LSD-induced changes in the functional connectivity of distinct thalamic nuclei.

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

Cerebral blood flow patterns in preterm and term neonates assessed with pseudo-continuous arterial spin labeling perfusion MRI.

In preterm (PT) infants, regional cerebral blood flow (CBF) disturbances may predispose to abnormal brain maturation even without overt brain injury. Therefore, it would be informative to determine the spatial distribution of grey matter (GM) CBF in PT and full-term (FT) newborns at term-equivalent age (TEA) and to assess the relationship between the features of the CBF pattern and both prematurity and prematurity-related brain lesions. In this prospective study, we obtained measures of CBF in 66 PT (51 without and 15 with prematurity-related brain lesions) and 38 FT newborns through pseudo-continuous arterial spin labeling (pCASL) MRI acquired at TEA. The pattern of GM CBF was characterized by combining an atlas-based automated segmentation of structural MRI with spatial normalization and hierarchical clustering. The effects of gestational age (GA) at birth and brain injury on the CBF pattern were investigated. We identified 4 physiologically-derived clusters of brain regions that were labeled Fronto-Temporal, Parieto-Occipital, Insular-Deep GM (DGM) and Sensorimotor, from the least to the most perfused. We demonstrated that GM perfusion was associated with GA at birth in the Fronto-Temporal and Sensorimotor clusters, positively and negatively, respectively. Moreover, the presence of periventricular leukomalacia was associated with significantly increased Fronto-Temporal GM perfusion and decreased Insular-DGM perfusion, while the presence of germinal matrix hemorrhage appeared to mildly decrease the Insular-DGM perfusion. Prematurity and prematurity-related brain injury heterogeneously affect brain perfusion. ASL MRI may, therefore, have strong potential as a noninvasive tool for the accurate stratification of individuals at risk of domain-specific impairment.

Altered Medial Prefrontal Connectivity in Parkinson's Disease Patients with Somatic Symptoms.

BACKGROUND: The high co-occurrence of somatic symptom disorder (SSD) in Parkinson's disease (PD) patients suggests overlapping pathophysiology. However, little is known about the neural correlates of SSD and their possible interactions with PD. Existing studies have shown that SSD is associated with reduced task-evoked activity in the medial prefrontal cortex (mPFC), a central node of the default-mode network (DMN). SSD is also associated with abnormal γ-aminobutyric acid (GABA) content, a marker of local inhibitory tone and regional hypoactivity, in the same area when SSD co-occurs with PD. OBJECTIVES: To disentangle the individual and shared effects of SSD and PD on mPFC neurotransmission and connectivity patterns and help disclose the neural mechanisms of comorbidity in the PD population. METHODS: The study cohort included 18 PD patients with SSD (PD + SSD), 18 PD patients, 13 SSD patients who did not exhibit neurologic disorders, and 17 healthy subjects (HC). Proton magnetic resonance (MR) spectroscopy evaluated GABA levels within a volume of interest centered on the mPFC. Resting-state functional MR imaging investigated the region's functional connectivity patterns. RESULTS: Compared to HC or PD groups, the mPFC of SSD subjects exhibited higher GABA levels and connectivity. Higher mPFC connectivity involved DMN regions in SSD patients without PD and regions of the executive and attentional networks (EAN) in patients with PD comorbidity. CONCLUSIONS: Aberrant reconfigurations of connectivity patterns between the mPFC and the EAN are distinct features of the PD + SSD comorbidity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Dedicated Tool for Presurgical Mapping of Brain Tumors and Mixed-Reality Navigation During Neurosurgery.

