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Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is a valid treatment for hematological oncological or metabolic diseases. Despite its therapeutic efficacy, it is an aggressive treatment that impacts negatively on quality of life (QoL) and may result in Post-Traumatic Stress Disorder (PTSD) symptoms. The aim of this study is to explore rates and risk factors for PTSD symptoms, and fatigue in post-HSCT patients with hematological malignancies., Methods: A total of 123 patients after HSCT were evaluated for PTSD symptoms, QoL and fatigue. PTSD symptoms were assessed with the Impact of Event Scale- Revised (IES-R), QoL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) and fatigue symptoms were assessed with Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)., Results: A total of 58.54% of the sample developed PTSD symptoms after transplant. Patients with PTSD symptoms reported significantly lower QoL total scores and significantly higher fatigue than those without PTSD symptoms ( p < 0.001). The SEM analysis showed that worse QoL and fatigue affected PTSD symptomatology along different pathways. Fatigue was found as a major influencing factor of PTSD symptoms directly (β = 0.31 **), while QoL only through the mediation of fatigue at a lesser extent. (β = 0.33 *)., Conclusions: Our findings indicate that QoL is a concurrent causative factor to the development of PTSD symptomatology through the mediating role of fatigue. Innovative interventions before transplantation to prevent PTSD symptoms should be investigated to improve survival and QoL in patients.

Background: Olfaction impairment in aging is associated with increased anxiety. We explored this association in cognitively healthy controls (HCs), Mild Cognitive Impairment (MCI) and Parkinson's disease (PD) patients. Both olfaction and anxiety have sex differences, therefore we also investigated these variances., Objectives: Investigate the association of olfaction with anxiety in three distinct clinical categories of aging, exploring the potential role of sex., Methods: 117 subjects (29 HCs, 43 MCI, and 45 PD patients) were assessed for olfaction and anxiety. We used regression models to determine whether B-SIT predicted anxiety and whether sex impacted that relationship., Results: Lower olfaction was related to greater anxiety traits in all groups (HCs: p = 0.015; MCI: p = 0.001 and PD: p = 0.038), significantly differed by sex. In fact, in HCs, for every unit increase in B-SIT, anxiety traits decreased by 7.63 in men ( p = 0.009) and 1.5 in women ( p = 0.225). In MCI patients for every unit increase in B-SIT, anxiety traits decreased by 1.19 in men ( p = 0.048) and 3.03 in women ( p = 0.0036). Finally, in PD patients for every unit increase in B-SIT, anxiety traits decreased by 1.73 in men ( p = 0.004) and 0.41 in women ( p = 0.3632)., Discussion: Olfaction and anxiety are correlated in all three distinct diagnostic categories, but differently in men and women.

Introduction: Late onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women., Hypothesis: We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women., Methods: We studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed., Result: Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men., Conclusion: Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD., Significance Statement: Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes., (© The Author(s) 2022. Published by Oxford University Press.)

Time exists in us, and our self exists in time. Our self is affected and shaped by time to the point that a better understanding of the former can aid the understanding of the latter. Psychoanalysis works through self and time, where the self is composed of the biopsychosocial history (the past) of the individual and able to map a trajectory for the future. The psychoanalytic relationship starts from a "measurement": an active process able to alter the system being measured-the self-continuously built over time. This manuscript, starts from the philosophical and scientific tradition of a proximity between time and self, suggesting a neural overlapping at the Default Network. A historical and scientific background will be introduced, proposing a multidisciplinary dimension that has characterized the birth of psychoanalysis (its past), influencing its present and future in the dialogue with physics and neuroscience. After a historical scientific introduction, a neural entanglement between past and future at the Default Network level will be proposed, tracing a link with the self at the level of this network. This hypothesis will be supported by studies in cognitive neurosciences and functional neuroimaging which have used the resting state functional Magnetic Resonance Imaging. The ontogenetic development of time perception will be discussed, consistent with self-development and the Default Network's function. The most common form of dementia, the Alzheimer's Disease, in which the perception of time is brutally impaired together with a loss of the self's functions will be proposed to support this idea. Finally, the potential theoretical and clinical significance for psychoanalysis and psychodynamic neurosciences, will be discussed., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cieri.)

