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Additional Figure 4. MRI (top), FDG PET (middle), tau PET (bottom) comparisons between young CN and EOnonAD and old CN and LOnonAD groups. The significance maps show p

Objective: To evaluate progressive white matter (WM) degeneration in ALS. Methods: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicentre study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centres including diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALSFRS-R) and upper motor neuron (UMN) function. Voxel-wise whole brain and quantitative tractwise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers that underwent the DTI protocol at each centre. Results: ALS patients had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tractwise analysis revealed reduced FA in the CST, corticopontine/corticorubral and corticostriatal tracts. CST FA correlated with UMN function and frontal lobe FA with the ALSFRS-R. A progressive decline in CST FA correlated with a decline in the ALSFRS-R and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. Conclusions: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes, and to a lesser degree in the corticopontine/corticorubral tracts and the corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytical methods to address site-related variances, this study is an important milestone towards developing DTI biomarkers for cerebral degeneration in ALS.

Additional file 7. Table S7: P values and regression coefficients for the correlation between DNA methylation in blood with four brain regions (prefrontal cortex, entorhinal cortex, superior temporal gyrus and cerebellum) from 71 to 75 matched samples for all the 8 CpG probes. The data are taken from the Blood Brain DNA Methylation Comparison Tool [17].

Representative flow cytometry plots of 3 pitutiary adenoma samples showing Sox2 and CD15 expression. (TIFF 791 kb)

Average vessel radius atlas (in mm)

Additional file 3: Figure S3. (A) Schematic representation of HA-mRFP1-tagged murine Rpl10a ribosomal protein construct under control of the NFL 848 promoter to make neuron specific expression (B) Representative sketch showing the process used for generating double transgenic mice (by breeding NFL-RFP1 mice with mhTDP-43A315T mice) (C) Representative image showing DAPI (blue), NeuN a neuronal marker and RFP (red) in the brain of hTDP-43A315T mice and NfL-RFP;hTDP-43A315T double transgenic mice. (D) Representative image of experimental protocol used for the Ribotrap experiment.

Additional file 19: Supplementary Movie 12. Description: Time-lapse imaging of GFP-0N4R reporter cells seeded with S1 brain fractions including pathogenic tau derived from aged TgTauP301L mice with neurological signs. Images were obtained for 16 hours (10 min/frame for 96 frames). Scale bars, 10 μm.

Background: Deep brain stimulation (DBS) is a neuromodulatory technique that delivers adjustable electrical stimuli to brain targets to relieve symptoms associated with dysregulated neural circuitry. Over the last several decades, DBS has been applied to a number of conditions, including motor, pain, mood, and cognitive disorders. An assessment of the body of work in this field is warranted to determine where we have been, define the current state of the field, and chart a path toward the future. Objective: The aim of the study was to assess the state of DBS-related research by analyzing the DBS literature as well as active studies sponsored by the National Institutes of Health (NIH) or German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]). Methods: Peer-reviewed DBS publications were extracted from PubMed. Active NIH-funded DBS projects were extracted from the RePORT database and active DFG projects from the German Research Foundation database. Records were analyzed using custom-developed algorithms to generate a detailed overview of past and present DBS-related research. Specifically, records were categorized by publication year, journal, language, country of origin, contributing authors, disorder, brain target, study design, and topic. Expected project duration and costs were also provided for active studies. Results: In total, 8,974 publications, 172 active NIH-funded projects, and 34 active DFG projects were identified. Records spanned 52 different disorders across 31 distinct brain targets and showed a recent shift toward studies examining conditions other than movement disorders. Most published works involved human research (80.6% of published studies), of which 10.2% were identified as clinical trials. Increasingly, studies focused on imaging or electrophysiological changes associated with DBS (69.8% NIH-active and 70.6% DFG-active vs. 25.8% published) or developing new stimulation techniques and adaptive technologies (37.8% NIH-active and 17.6% DFG-active vs. 6.5% published). Conclusions: This overview of past and present DBS-related studies provides insight into the status of DBS research and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS.

Additional file 15: Supplementary Movie 8. Description: Time-lapse imaging of 4RD-YFP reporter cells seeded with S1 brain fractions including pathogenic tau derived from aged TgTauP301L mice with neurological signs. Images were obtained for 7 hours (10 min/frame for 42 frames). Scale bars, 10 μm.