Brain tumor surgery requires a delicate tradeoff between complete removal of neoplastic tissue while minimizing loss of brain function. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) have emerged as valuable tools for non-invasive assessment of human brain function and are now used to determine brain regions that should be spared to prevent functional impairment after surgery. However, image analysis requires different software packages, mainly developed for research purposes and often difficult to use in a clinical setting, preventing large-scale diffusion of presurgical mapping. We developed a specialized software able to implement an automatic analysis of multimodal MRI presurgical mapping in a single application and to transfer the results to the neuronavigator. Moreover, the imaging results are integrated in a commercially available wearable device using an optimized mixed-reality approach, automatically anchoring 3-dimensional holograms obtained from MRI with the physical head of the patient. This will allow the surgeon to virtually explore deeper tissue layers highlighting critical brain structures that need to be preserved, while retaining the natural oculo-manual coordination. The enhanced ergonomics of this procedure will significantly improve accuracy and safety of the surgery, with large expected benefits for health care systems and related industrial investors.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

BACKGROUND: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. METHODS: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. RESULTS: Significant MRI site and vendor effects (p â€‹< â€‹.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p â€‹< â€‹1.39E-36). In particular, volumes larger than 200 â€‹mm3 (for amygdalar nuclei) and 300 â€‹mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε â€‹< â€‹5% and DICE â€‹> â€‹0.80). CONCLUSION: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

High γ-Aminobutyric Acid Content Within the Medial Prefrontal Cortex Is a Functional Signature of Somatic Symptoms Disorder in Patients With Parkinson's Disease.

BACKGROUND: The dysfunctional activity of the medial prefrontal cortex has been associated with the appearance of the somatic symptom disorder, a key feature of the Parkinson's disease (PD) psychosis complex. OBJECTIVES: The objectives of this study were to investigate whether the basal contents of inhibitory γ-aminobutyric acid and excitatory glutamate plus glutamine neurotransmitter levels are changed in the medial prefrontal cortex of patients with PD with somatic symptom disorder and whether this alteration represents a marker of susceptibility of PD to somatic symptom disorder, thus representing a signature of psychosis complex of PD. METHODS: Levels of the γ-aminobutyric acid and glutamate plus glutamine were investigated, at rest, with proton magnetic resonance spectroscopy. Total creatine was used as an internal reference. The study cohort included 23 patients with somatic symptom disorder plus PD, 19 patients with PD without somatic symptom disorder, 19 healthy control subjects, and 14 individuals with somatic symptom disorder who did not show other psychiatric or neurological disorders. RESULTS: We found that, compared with patients with PD without somatic symptom disorder or healthy control individuals, patients with somatic symptom disorder, with or without PD, show increased γ-aminobutyric acid/total creatine levels in the medial prefrontal cortex. The medial prefrontal cortex contents of glutamate plus glutamine/total creatine levels or γ-aminobutyric acid/glutamate plus glutamine were not different among groups. CONCLUSIONS: Our findings highlight a crucial pathophysiologic role played by high γ-aminobutyric acid within the medial prefrontal cortex in the production of somatic symptom disorder. This phenomenon represents a signature of psychosis complex in patients with PD. © 2020 International Parkinson and Movement Disorder Society.

Free water elimination improves test-retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects.

Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects. Hum Brain Mapp 38:12-26, 2017. © 2016 Wiley Periodicals, Inc.

Intertrial Variability in the Premotor Cortex Accounts for Individual Differences in Peripersonal Space.

We live in a dynamic environment, constantly confronted with approaching objects that we may either avoid or be forced to address. A multisensory and sensorimotor interface, the peripersonal space (PPS), mediates every physical interaction between our body and the environment. Behavioral investigations show high variability in the extension of PPS across individuals, but there is a lack of evidence on the neural underpinnings of these large individual differences. Here, we used approaching auditory stimuli and fMRI to capture the individual boundary of PPS and examine its neural underpinnings. Precisely, we tested the hypothesis that intertrial variability (ITV) in brain regions coding PPS predicts individual differences of its boundary at the behavioral level. Selectively in the premotor cortex, we found that ITV, rather than trial-averaged amplitude, of BOLD responses to far rather than near dynamic stimuli predicts the individual extension of PPS. Our results provide the first empirical support for the relevance of ITV of brain responses for individual differences in human behavior. SIGNIFICANCE STATEMENT: Peripersonal space (PPS) is a multisensory and sensorimotor interface mediating every physical interaction between the body and the environment. A major characteristic of the boundary of PPS in humans is the extremely high variability of its location across individuals. We show that interindividual differences in the extension of the PPS are predicted by variability of BOLD responses in the premotor cortex to far stimuli approaching our body. Our results provide the first empirical support to the relevance of variability of evoked responses for human behavior and its variance across individuals.

