Lasting effects of transcranial direct current stimulation on the inducibility of synaptic plasticity by paired-associative stimulation in humans.

BACKGROUND: Transcranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications. OBJECTIVE: The study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics. METHODS: Amplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each). RESULTS: tDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects. CONCLUSIONS: tDCS is capable of inducing lasting changes in the brain's capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.

Photon-Counting Detector CT Virtual Monoenergetic Images for Coronary Artery Stenosis Quantification: Phantom and In Vivo Evaluation.

BACKGROUND. Calcium blooming causes stenosis overestimation on coronary CTA. OBJECTIVE. The purpose of this article was to evaluate the impact of virtual monoenergetic imaging (VMI) reconstruction level on coronary artery stenosis quantification using photon-counting detector (PCD) CT. METHODS. A phantom containing two custom-made vessels (representing 25% and 50% stenosis) underwent PCD CT acquisitions without and with simulated cardiac motion. A retrospective analysis was performed of 33 patients (seven women, 26 men; mean age, 71.3 ± 9.0 [SD] years; 64 coronary artery stenoses) who underwent coronary CTA by PCD CT followed by invasive coronary angiography (ICA). Scans were reconstructed at nine VMI energy levels (40-140 keV). Percentage diameter stenosis (PDS) was measured, and bias was determined from the ground-truth stenosis percentage in the phantom and ICA-derived quantitative coronary angiography measurements in patients. Extent of blooming artifact was measured in the phantom and in calcified and mixed plaques in patients. RESULTS. In the phantom, PDS decreased for 25% stenosis from 59.9% (40 keV) to 13.4% (140 keV) and for 50% stenosis from 81.6% (40 keV) to 42.3% (140 keV). PDS showed lowest bias for 25% stenosis at 90 keV (bias, 1.4%) and for 50% stenosis at 100 keV (bias, -0.4%). Blooming artifacts decreased for 25% stenosis from 61.5% (40 keV) to 35.4% (140 keV) and for 50% stenosis from 82.7% (40 keV) to 52.1% (140 keV). In patients, PDS for calcified plaque decreased from 70.8% (40 keV) to 57.3% (140 keV), for mixed plaque decreased from 69.8% (40 keV) to 56.3% (140 keV), and for noncalcified plaque was 46.6% at 40 keV and 54.6% at 140 keV. PDS showed lowest bias for calcified plaque at 100 keV (bias, 17.2%), for mixed plaque at 140 keV (bias, 5.0%), and for noncalcified plaque at 40 keV (bias, -0.5%). Blooming artifacts decreased for calcified plaque from 78.4% (40 keV) to 48.6% (140 keV) and for mixed plaque from 73.1% (40 keV) to 44.7% (140 keV). CONCLUSION. For calcified and mixed plaque, stenosis severity measurements and blooming artifacts decreased at increasing VMI reconstruction levels. CLINICAL IMPACT. PCD CT with VMI reconstruction helps overcome current limitations in stenosis quantification on coronary CTA.

Photon-counting detector CT-based virtual monoenergetic reconstructions: repeatability and reproducibility of radiomics features of an organic phantom and human myocardium.