Background: An aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia. This neurodegenerative disease disproportionately affects women., Methods: We use data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine sex differences in cortical thickness (CT) and memory performance. Analyses of covariance (ANCOVA) models were used to examine effects of sex and diagnosis (DX) on CT and verbal memory. For regions demonstrating significant interaction effects of sex and DX, we tested whether sex moderated cognition-thickness relationships. We used machine learning as a complementary method to explore multivariate CT differences between women and men., Results: Women demonstrated greater CT in many brain regions. More specifically, men showed relatively consistent CT declines in all stages, from normal control (NC) to ADD in the bilateral cingulate cortex, bilateral temporal regions, and left precuneus; women had more stable CT in these regions between NC and mild cognitive impairment (MCI) stages, but sharper declines from MCI to ADD. Similarly, for the Rey Auditory Verbal Learning Test (RAVLT), ANCOVA analyses showed that women had significantly better immediate and delayed recall scores than men, at NC and MCI stages, but greater differences, cross-sectionally, from MCI to ADD than men. We found significant sex moderation effects between RAVLT-immediate scores and CT of right isthmus-cingulate for all subjects across DX. Partial correlation analyses revealed that increased CT of right isthmus-cingulate was associated with better verbal learning in women, driven by positron emission tomography defined amyloid positive (Aβ+) subjects. Significant sex-moderation effects in cognition-thickness relationships were further found in the right middle-temporal, left precuneus, and left superior temporal regions in Aβ+ subjects. Using a machine learning approach, we investigated multivariate CT differences between women and men, showing an accuracy in classification of 75% for Aβ+ cognitively NC participants., Conclusions: Sex differences in memory and CT can play a key role in the different vulnerability and progression of ADD in women compared to men. Machine learning indicates sex differences in CT are most relevant early in the ADD neurodegeneration., (© 2022. The Author(s).)

Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene ( SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45 Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway., Competing Interests: The authors declare no competing interest.

Neural complexity and brain entropy (BEN) have gained greater interest in recent years. The dynamics of neural signals and their relations with information processing continue to be investigated through different measures in a variety of noteworthy studies. The BEN of spontaneous neural activity decreases during states of reduced consciousness. This evidence has been showed in primary consciousness states, such as psychedelic states, under the name of "the entropic brain hypothesis." In this manuscript we propose an extension of this hypothesis to physiological and pathological aging. We review this particular facet of the complexity of the brain, mentioning studies that have investigated BEN in primary consciousness states, and extending this view to the field of neuroaging with a focus on resting-state functional Magnetic Resonance Imaging. We first introduce historic and conceptual ideas about entropy and neural complexity, treating the mindbrain as a complex nonlinear dynamic adaptive system, in light of the free energy principle. Then, we review the studies in this field, analyzing the idea that the aim of the neurocognitive system is to maintain a dynamic state of balance between order and chaos, both in terms of dynamics of neural signals and functional connectivity. In our exploration we will review studies both on acute psychedelic states and more chronic psychotic states and traits, such as those in schizophrenia, in order to show the increase of entropy in those states. Then we extend our exploration to physiological and pathological aging, where BEN is reduced. Finally, we propose an interpretation of these results, defining a general trend of BEN in primary states and cognitive aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cieri, Zhuang, Caldwell and Cordes.)

Purpose: Resting-state functional Magnetic Resonance Imaging studies revealed that the brain is organized into specialized networks constituted by regions that show a coherent fluctuation of spontaneous activity. Among these networks, the cingulate cortex appears to play a crucial role, particularly in the default mode network, the dorsal attention network and the salience network. In the present study, we mapped the functional connectivity (FC) pattern of different regions of the cingulate cortex: the anterior cingulate cortex, midcingulate cortex and posterior cingulate cortex/retro splenial cortex, which have been in turn divided into a total of 9 subregions. We compared FC patterns of the cingulate subregions in a sample of mild cognitive impairment patients and healthy elderly subjects., Methods: We enrolled 19 healthy elders (age range: 61-72 y.o.) and 16 Mild cognitive impairment patients (age range 64-87 y.o.). All participants had comparable levels of education (8-10 years) and were neurologically examined to exclude visual and motor impairments, major medical conditions, psychiatric or neurological disorders and consumption of psychotropic drugs. The diagnosis of mild cognitive impairment was performed according to Petersen criteria. Subjects were evaluated with Mini-Mental State Examination, Frontal Assessment Battery, and prose memory (Babcock story) tests. In addition, with functional Magnetic Resonance Imaging, we investigated resting-state network activities., Results: Healthy elderly, compared to mild cognitive impairment, showed significant increased level of FC for the ventral part of the anterior cingulate cortex in correspondence to the bilateral caudate and ventromedial prefrontal cortex. Moreover, for the midcingulate cortex the healthy elderly group showed increased levels of FC in the somatomotor region, prefrontal cortex, and superior parietal lobule. Meanwhile, the mild cognitive impairment group showed an increased level of FC for the superior frontal gyrus, frontal eye field and orbitofrontal cortex compared to the healthy elderly group., Conclusion: Our findings indicate that cognitive decline observed in mild cognitive impairment patients damages the global FC of the cingulate cortex, supporting the idea that abnormalities in resting-state activities of the cingulate cortex could be a useful additional tool in order to better understand the brain mechanisms of MCI., (Copyright © 2019 Cera, Esposito, Cieri and Tartaro.)

