slightly adjusted according to the experiments.
Participants As it is not possible to run power analyses for multi-factorial repeated-measures designs with G * Power 3. 1  (Faul et al. , 2007) , we followed the same procedure found in previous studies with similar study design (e. g. ,  Liepelt et al. , 2019). Accordingly, we matched the average number of participants in the studies that investigated executive functions with tVNS using a within-subject design (summarized in Table  1 ). Since we also measured cardiac vagal activity, we additionally considered the average sample size in  Borges et al. (2019) , because this study systematically investigated the effect of tVNS on cardiac vagal activity in different experiments. Twenty-nine participants were calculated to be necessary to find an effect. Anticipating possible exclusions due to drop-outs and after data cleaning, we recruited 35 participants.
Mutual information The Synapse J z is treated as a communication channel, conveying the train of presynaptic spikes to the original network, and affecting the spike trains at the post synaptic neurons, X and Y. To quantify the amount of such effect, or in other words, to specify how much information is transmitted from Z to X and Y , the MI-toolbox of Matlab  [42]  , is employed, to compute the Mutual Information (MI) between the input signal and the output spikes of the network at different noisy conditions. MI, an information theory measure  [43, 44]  is defined by the equation: MI = H( S out ) -H( S out | S in ) (6) where H ( S out ) is the estimated entropy of the output signal, and H ( S out | S in ) is the conditional entropy of the output, S out , given the input S in. The entropy denoted H(S) itself, is a measure that quantifies the uncertainty present in the distribution of signal S , and is defined as: H ( S ) = - s ∈ δ P ( s ) logP ( s ) (7) here, the lower case s denotes a possible value that the random variable S can adopt from the alphabet δ, and P(s) is the probability distribution function which can be estimated as the fraction of observations taking on value s from the total N samples; ˆ P (s ) = #s N.
Gene Replacement The most common form of gene therapy involves the delivery of a functional or therapeutic "transgene" that replaces or complements the defective gene responsible for the disease. The transgene is delivered directly to target cells or is reconstituted in the target cell nuclei. Biallelic recessive mutations and loss-of-function dominant mutations can generally be treated by this strategy. Clinical trials of gene replacement therapy for the treatment of certain forms of blindness in humans, including Leber's congenital amaurosis (RPE65, NCT00999609)  [113] [114] [115]  and choroideremia (REP1, NCT02407678)  [116] , as well as development of therapeutic approaches for inner ear and central hearing disorders  [17, 19, 117]  have raised hopes that such a strategy could also be applied to the treatment of auditory and/or vestibular conditions.
The first trial of gene therapy for the treatment of deafness in humans, based on this approach, was recently launched in the US by the team of Professor Hinrich Staecker (NCT02132130). This trial includes volunteers aged between 18 and 70 years, with almost total hearing loss, but with a large number of supporting cells remaining in the cochlea. The objective is to deliver a Math1-expressing adenovirus to the cochlea of these patients, with the aim of evaluating the safety of the treatment. The results of this trial are expected shortly. Information on its progression and outcomes will certainly benefit actions for future inner ear clinical trials. Indeed, a study in mice has shown that the injection of Math1 into two-week-old mice, a stage equivalent to puberty in humans, has little or no effect.
Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses. K E Y W O R D S ADHD, ASD, cortex, ENIGMA, neuroimaging, subcortical volumes.
Opportunities to remedy at least some of these shortcomings are facilitated by the ENIGMA consortium. Over the past decade, this consortium has provided a platform for combining genetic and brain imaging datasets  (Adams et al. , 2016; Hibar et al. , 2015 Hibar et al. , , 2017;; Stein et al. , 2012) , while using unified Both working groups' initial projects focused on subcortical brain volume and cortical thickness and surface area analyses.
| KEY FINDINGS FROM THE ENIGMA-ADHD AND ENIGMA-ASD STUDIES: SUBCORTICAL AND CORTICAL MEASURES In the ENIGMA-ADHD's first project, the volumes of subcortical structures including nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, thalamus, putamen, and also the total intracranial volume (ICV) were compared between cases with ADHD and controls. These regional brain volumes were segmented based on protocols provided by ENIGMA using FreeSurfer software. All participating sites segmented their raw data and quality checked of these segmentations locally using protocols provided by ENIGMA. Detailed instructions for analysis and quality control are found on the ENIGMA website (http://enigma. ini. usc. edu/protocols/imaging-protocols/). The resulting outputs were sent by each site to the coordinator of ENIGMA-ADHD.
Analyses were performed on data collected at 23 sites, that included a total of 1,713 cases with ADHD and 1,529 controls, with an age range of 4-63 years of age. A cross-sectional megaanalysis examined case-control differences within the whole sample, and also separately in children (<15 years), adolescents (15-21 years), and adults (>21 years). A linear mixed model was run with age, sex, and ICV as fixed variables and site as a random variable. Results for the total sample showed significant but small differences in the total volume of nucleus accumbens (Cohen's d = -0. 15), amygdala (d = -0. 19), caudate nucleus (d = -0. 11), hippocampus (d = -0. 11), putamen (d = -0. 14), and ICV (d = -0. 10), where the subjects with ADHD had smaller volumes as compared to controls  (Hoogman et al. , 2017).
First, the subcortical volumes for all subjects were entered in an exploratory factor analysis (EFA), which is used to summarize the nine subcortical volumes into a couple of underlying factors. Next, these factors were used in a Community Detection clustering analysis, to see if there were specific subgroups within the patient and control populations that differ in their subcortical brain profile  (Li et al. , 2019). In an ongoing study, similar analyses are being carried out for both the ENIGMA-ADHD and ASD datasets. The EFA results showed that variations in subcortical volumes can be reduced to three main factors, in males aligning with the striatum, limbic system, and thalamus. This factor structure was based on both cases and controls, and was stable between the ADHD and ASD cohorts. There were some differences between males and females, and among female children, adolescents, and adults.
In general, the statistical models that are used to calculate case-control differences are also similar among working groups. Mixed linear models using the nlme package in R are implemented with age, sex and case-control status as fixed variables and "site" as a random factor. Varying among working groups, interactions of the fixed factors are sometimes added to the model to acquire a better model fit. This varies among the working groups. Depending on the brain measures analyzed, additional covariates accounting for global head size are added. In subcortical volume projects intra cranial volume was added as covariate, and in cortical surface area projects, analyses were performed with and without total surface area as covariate. Even with these efforts, several challenges and limitations remain.