BACKGROUND: Photon-counting detector computed tomography (PCD-CT) may influence imaging characteristics for various clinical conditions due to higher signal and contrast-to-noise ratio in virtual monoenergetic images (VMI). Radiomics analysis relies on quantification of image characteristics. We evaluated the impact of different VMI reconstructions on radiomic features in in vitro and in vivo PCD-CT datasets. METHODS: An organic phantom consisting of twelve samples (four oranges, four onions, and four apples) was scanned five times. Twenty-three patients who had undergone coronary computed tomography angiography on a first generation PCD-CT system with the same image acquisitions were analyzed. VMIs were reconstructed at 6 keV levels (40, 55, 70, 90, 120, and 190 keV). The phantoms and the patients' left ventricular myocardium (LVM) were segmented for all reconstructions. Ninety-three original radiomic features were extracted. Repeatability and reproducibility were evaluated through intraclass correlations coefficient (ICC) and post hoc paired samples ANOVA t test. RESULTS: There was excellent repeatability for radiomic features in phantom scans (all ICC = 1.00). Among all VMIs, 36/93 radiomic features (38.7%) in apples, 28/93 (30.1%) in oranges, and 33/93 (35.5%) in onions were not significantly different. For LVM, the percentage of stable features was high between VMIs ≥ 90 keV (90 versus 120 keV, 77.4%; 90 versus 190 keV, 83.9%; 120 versus 190 keV, 89.3%), while comparison to lower VMI levels led to fewer reproducible features (40 versus 55 keV, 8.6%). CONCLUSIONS: VMI levels influence the stability of radiomic features in an organic phantom and patients' LVM; stability decreases considerably below 90 keV. RELEVANCE STATEMENT: Spectral reconstructions significantly influence radiomic features in vitro and in vivo, necessitating standardization and careful attention to these reconstruction parameters before clinical implementation. KEY POINTS: • Radiomic features have an excellent repeatability within the same PCD-CT acquisition and reconstruction. • Differences in VMI lead to decreased reproducibility for radiomic features. • VMI ≥ 90 keV increased the reproducibility of the radiomic features.

Optimization of Kernel Type and Sharpness Level Improves Objective and Subjective Image Quality for High-Pitch Photon Counting Coronary CT Angiography.

(1) Background: Photon-counting detector (PCD) CT offers a wide variety of kernels and sharpness levels for image reconstruction. The aim of this retrospective study was to determine optimal settings for coronary CT angiography (CCTA). (2) Methods: Thirty patients (eight female, mean age 63 ± 13 years) underwent PCD-CCTA in a high-pitch mode. Images were reconstructed using three different kernels and four sharpness levels (Br36/40/44/48, Bv36/40/44/48, and Qr36/40/44/48). To analyze objective image quality, the attenuation, image noise, contrast-to-noise ratio (CNR), and vessel sharpness were quantified in proximal and distal coronaries. For subjective image quality, two blinded readers assessed image noise, visually sharp reproduction of coronaries, and the overall image quality using a five-point Likert scale. (3) Results: Attenuation, image noise, CNR, and vessel sharpness significantly differed across kernels (all p < 0.001), with the Br-kernel reaching the highest attenuation. With increasing kernel sharpness, image noise and vessel sharpness increased, whereas CNR continuously decreased. Reconstruction with Br-kernel generally had the highest CNR (Br > Bv > Qr), except Bv-kernel had a superior CNR at sharpness level 40. Bv-kernel had significantly higher vessel sharpness than Br- and Qr-kernel (p < 0.001). Subjective image quality was rated best for kernels Bv40 and Bv36, followed by Br36 and Qr36. (4) Conclusion: Reconstructions with kernel Bv40 are beneficial to achieve optimal image quality in spectral high-pitch CCTA using PCD-CT.

Ultra-high resolution photon-counting coronary CT angiography improves coronary stenosis quantification over a wide range of heart rates - A dynamic phantom study.

