Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived ...astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.
Delay discounting (DD) is a quantifiable psychological phenomenon that regulates decision-making. Nevertheless, the neural substrates of DD and its relationship with other cognitive domains are not ...well understood. The orbitofrontal cortex (OFC) is a potential candidate for supporting the expression of DD, but due to its wide involvement in several psychological functions and neural networks, its central role remains elusive. In this study, healthy subjects underwent transcranial direct current stimulation (tDCS) while performing an intertemporal choice task for the quantification of DD and a working memory task. To selectively engage the OFC, two electrode configurations have been tested, namely, anodal Fp1–cathodal Fp2 and cathodal Fp1–anodal Fp2. Our results show that stimulation of the OFC reduces DD, independently from electrode configuration. In addition, no relationship was found between DD measures and either working memory performance or baseline impulsivity assessed through established tests. Our work will direct future investigations aimed at unveiling the specific neural mechanisms underlying the involvement of the OFC in DD, and at testing the efficacy of OFC tDCS in reducing DD in psychological conditions where this phenomenon has been strongly implicated, such as addiction and eating disorders.
In decision making, the subjective value of a reward declines with the delay to its receipt, describing a hyperbolic function. Although this phenomenon, referred to as delay discounting (DD), has ...been extensively characterized and reported in many animal species, still, little is known about the neuronal processes that support it. Here, after drawing a comprehensive portrait, we consider the latest neuroimaging and lesion studies, the outcomes of which often appear contradictory among comparable experimental settings. In the second part of the manuscript, we focus on a more recent and effective route of investigation: non-invasive brain stimulation (NIBS). We provide a comprehensive review of the available studies that applied transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to affect subjects' performance in DD tasks. The aim of our survey is not only to highlight the superiority of NIBS in investigating DD, but also to suggest targets for future experimental studies, since the regions considered in these studies represent only a fraction of the possible ones. In particular, we argue that, based on the available neurophysiological evidence from lesion and brain imaging studies, a very promising and underrepresented region for future neuromodulation studies investigating DD is the orbitofrontal cortex.
Advancements in neuroscience research present opportunities and challenges, requiring substantial resources and funding. To address this, we describe here “Poke And Delayed Drink Intertemporal Choice ...Task (POKE‐ADDICT)”, an open‐source, versatile, and cost‐effective apparatus for intertemporal choice testing in rodents. This allows quantification of delay discounting (DD), a cross‐species phenomenon observed in decision making which provides valuable insights into higher‐order cognitive functioning. In DD, the subjective value of a delayed reward is reduced as a function of the delay for its receipt. Using our apparatus, we implemented an effective intertemporal choice paradigm for the quantification of DD based on an adjusting delayed amount (ADA) algorithm using mango juice as a reward. Our paradigm requires limited training, a few 3D‐printed parts and inexpensive electrical components, including a Raspberry Pi control unit. Furthermore, it is compatible with several in vivo procedures and the use of nose pokes instead of levers allows for faster task learning. Besides the main application described here, the apparatus can be further extended to implement other behavioral tests and protocols, including standard operant conditioning. In conclusion, we describe a versatile and cost‐effective design based on Raspberry Pi that can support research in animal behavior, decision making and, more specifically, delay discounting.
Poke And Delayed Drink Intertemporal Choice Task (POKE‐ADDICT) is an open‐source and cost‐effective apparatus for studying delay discounting (DD) in rodents, a phenomenon relevant to decision‐making and cognitive function. This versatile tool employs an adjusting delayed amount (ADA) algorithm with mango juice rewards, requiring minimal training. It's adaptable for human translation with monetary rewards, constructed using 3D‐printed components and a Raspberry Pi control unit. This setup facilitates rapid task learning using nose pokes, compatible with various in vivo procedures, and extensible for other behavioral tests. This Raspberry Pi‐based design offers a budget‐friendly solution for research in animal behavior, decision‐making, and DD.