Longitudinal reproducibility of default-mode network connectivity in healthy elderly participants: A multicentric resting-state fMRI study.

To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test-retest reproducibility in the consortium was high (ICC=0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test-retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈4% test-retest error, ICC=0.85), the medial frontal cortex the least reliable (≈12%, ICC=0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.

Test-retest reliability of the default mode network in a multi-centric fMRI study of healthy elderly: Effects of data-driven physiological noise correction techniques.

Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within-site test-retest reliability and the across-site reproducibility consistency of DMN-derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue-based regression, PESTICA and FSL-FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z-scores and, albeit less markedly, the cluster-size in the DMN; in particular, FSL-FIX tended to increase the DMN z-scores compared to others. Within-site test-retest reliability was consistent across sites, with no differences across rPNC methods. The absolute percent errors were in the range of 5-11% for DMN z-scores and cluster-size reliability. DMN pattern overlap was in the range 60-65%. In particular, no rPNC method showed a significant reliability improvement relative to NPC. However, FSL-FIX and Tissue-based physiological correction methods showed both similar and significant improvements of reproducibility consistency across the consortium (ICC = 0.67) for the DMN z-scores relative to NPC. Overall these findings support the use of rPNC methods like tissue-based or FSL-FIX to characterize multisite longitudinal changes of intrinsic functional connectivity. Hum Brain Mapp 37:2114-2132, 2016. © 2016 Wiley Periodicals, Inc.

Longitudinal reproducibility of automatically segmented hippocampal subfields: A multisite European 3T study on healthy elderly.

Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of all hippocampal subfields but not that of the whole hippocampus. Volumetric and spatial reproducibility across MRI sites were very good for the whole hippocampus, CA2-3, CA4-dentate gyrus (DG), subiculum (reproducibility error∼2% and DICE > 0.90), good for CA1 and presubiculum (reproducibility error ∼ 5% and DICE ∼ 0.90), and poorer for fimbria and hippocampal fissure (reproducibility error ∼ 15% and DICE < 0.80). Spearman's correlations confirmed that test-retest reproducibility improved with volume size. Despite considerable differences of MRI scanner configurations, we found consistent hippocampal subfields volumes estimation. CA2-3, CA4-DG, and sub-CA1 (subiculum, presubiculum, and CA1 pooled together) gave test-retest reproducibility similar to the whole hippocampus. Our findings suggest that the larger hippocampal subfields volume may be reliable longitudinal markers in multisite studies.

Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects.

Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 × 2 × 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7 ± 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.

Atrophy of hippocampal subfields and amygdala nuclei in subjects with mild cognitive impairment progressing to Alzheimer's disease.

The hippocampus and amygdala are the first brain regions to show early signs of Alzheimer's Disease (AD) pathology. AD is preceded by a prodromal stage known as Mild Cognitive Impairment (MCI), a crucial crossroad in the clinical progression of the disease. The topographical development of AD has been the subject of extended investigation. However, it is still largely unknown how the transition from MCI to AD affects specific hippocampal and amygdala subregions. The present study is set to answer that question. We analyzed data from 223 subjects: 75 healthy controls, 52 individuals with MCI, and 96 AD patients obtained from the ADNI. The MCI group was further divided into two subgroups depending on whether individuals in the 48 months following the diagnosis either remained stable (N = 21) or progressed to AD (N = 31). A MANCOVA test evaluated group differences in the volume of distinct amygdala and hippocampal subregions obtained from magnetic resonance images. Subsequently, a stepwise linear discriminant analysis (LDA) determined which combination of magnetic resonance imaging parameters was most effective in predicting the conversion from MCI to AD. The predictive performance was assessed through a Receiver Operating Characteristic analysis. AD patients displayed widespread subregional atrophy. MCI individuals who progressed to AD showed selective atrophy of the hippocampal subiculum and tail compared to stable MCI individuals, who were undistinguishable from healthy controls. Converter MCI showed atrophy of the amygdala's accessory basal, central, and cortical nuclei. The LDA identified the hippocampal subiculum and the amygdala's lateral and accessory basal nuclei as significant predictors of MCI conversion to AD. The analysis returned a sensitivity value of 0.78 and a specificity value of 0.62. These findings highlight the importance of targeted assessments of distinct amygdala and hippocampus subregions to help dissect the clinical and pathophysiological development of the MCI to AD transition.