PURPOSE: To investigate the effect of using photon-counting detector (PCD)-CT with ultra-high resolution (UHR) on stenosis quantification accuracy and blooming artifacts from low to high heart rates in a dynamic motion phantom. METHOD: Two vessel phantoms (diameter: 4 mm) containing solid calcified lesions (25%, 50% stenoses), filled with different concentrations of iodine, inside an anthropomorphic thorax phantom attached to a coronary motion simulator were used. Scanning was performed on a PCD-CT system using an ECG-gated mode at UHR and standard resolution (SR) (0.2, 0.6 mm slice thickness, respectively). Images were reconstructed at 60, 80 and 100 beats per minute (bpm) (UHR: Bv56 kernel, quantum iterative reconstruction (QIR) level 3; SR: 55 keV, Bv40 kernel, QIR3). Percent diameter stenosis (PDS) and blooming artifacts were measured by two readers. RESULTS: PDS measurements derived from UHR were more accurate than SR for both lesions at every heart rate (p ≤ 0.005 for all, e.g. 50% lesion SR vs. UHR: at 60 bpm 57.1% [55.2-59.2] vs. 50.0% [48.5-51.2], at 100 bpm 61.0% [58.6-64.3] vs. 52.4% [51.3-54.3]). Overall mean difference across heart rates and lesions compared to the nominal stenoses was 9.2% (Limit of Agreement (LoA), 2.4%/16.0%) for SR vs. 2.4% (LoA, -2.8%/7.5%) for UHR. Blooming artifacts decreased with UHR compared to SR for both lesions at every heart rate (p < 0.001 for all, e.g. 50% lesion SR vs. UHR: at 60 bpm 63.8% [60.6-69.5] vs. 52.5% [50.0-57.5], at 100 bpm 70.2% [64.8-78.1] vs. 56.1% [51.2-60.8]). CONCLUSIONS: This motion phantom study demonstrates improved stenosis quantification accuracy and reduced blooming artifacts with UHR-PCD-CT compared to SR, independent of heart rate.

Photon Counting Detector CT-Based Virtual Noniodine Reconstruction Algorithm for In Vitro and In Vivo Coronary Artery Calcium Scoring: Impact of Virtual Monoenergetic and Quantum Iterative Reconstructions.

OBJECTIVES: The aim of this study was to evaluate the impact of virtual monoenergetic imaging (VMI) and quantum iterative reconstruction (QIR) on the accuracy of coronary artery calcium scoring (CACS) using a virtual noniodine (VNI) reconstruction algorithm on a first-generation, clinical, photon counting detector computed tomography system. MATERIALS AND METHODS: Coronary artery calcium scoring was evaluated in an anthropomorphic chest phantom simulating 3 different patient sizes by using 2 extension rings (small: 300 × 200 mm, medium: 350 × 250 mm, large: 400 × 300 mm) and in patients (n = 61; final analyses only in patients with coronary calcifications [n = 34; 65.4 ± 10.0 years; 73.5% male]), who underwent nonenhanced and contrast-enhanced, electrocardiogram-gated, cardiac computed tomography on a photon counting detector system. Phantom and patient data were reconstructed using a VNI reconstruction algorithm at different VMI (55-80 keV) and QIR (strength 1-4) levels (CACS VNI ). True noncontrast (TNC) scans at 70 keV and QIR "off" were used as reference for phantom and patient studies (CACS TNC ). RESULTS: In vitro and in vivo CACS VNI showed strong correlation ( r > 0.9, P < 0.001 for all) and excellent agreement (intraclass correlation coefficient > 0.9 for all) with CACS TNC at all investigated VMI and QIR levels. Phantom and patient CACS VNI significantly increased with decreasing keV levels (in vitro: from 475.2 ± 26.3 at 80 keV up to 652.5 ± 42.2 at 55 keV; in vivo: from 142.5 [7.4/737.7] at 80 keV up to 248.1 [31.2/1144] at 55 keV; P < 0.001 for all), resulting in an overestimation of CACS VNI at 55 keV compared with CACS TNC at 70 keV in some cases (in vitro: 625.8 ± 24.4; in vivo: 225.4 [35.1/959.7]). In vitro CACS increased with rising QIR at low keV. In vivo scores were significantly higher at QIR 1 compared with QIR 4 only at 60 and 80 keV (60 keV: 220.3 [29.6-1060] vs 219.5 [23.7/1048]; 80 keV: 152.0 [12.0/735.6] vs 142.5 [7.4/737.7]; P < 0.001). CACS VNI was closest to CACS TNC at 60 keV, QIR 2 (+0.1%) in the small; 55 keV, QIR 1 (±0%) in the medium; 55 keV, QIR 4 (-0.1%) in the large phantom; and at 60 keV, QIR 1 (-2.3%) in patients. CONCLUSIONS: Virtual monoenergetic imaging reconstructions have a significant impact on CACS VNI . The effects of different QIR levels are less consistent and seem to depend on several individual conditions, which should be further investigated.