In 1895 in the Project for a Scientific Psychology, Freud tried to integrate psychology and neurology in order to develop a neuroscientific psychology. Since 1880, Freud made no distinction between psychology and physiology. His papers from the end of the 1880s to 1890 were very clear on this scientific overlap: as with many of his contemporaries, Freud thought about psychology essentially as the physiology of the brain. Years later he had to surrender, realizing a technological delay, not capable of pursuing its ambitious aim, and until that moment psychoanalysis would have to use its more suitable clinical method. Also, he seemed skeptical about phrenology drift, typical of that time, in which any psychological function needed to be located in its neuroanatomical area. He could not see the progresses of neuroscience and its fruitful dialogue with psychoanalysis, which occurred also thanks to the improvements in the field of neuroimaging, which has made possible a remarkable advance in the knowledge of the mind-brain system and a better observation of the psychoanalytical theories. After years of investigations, deriving from research and clinical work of the last century, the discovery of neural networks, together with the free energy principle, we are observing under a new light psychodynamic neuroscience in its exploration of the mind-brain system. In this manuscript, we summarize the important developments of psychodynamic neuroscience, with particular regard to the free energy principle, the resting state networks, especially the Default Mode Network in its link with the Self, emphasizing our view of a bridge between psychoanalysis and neuroscience. Finally, we suggest a discussion by approaching the concept of Alpha Function, proposed by the psychoanalyst Wilfred Ruprecht Bion, continuing the association with neuroscience.

Anorexia nervosa is a severe psychiatric illness characterized by intense fear of gaining weight, relentless pursuit of thinness, deep concerns about food and a pervasive disturbance of body image. Functional magnetic resonance imaging tries to shed light on the neurobiological underpinnings of anorexia nervosa. This review aims to evaluate the empirical neuroimaging literature about self-perception in anorexia nervosa. This narrative review summarizes a number of task-based and resting-state functional magnetic resonance imaging studies in anorexia nervosa about body image and self-perception. The articles listed in references were searched using electronic databases (PubMed and Google Scholar) from 1990 to February 2016 using specific key words. All studies were reviewed with regard to their quality and eligibility for the review. Differences in brain activity were observed using body image perception and body size estimation tasks showing significant modifications in activity of specific brain areas (extrastriate body area, fusiform body area, inferior parietal lobule). Recent studies highlighted the role of emotions and self-perception in anorexia nervosa and their neural substrate involving resting-state networks and particularly frontal and posterior midline cortical structures within default mode network and insula. These findings open new horizons to understand the neural substrate of anorexia nervosa., (© 2016 The British Psychological Society.)

