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Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.

Diffusion MRI files in Nifti format (DWI in nifti + B-matrix in txt) for 37 pateints with Alcohol use disorders and 20 control subjects. In addition to their demographics

Alcohol use disorder (AUD) is the most prevalent form of addiction, with a great burden on society and limited treatment options. A recent clinical trial reported significant clinical benefits of deep transcranial magnetic stimulations (Deep TMS) targeting midline frontocortical areas. However, the underlying biological substrate remained elusive. Here, we report the effect of Deep TMS on the microstructure of white matter.

Magnetic Resonance Imaging data collected in rats injected with isotonic acid in the left hippocampus, and humans with multiple sclerosis and controls.

The brain parenchyma undergoes several structural changes throughout life, which have a ma- jor impact on its physiological evolution, and which are behaviorally reflected as changes in cognition and ability. A key question is how age-related structural alterations impact the func- tion of the different areas. Functional connectivity, measured as correlation between brain re- gions during the resting state Magnetic Resonance Imaging (MRI), is a quantitative measure of function that can be reliably used to characterize the evolution of the communication between regions across the lifespan. However, most of the works so far have done it with a hypothesis driven approach. The present work aims to identify the functional connectivity patterns of the whole brain during resting state in a rodent model of healthy ageing. For this purpose, we have followed the standard workflow recently proposed in a consensus paper on functional imag- ing processing in preclinical MRI. We have set up a longitudinal functional MRI experiment to measure functional connectivity in rats at different times. Independent component analysis has been used to identify characteristic resting-state networks and compare them between three different ages, corresponding to adulthood to early senescence. The goal is to highlight region- , sex-, and age-specific patterns that drive the physiological decline in cognition observed in senescence, with potential to identify vulnerable regions in and define targets for intervention. Our results uncovered patterns of increased functional connectivity between adulthood and senescence in several key regions controlling the functions known to be affected by age. Such increase in connectivity can be explained as a compensatory mechanism that allows the brain to cope with reduced microstructural integrity. The study of healthy ageing in absence of disease sets the baseline for the identification of pathological conditions, El parénquima cerebral experimenta varios cambios estructurales a lo largo de la vida, que tienen un gran impacto en su evolución fisiológica, y que se reflejan conductualmente como cambios en la cognición y la capacidad. Una cuestión clave es cómo repercuten las alteraciones estructurales relacionadas con la edad en la función de las distintas áreas. La conectividad fun- cional, medida como correlación entre regiones cerebrales durante la Resonancia Magnética (RM) en estado de reposo, es una medida cuantitativa de la función que puede utilizarse de forma fiable para caracterizar la evolución de la comunicación entre regiones a lo largo de la vida. Sin embargo, la mayoría de los trabajos realizados hasta ahora lo han hecho con un en- foque basado en hipótesis. El presente trabajo pretende identificar los patrones de conectividad funcional de todo el cerebro durante el estado de reposo en un modelo de roedor de envejec- imiento sano. Para ello, hemos seguido el flujo de trabajo estándar propuesto recientemente en un documento de consenso sobre el procesamiento de imágenes funcionales en RM preclínica. Hemos establecido un experimento de RM funcional longitudinal para medir la conectividad funcional en ratas en diferentes momentos. Se ha utilizado el análisis de componentes indepen- dientes para identificar redes características en estado de reposo y compararlas entre tres edades diferentes, correspondientes a la edad adulta y a la senescencia temprana. El objetivo es destacar los patrones específicos de región, sexo y edad que impulsan el declive fisiológico de la cogni- ción observado en la senescencia, con potencial para identificar regiones vulnerables y definir objetivos de intervención. Nuestros resultados descubrieron patrones de aumento de la conec- tividad funcional entre la edad adulta y la senescencia en varias regiones clave que controlan las funciones que se sabe que se ven afectadas por la edad. Este aumento de la conectividad puede explicarse como un me, El parènquima cerebral experimenta diversos canvis estructurals al llarg de la vida, que tenen un gran impacte en la seua evolució fisiològica, i que es reflecteixen conductualment com a canvis en la cognició i la capacitat. Una qüestió clau és com repercuteixen les alteracions estructurals relacionades amb l’edat en la funció de les diferents àrees. La connectivitat funcional, mesurada com a correlació entre regions cerebrals durant la Ressonància Magnètica (RM) en estat de repòs, és una mesura quantitativa de la funció que pot utilitzar-se de manera fiable per a carac- teritzar l’evolució de la comunicació entre regions al llarg de la vida. No obstant això, la majoria dels treballs realitzats fins ara ho han fet amb un enfocament basat en hipòtesi. El present tre- ball pretén identificar els patrons de connectivitat funcional de tot el cervell durant l’estat de repòs en un model de rosegador d’envelliment sa. Per a això, hem seguit el flux de treball estàndard proposat recentment en un document de consens sobre el processament d’imatges funcionals en RM preclínica. Hem establit un experiment de RM funcional longitudinal per a mesurar la connectivitat funcional en rates en diferents moments. S’ha utilitzat l’anàlisi de com- ponents independents per a identificar xarxes característiques en estat de repòs i comparar-les entre tres edats diferents, corresponents a l’edat adulta i a la senescència primerenca. L’objectiu és destacar els patrons específics de regió, sexe i edat que impulsen el declivi fisiològic de la cognició observat en la senescència, amb potencial per a identificar regions vulnerables i definir objectius d’intervenció. Els nostres resultats van descobrir patrons d’augment de la connec- tivitat funcional entre l’edat adulta i la senescència en diverses regions clau que controlen les funcions que se sap que es veuen afectades per l’edat. Aquest augment de la connectivitat pot explicar-se com un mecanisme compensatori que permet al cervell fer front a l