Myocardial Characterization with Extracellular Volume Mapping with a First-Generation Photon-counting Detector CT with MRI Reference.

Background Photon-counting detector (PCD) CT provides comprehensive spectral data with every acquisition, but studies evaluating myocardial extracellular volume (ECV) quantification with use of PCD CT compared with an MRI reference remain lacking. Purpose To compare ECV quantification for myocardial tissue characterization between a first-generation PCD CT system and cardiac MRI. Materials and Methods In this single-center prospective study, adults without contraindication to iodine-based contrast media underwent same-day cardiac PCD CT and MRI with native and postcontrast T1 mapping and late gadolinium enhancement for various clinical indications for cardiac MRI (the reference standard) between July 2021 and January 2022. Global and midventricular ECV were assessed with use of three methods: single-energy PCD CT, dual-energy PCD CT, and MRI T1 mapping. Quantitative comparisons among all techniques were performed. Correlation and reliability between different methods of ECV quantification were assessed with use of the Pearson correlation coefficient (r) and the intraclass correlation coefficient. Results The final sample included 29 study participants (mean age ± SD, 54 years ± 17; 15 men). There was a strong correlation of ECV between dual- and single-energy PCD CT (r = 0.91, P < .001). Radiation dose was 40% lower with dual-energy versus single-energy PCD CT (volume CT dose index, 10.1 mGy vs 16.8 mGy, respectively; P < .001). In comparison with MRI, dual-energy PCD CT showed strong correlation (r = 0.82 and 0.91, both P < .001) and good to excellent reliability (intraclass correlation coefficients, 0.81 and 0.90) for midventricular and global ECV quantification, but it overestimated ECV by approximately 2%. Single-energy PCD CT showed similar relationship with MRI but underestimated ECV by 3%. Conclusion Myocardial tissue characterization with photon-counting detector CT-based quantitative extracellular volume analysis showed a strong correlation to MRI. © RSNA, 2023 Supplemental material is available for this article.

Intra-individual comparison of coronary calcium scoring between photon counting detector- and energy integrating detector-CT: Effects on risk reclassification.

Purpose: To compare coronary artery calcium volume and score (CACS) between photon-counting detector (PCD) and conventional energy integrating detector (EID) computed tomography (CT) in a phantom and prospective patient study. Methods: A commercially available CACS phantom was scanned with a standard CACS protocol (120 kVp, slice thickness/increment 3/1.5 mm, and a quantitative Qr36 kernel), with filtered back projection on the EID-CT, and with monoenergetic reconstruction at 70 keV and quantum iterative reconstruction off on the PCD-CT. The same settings were used to prospectively acquire data in patients (n = 23, 65 ± 12.1 years), who underwent PCD- and EID-CT scans with a median of 5.5 (3.0-12.5) days between the two scans in the period from August 2021 to March 2022. CACS was quantified using a commercially available software solution. A regression formula was obtained from the aforementioned comparison and applied to simulate risk reclassification in a pre-existing cohort of 514 patients who underwent a cardiac EID-CT between January and December 2021. Results: Based on the phantom experiment, CACS PCD-CT showed a more accurate measurement of the reference CAC volumes (overestimation of physical volumes: PCD-CT 66.1 ± 1.6% vs. EID-CT: 77.2 ± 0.5%). CACS EID-CT and CACS PCD-CT were strongly correlated, however, the latter measured significantly lower values in the phantom (CACS PCD-CT : 60.5 (30.2-170.3) vs CACS EID-CT 74.7 (34.6-180.8), p = 0.0015, r = 0.99, mean bias -9.7, Limits of Agreement (LoA) -36.6/17.3) and in patients (non-significant) (CACS PCD-CT : 174.3 (11.1-872.7) vs CACS EID-CT 218.2 (18.5-876.4), p = 0.10, r = 0.94, mean bias -41.1, LoA -315.3/232.5). The systematic lower measurements of Agatston score on PCD-CT system led to reclassification of 5.25% of our simulated patient cohort to a lower classification class. Conclusion: CACS PCD-CT is feasible and correlates strongly with CACS EID-CT , however, leads to lower CACS values. PCD-CT may provide results that are more accurate for CACS than EID-CT.