Kinetic properties of an RNA enzyme that undergoes self-sustained exponential amplification.

A special class of biochemical reactions involves a set of enzymes that generate additional copies of themselves and transfer heritable information from parent to progeny molecules, thus providing the basis for genetics and Darwinian evolution. Such a process has been realized with a pair of self-replicating RNA enzymes that undergo exponential amplification at a constant temperature. Exponential growth requires that the rate of production of new enzymes be directly proportional to the existing concentration of enzymes, which is the case for this system and provides a doubling time of ~20 min. However, the catalytic rate of the underlying enzymes is ~100-fold faster than the observed rate of replication. As in biological replication, other aspects of the system limit the generation time, chiefly the propensity of the substrate molecules to form nonproductive complexes that limit their availability for replication. An analysis of this and other kinetic properties of the self-replicating RNA enzymes reveals how exponential amplification is achieved and how the rate of amplification might be increased.

Sensitivity of BOLD response to increasing visual contrast: spin echo versus gradient echo EPI.

Previous evidence showed that spin-echo (SE) BOLD signals offer an increased linearity and promptness with respect to gradient-echo (GE) acquisition, possibly providing a more accurate estimate of the amplitude of neuronal activity. However there is no evidence that the two sequences differ in representing different activation levels due to changes in stimulus intensity. In this study at 3T we compared GE and SE BOLD responses to visual stimuli at increasing contrast levels (5%, 20%, 60%, and 100%). Both sequences showed a monotonic increase of the BOLD response with stimulus contrast. While the larger sensitivity of GE yielded overall larger signal changes, step-wise increase in activation for GE was significant only when comparing 20% with 5% contrast, whereas for SE a significant increase was observed also when comparing 60% with 20% contrast. Moreover, BOLD responses normalized to the lowest contrast showed that relative increases of SE fMRI signal with increasing stimulus strength are larger with respect to the corresponding values of GE signal. This difference was observed also when excluding voxels attributed to large vessels, suggesting a non negligible role of the extravascular contribution to the modulation of SE fMRI signal with stimulus intensity. These results are shown to be in agreement with theoretical predictions that we derived from a recently proposed model of GE and SE functional signals. The present findings suggest that, despite the limited increase in functional localization accuracy at low field, SE fMRI might offer a potential advantage in distinguishing different levels of stimulus-evoked brain activity.

BOLD cardiorespiratory pulsatility in the brain: from noise to signal of interest.

Functional magnetic resonance imaging (fMRI) based on the Blood Oxygen Level Dependent (BOLD) contrast has been extensively used to map brain activity and connectivity in health and disease. Standard fMRI preprocessing includes different steps to remove confounds unrelated to neuronal activity. First, this narrative review explores how signal fluctuations due to cardiac and respiratory activity, usually considered as "physiological noise" and regressed out from fMRI time series. However, these signal components bear useful information about some mechanisms of brain functioning (e.g., glymphatic clearance) or cerebrovascular compliance in response to arterial pressure waves. Aging and chronic diseases can cause stiffening of the aorta and other main arteries, with a reduced dampening effect resulting in greater transmission of pressure impulses to the brain. Importantly, the continuous hammering of cardiac pulsations can produce local alterations of the mechanical properties of the small cerebral vessels, with a progressive deterioration that ultimately affects neuronal functionality. Second, the review emphasizes how fMRI can study the brain patterns most affected by cardiac pulsations in health and disease with high spatiotemporal resolution, offering the opportunity to identify much more specific risk markers than systemic factors based on measurements of the vascular compliance of large arteries or other global risk factors. In this regard, modern fast fMRI acquisition techniques allow a better characterization of these pulsatile signal components due to reduced aliasing effects, turning what has been traditionally considered as noise in a signal of interest that can be used to develop novel non-invasive biomarkers in different clinical contexts.