Supplementary Figures: Supplementary Figure 1. Short and long-term synaptic plasticity are preserved in the hippocampus of PD rats. (A) Pair pulse stimulation of the perforant pathway. Suprathreshold and equal intensity pairs of pulses (upper panel) are delivered at varying inter-stimulus time intervals (ISI). The results (lower panel) are expressed as the PS amplitude ratio (PS2/PS1). PS ratios below 1 indicate response depression and vice versa. Insets show pair pulse inhibition (left) and facilitation (right). (B) LTP of the perforant pathway. The upper panel shows the stimulation protocol used to induce LTP. Lower panel: synaptic potentiation in PD (orange) and control (black) rats quantified as the percentage increase of the PS amplitude after vs. before LTP induction. (C) Same as B but for the EPSP slope. (D) Evolution of the PS amplitude in response to perforant path stimulation before and 1 h after LTP induction. LTP protocol is applied at minute 6 (lasting 16 min) and PS amplitude is not tested until 1h later (grey shadow). The PS is normalized to pre-LTP measurements, and averaged across animals (n=5 per group). Data represents mean ± SEM. Supplementary Figure 2. Effect size of FA alterations in AUD patients analyzed with CSF correction (see Methods). Supplementary Figure 3. Effect size of FA alterations in a group of AUD patients chosen to avoid the age differences between groups. Supplementary Figure 4. Linear correlations between FA in the fimbria/fornix and cognitive variables: (A) NST, (B) TMT-A, (C) TMT-B, (D) number of perseverative errors in the WCST, (E) reaction times in the WCST, and (F) the Stroop test. (G) Correlation between FA in the fimbria/fornix and age. Supplementary Table 1. List of regions employed for the effect size analysis. Supplementary Table 2. List of cognitive test scores and age from AUD patients.

[Introduction] Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology., [Summary] Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Aim: Alcohol use disorder (AUD) is the most prevalent form of addiction, with a great burden on society and limited treatment options. A recent clinical trial reported significant clinical benefits of deep transcranial magnetic stimulations (Deep TMS) targeting midline frontocortical areas. However, the underlying biological substrate remained elusive. Here, we report the effect of Deep TMS on the microstructure of white matter.Methods: A total of 37 (14 females) AUD treatment-seeking patients were randomized to sham or active Deep TMS. Twenty (six females) age-matched healthy controls were included. White matter integrity was evaluated by fractional anisotropy (FA). Secondary measures included brain functional connectivity and self-reports of craving and drinking units in the 3 months of follow-up period.Results: White matter integrity was compromised in patients with AUD relative to healthy controls, as reflected by the widespread reduction in FA. This alteration progressed during early abstinence (3 weeks) in the absence of Deep TMS. However, stimulation of midline frontocortical areas arrested the progression of FA changes in association with decreased craving and relapse scores. Reconstruction of axonal tracts from white-matter regions showing preserved FA values identified cortical regions in the posterior cingulate and dorsomedial prefrontal cortices where functional connectivity was persistently modulated. These effects were absent in the sham-stimulated group.Conclusions: By integrating brain structure and function to characterize the alcohol-dependent brain, this study provides mechanistic insights into the TMS effect, pointing to myelin plasticity as a possible mediator., Funding Agencies|European Union [668863-SyBil-AA]; Spanish Ministerio de Ciencia e Innovacion, Agencia Estatal de Investigacion [PID2021-128158NB-C21, PID2021-128909NA-I00]; Programs for Centres of Excellence in R&D Severo Ochoa, Agencia Estatal de Investigacion [CEX2021-001165-S]; Swedish Research Council [100010434]; La Caixa Foundation [LCF/BQ/DI18/11660067, 713673]; Marie Sklodowska-Curie- COFUND [CIPROM/2022/15]; CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI); Spanish Generalitat Valenciana Government (PROMETEO) [CIDEGENT/2021/015]; [2013-07434]

Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) have been previously used to explore white matter related to human immunodeficiency virus (HIV) infection. While DTI and DKI suffer from low specificity, the Combined Hindered and Restricted Model of Diffusion (CHARMED) provides additional microstructural specificity. We used these three models to evaluate microstructural differences between 35 HIV-positive patients without neurological impairment and 20 healthy controls who underwent diffusion-weighted imaging using three b-values. While significant group effects were found in all diffusion metrics, CHARMED and DKI analyses uncovered wider involvement (80% vs. 20%) of all white matter tracts in HIV infection compared with DTI. In restricted fraction (FR) analysis, we found significant differences in the left corticospinal tract, middle cerebellar peduncle, right inferior cerebellar peduncle, right corticospinal tract, splenium of the corpus callosum, left superior cerebellar peduncle, left superior cerebellar peduncle, pontine crossing tract, left posterior limb of the internal capsule, and left/right medial lemniscus. These are involved in language, motor, equilibrium, behavior, and proprioception, supporting the functional integration that is frequently impaired in HIV-positivity. Additionally, we employed a machine learning algorithm (XGBoost) to discriminate HIV-positive patients from healthy controls using DTI and CHARMED metrics on an ROIwise basis, and unique contributions to this discrimination were examined using Shapley Explanation values. The CHARMED and DKI estimates produced the best performance. Our results suggest that biophysical multishell imaging, combining additional sensitivity and built-in specificity, provides further information about the brain microstructural changes in multimodal areas involved in attentive, emotional and memory networks often impaired in HIV patients.

While glia are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders, available methods for imaging these cells in vivo involve either invasive procedures or positron emission tomography radiotracers, which afford low resolution and specificity. Here, we present a noninvasive diffusion-weighted magnetic resonance imaging (MRI) method to image changes in glia morphology. Using rat models of neuroinflammation, degeneration, and demyelination, we demonstrate that diffusion-weighted MRI carries a fingerprint of microglia and astrocyte activation and that specific signatures from each population can be quantified noninvasively. The method is sensitive to changes in glia morphology and proliferation, providing a quantitative account of neuroinflammation, regardless of the existence of a concomitant neuronal loss or demyelinating injury. We prove the translational value of the approach showing significant associations between MRI and histological microglia markers in humans. This framework holds the potential to transform basic and clinical research by clarifying the role of inflammation in health and disease.

Software to analyse diffusion weighted MRI data collected with varying b-value/diffusion times to fit the AxCaliber model for white matter diffusion by Barazany et al. 2009, adapted for including different fiber orientations (De Santis et al, EMBC 2019)

[EN] Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol's progressively enhanced addictive potency

Preclinical MRI approaches constitute a key tool to study a wide variety of neurological and psychiatric illnesses, allowing a more direct investigation of the disorder substrate and, at the same time, the possibility of back-translating such findings to human subjects. However, the lack of consensus on the optimal experimental scheme used to acquire the data has led to relatively high heterogeneity in the choice of protocols, which can potentially impact the comparison between results obtained by different groups, even using the same animal model. This is especially true for diffusion-weighted MRI data, where certain experimental choices can impact not only on the accuracy and precision of the extracted biomarkers, but also on their biological meaning. With this in mind, we extensively examined preclinical imaging studies that used diffusion-weighted MRI to investigate neurodegenerative, neurodevelopmental and psychiatric disorders in rodent models. In this review, we discuss the main findings for each preclinical model, with a special focus on the analysis and comparison of the different acquisition strategies used across studies and their impact on the heterogeneity of the findings.

Neuroinflammation is currently a hot topic in brain research, due to its involvement in the pathogenesis of several neurodegenerative and psychiatric disorders. However, non-invasive techniques capable to characterize brain inflammation in vivo are lacking. Here, we present a strategy to image microglia and astrocyte activation in grey matter using diffusion MRI in rats, and demonstrate its translational value in humans.

Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol’s progressively enhanced addictive potency.

During aging, human white matter (WM) is subject to dynamic structural changes which have a deep impact on healthy and pathological evolution of the brain through the lifespan; characterizing this pattern is of key importance for understanding brain development, maturation, and aging as well as for studying its pathological alterations. Diffusion magnetic resonance imaging (MRI) can provide a quantitative assessment of the white-matter microstructural organization that characterizes these trajectories. Here, we use both conventional and advanced diffusion MRI in a cohort of 91 individuals (age range: 13–62 years) to study region- and sex-specific features of WM microstructural integrity in healthy aging. We focus on the age at which microstructural imaging parameters invert their development trend as the time point which marks the onset of microstructural decline in WM. Importantly, our results indicate that age-related brain changes begin earlier in males than females and affect more frontal regions—in accordance with evolutionary theories and numerous evidences across non-MRI domains. Advanced diffusion MRI reveals age-related WM modification patterns which cannot be detected using conventional diffusion tensor imaging.