Indices of cortical plasticity after therapeutic sleep deprivation in patients with major depressive disorder.

BACKGROUND: Therapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. METHODS: We used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. RESULTS: We demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. LIMITATIONS: Repetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. CONCLUSION: After a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.

Effect of naturally occurring α-synuclein-antibodies on toxic α-synuclein-fragments.

Alpha-synuclein (α-Syn) is a soluble protein primarily expressed in presynaptic terminals in the central nervous system (CNS). Aggregates of fibrillated α-Syn are the major component of Lewy bodies (LB), a pathologic hallmark of idiopathic Parkinson's disease (PD). Recently, naturally occurring autoantibodies against human α-Syn (nAbs α-Syn) were detected in the peripheral blood of PD patients and controls. Here, we investigated the inhibitory effects of nAbs α-Syn on distinct α-Syn fragments, as well as inflammatory responses and cytotoxicity evoked by nAbs α-Syn in primary microglia. All α-Syn fragments induced the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) from microglia in primary culture. Cotreatment with nAbs α-Syn alleviated the release of pro-inflammatory cytokines induced by α-Syn fragments α-Syn 1-95, α-Syn 61-140, α-Syn 96-140 and α-Syn 112. Treatment with the α-Syn fragments α-Syn 1-95, α-Syn 61-140 and α-Syn 112 impaired the viability of primary microglia. This effect could not be counteracted by cotreatment with nAbs α-Syn. Data suggest an important role of nAbs α-Syn in the α-Syn-induced inflammation cascade, and indicate the potential importance of nAbs in the pathogenesis of PD. This could provide an experimental therapeutic target for patients with PD.

Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex.

Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep-wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans.

Synaptic plasticity model of therapeutic sleep deprivation in major depression.

Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide.

Naturally occurring α-synuclein autoantibody levels are lower in patients with Parkinson disease.

OBJECTIVE: Biomarkers are required for the diagnosis and monitoring of disease progression in Parkinson disease (PD). To date, most studies have concentrated on α-synuclein (α-Syn), a protein involved in Parkinson disease pathogenesis, as a potential biomarker, with inconsistent outcomes. Recently, naturally occurring autoantibodies against α-Syn (α-Syn-nAbs) have been detected in the serum of patients with PD. They represent a putative diagnostic marker for PD. METHODS: We established and validated an ELISA to quantify α-Syn-nAbs in serum samples. We analyzed serum samples from 62 patients with PD, 46 healthy controls (HC), and 42 patients with Alzheimer disease (AD) using this newly established ELISA. Additionally, serum levels of endogenous α-Syn were measured. RESULTS: There was a significant difference in α-Syn-nAbs levels between the investigated groups (p = 0.005; Kruskal-Wallis test). Levels of α-Syn-nAbs were significantly lower in patients with PD compared to HC (p < 0.05; Dunn multiple comparison post hoc test) or patients with AD (p < 0.05). Furthermore, we detected no difference between patients with AD and HC. The sensitivity and specificity of the assay for patients with PD vs. HC were 85% and 25%, respectively. The α-Syn-nAbs levels did not correlate with age, Hoehn & Yahr status, or duration of disease. Endogenous α-Syn had no influence on α-Syn-nAbs levels in sera. CONCLUSIONS: Using a well-validated assay, we detected reduced α-Syn-nAbs levels in patients with PD compared to patients with AD and HC. The assay did not achieve criteria for use as a diagnostic tool to reliably distinguish PD from HC. Further studies are needed to assess α-Syn-nAbs as a biomarker in PD.