Spatial Correspondence of LSD-Induced Variations on Brain Functioning at Rest With Serotonin Receptor Expression.

BACKGROUND: Lysergic acid diethylamide (LSD) is an atypical psychedelic compound that exerts its effects through pleiotropic actions, mainly involving 1A/2A serotoninergic (5-HT) receptor subtypes. However, the mechanisms by which LSD promotes a reorganization of the brain's functional activity and connectivity are still partially unknown. METHODS: Our study analyzed resting-state functional magnetic resonance imaging data acquired from 15 healthy volunteers undergoing LSD single-dose intake. A voxelwise analysis investigated the alterations of the brain's intrinsic functional connectivity and local signal amplitude induced by LSD or by a placebo. Quantitative comparisons assessed the spatial overlap between these 2 indices of functional reorganization and the topography of receptor expression obtained from a publicly available collection of in vivo, whole-brain atlases. Finally, linear regression models explored the relationships between changes in resting-state functional magnetic resonance imaging and behavioral aspects of the psychedelic experience. RESULTS: LSD elicited modifications of the cortical functional architecture that spatially overlapped with the distribution of serotoninergic receptors. Local signal amplitude and functional connectivity increased in regions belonging to the default mode and attention networks associated with high expression of 5-HT2A receptors. These functional changes correlate with the occurrence of simple and complex visual hallucinations. At the same time, a decrease in local signal amplitude and intrinsic connectivity was observed in limbic areas, which are dense with 5-HT1A receptors. CONCLUSIONS: This study provides new insights into the neural processes underlying the brain network reconfiguration induced by LSD. It also identifies a topographical relationship between opposite effects on brain functioning and the spatial distribution of different 5-HT receptors.

Atrophy of specific amygdala subfields in subjects converting to mild cognitive impairment.

Introduction: Accumulating evidence indicates that the amygdala exhibits early signs of Alzheimer's disease (AD) pathology. However, it is still unknown whether the atrophy of distinct subfields of the amygdala also participates in the transition from healthy cognition to mild cognitive impairment (MCI). Methods: Our sample was derived from the AD Neuroimaging Initiative 3 and consisted of 97 cognitively healthy (HC) individuals, sorted into two groups based on their clinical follow-up: 75 who remained stable (s-HC) and 22 who converted to MCI within 48 months (c-HC). Anatomical magnetic resonance (MR) images were analyzed using a semi-automatic approach that combines probabilistic methods and a priori information from ex vivo MR images and histology to segment and obtain quantitative structural metrics for different amygdala subfields in each participant. Spearman's correlations were performed between MR measures and baseline and longitudinal neuropsychological measures. We also included anatomical measurements of the whole amygdala, the hippocampus, a key target of AD-related pathology, and the whole cortical thickness as a test of spatial specificity. Results: Compared with s-HC individuals, c-HC subjects showed a reduced right amygdala volume, whereas no significant difference was observed for hippocampal volumes or changes in cortical thickness. In the amygdala subfields, we observed selected atrophy patterns in the basolateral nuclear complex, anterior amygdala area, and transitional area. Macro-structural alterations in these subfields correlated with variations of global indices of cognitive performance (measured at baseline and the 48-month follow-up), suggesting that amygdala changes shape the cognitive progression to MCI. Discussion: Our results provide anatomical evidence for the early involvement of the amygdala in the preclinical stages of AD. Highlights: Amygdala's atrophy marks elderly progression to mild cognitive impairment (MCI).Amygdala's was observed within the basolateral and amygdaloid complexes.Macro-structural alterations were associated with cognitive decline.No atrophy was found in the hippocampus and cortex.