Resting state brain activity incorporates different components, including the Default Mode Network and the Dorsal Attention Network, also known as task-negative network and task-positive network respectively. These two networks typically show an anticorrelated activity during both spontaneous oscillations and task execution. However modifications of this anticorrelated activity pattern with age and pathology are still unclear. The present study aimed to investigate differences in resting state Default Mode Network-Dorsal Attention Network functional anticorrelation among young adults, healthy elders and Mild Cognitive Impairment patients. We retrospectively enrolled in this study 27 healthy young adults (age range: 25-35 y.o.; mean age: 28,5), 26 healthy elders (age range: 61-72 y.o.; mean age: 65,1) and 17 MCI patients (age range 64-87 y.o.; mean age: 73,6). Mild Cognitive Impairment patients were selected following Petersen criteria. All participants underwent neuropsychological evaluation and resting state functional Magnetic Resonance Imaging. Spontaneous anticorrelated activity between Default Mode Network and Dorsal Attention Network was observed in each group. This anticorrelation was significantly decreased with age in most Default Mode Network-Dorsal Attention Network connections (p < 0.001, False Discovery Rate corrected). Moreover, the anticorrelation between the posterior cingulate cortex node of the Default Mode Network and the right inferior parietal sulcus node of the Dorsal Attention Network was significantly decreased when comparing Mild Cognitive Impairment with normal elders (p < 0.001, False Discovery Rate corrected). The functional connectivity changes in patients were not related to significant differences in grey matter content. Our results suggest that a reduced anticorrelated activity between Default Mode Network and Dorsal Attention Network is part of the normal aging process and that Mild Cognitive Impairment status is associated with more evident inter-networks functional connectivity changes.

Resting state functional magnetic resonance imaging (rs-fMRI) allows studying spontaneous brain activity in absence of task, recording changes of Blood Oxygenation Level Dependent (BOLD) signal. rs-fMRI enables identification of brain networks also called Resting State Networks (RSNs) including the most studied Default Mode Network (DMN). The simplicity and speed of execution make rs-fMRI applicable in a variety of normal and pathological conditions. Since it does not require any task, rs-fMRI is particularly useful for protocols on patients, children, and elders, increasing participant's compliance and reducing intersubjective variability due to the task performance. rs-fMRI has shown high sensitivity in identification of RSNs modifications in several diseases also in absence of structural modifications. In this narrative review, we provide the state of the art of rs-fMRI studies about physiological and pathological aging processes. First, we introduce the background of resting state; then we review clinical findings provided by rs-fMRI in physiological aging, Mild Cognitive Impairment (MCI), Alzheimer Dementia (AD), and Late Life Depression (LLD). Finally, we suggest future directions in this field of research and its potential clinical applications.

Late-life depression (LLD) is a common emotional and mental disability in the elderly population characterized by the presence of depressed mood, the loss of interest or pleasure in daily activities, and other depression symptoms. It has a serious effect on the quality of life of elderly individuals and increases their risk of developing physical and mental diseases. It is an important area of research, given the growing elderly population. Brain functional connectivity modifications represent one of the neurobiological biomarker for LLD even if to date remains poorly understood. In our study, we enrolled 10 elderly patients with depressive symptoms compared to 11 age-matched healthy controls. All participants were evaluated by means of neuropsychological tests and underwent the same functional magnetic resonance imaging (fMRI) protocol to evaluate modifications of brain resting state functional connectivity. Between-group differences were observed for the Geriatric Depression Scale and Hamilton Depression Rating Scale, with higher scores for patients with LLD. Voxel-wise, 1-way analysis of variance revealed between-group differences in left frontoparietal network (lFPN) and sensory motor network (SMN): Increased intrinsic connectivity in the LLD group was observed in the left dorsolateral prefrontal cortex and in the left superior parietal lobule of the lFPN and increased intrinsic connectivity in the LLD group was observed in the bilateral primary somatosensory cortex of the SMN. Our findings support the use of resting state fMRI as a potential biomarker for LLD; even if to confirm the relationship between brain changes and the pathophysiology of LLD, longitudinal neuroimaging studies are required.

Background: The association between alexithymia and post-traumatic stress disorder (PTSD) symptoms has been demonstrated in several studies, but never in victims of a collective trauma such as a natural disaster, which has an impact on an entire community., Aims: The aim was to assess the relationship between alexithymia and post-traumatic symptoms in a group of people who lived in L'Aquila exposed to the earthquake that hit the town in 2009., Methods: Eighty-seven participants were included and assessed for alexithymia, PTSD symptoms, depression, anxiety, and psychiatric symptoms. Linear regression models were used to test the hypothesis., Results: The main finding was an association between "Difficulty-Describing-Feelings" and the intensity of post-traumatic symptoms in the worst month after trauma. Depression, anxiety and psychiatric comorbidity also showed a significant association with PTSD symptoms., Conclusions: In the present study of a collectively shared trauma, the alexithymic factor "difficulty-describing-feelings" was significantly associated with the intensity of post-traumatic symptoms.