First-line treatments for post-traumatic stress disorder (PTSD) encompass a wide range of pharmacotherapies and psychotherapies. However, many patients fail to respond to such interventions, ...highlighting the need for novel approaches. Due to its ability to modulate cortical activity, non-invasive brain stimulation (NIBS) could represent a valuable therapeutic tool. Therefore, the aim of this systematic review is to summarize and discuss the existing evidence on the ameliorative effects of NIBS on PTSD and comorbid anxiety and depressive symptoms. Our goal is also to debate the effectiveness of an integrated approach characterized by the combination of NIBS and psychotherapy. This search was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines in the PubMed, PsycINFO, PsycARTICLES, PSYINDEX, MEDLINE, and ERIC databases. Overall, 31 studies met the eligibility criteria, yielding a total of 26 clinical trials employing transcranial magnetic stimulation (TMS) and 5 making use of transcranial direct-current stimulation (tDCS). From these studies, it emerged that NIBS consistently reduced overall PTSD symptoms' severity as well as comorbid anxiety and depressive symptoms. Moreover, we speculate that combining NIBS with prolonged exposure or cognitive processing therapy might represent a promising therapeutic approach for consistently ameliorating subjects' clinical conditions.
The utilization of non-invasive neurostimulation techniques, such as transcranial magnetic stimulation (TMS), is increasingly prevalent in psychiatry due to their efficacy and safety. Although the ...precise therapeutic mechanisms remain partially unclear, repetitive TMS, particularly high-frequency stimulation, may enhance cognitive functions, contributing to therapeutic benefits. This within-subjects study examined the impact of TMS on cognitive and symptomatic outcomes in patients with obsessive–compulsive disorder (OCD), substance use disorder (SUD), and major depressive disorder (MDD). A total of 44 patients underwent cognitive tests and symptom assessments before and after an intensive four-week TMS treatment phase, followed by a four-week maintenance phase. Cognitive assessments included Raven’s matrices, verbal fluency, and digit span tests, while symptom severity was measured using the Italian version of the SCL-90-R. Decision-making performance was also evaluated by administering a delay discounting (DD) test. Principal component analysis was used to generate a dimensional characterization of subjects along cognitive and symptom-related axes before and after treatment. The results indicated that TMS significantly improved symptom scores, but no significant cognitive enhancement was observed. Statistical analysis based on linear mixed-effects models confirmed these findings, showing a significant fixed effect of TMS treatment on symptoms but not on cognitive performance. DD metrics remained unchanged. These findings suggest that while TMS effectively alleviates clinical symptoms, it does not produce consistent or appreciable enhancement of cognitive functions in these protocols. This study highlights the need for more personalized and combined therapeutic approaches to maximize the benefits of TMS, potentially incorporating cognitive enhancement strategies. Future studies will be useful to explore whether the results we obtained are valid for other pathologies, cognitive tests, and stimulation protocols.
Iron imbalance in neurodegeneration Levi, Sonia; Ripamonti, Maddalena; Moro, Andrea Stefano ...
Molecular psychiatry,
01/2024, Letnik:
29, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Iron is an essential element for the development and functionality of the brain, and anomalies in its distribution and concentration in brain tissue have been found to be associated with the most ...frequent neurodegenerative diseases. When magnetic resonance techniques allowed iron quantification in vivo, it was confirmed that the alteration of brain iron homeostasis is a common feature of many neurodegenerative diseases. However, whether iron is the main actor in the neurodegenerative process, or its alteration is a consequence of the degenerative process is still an open question. Because the different iron-related pathogenic mechanisms are specific for distinctive diseases, identifying the molecular mechanisms common to the various pathologies could represent a way to clarify this complex topic. Indeed, both iron overload and iron deficiency have profound consequences on cellular functioning, and both contribute to neuronal death processes in different manners, such as promoting oxidative damage, a loss of membrane integrity, a loss of proteostasis, and mitochondrial dysfunction. In this review, with the attempt to elucidate the consequences of iron dyshomeostasis for brain health, we summarize the main pathological molecular mechanisms that couple iron and neuronal death.
A PTSD subtype with dissociative symptoms (D-PTSD) was included in the DSM-5 recognizing the existence of a more severe form of PTSD, associated to past trauma, high comorbidity, and complex clinical ...management. As research is rapidly growing and results are inconsistent, a better investigation of this subtype is of primary importance. We conducted a systematic review of studies using Latent Profile Analysis to investigate the existence of a D-PTSD subtype. Covariates of D-PTSD were included, to understand additional symptoms, risk factors and comorbidities. The search was performed on PubMed, EBSCOHost, and PTSDPubs according to 2020 PRISMA guidelines. Eligible articles assessed trauma exposure, PTSD symptoms and diagnosis, and dissociation, in adult samples. 13 of 165 articles met the inclusion criteria. All identified a dissociative subtype of PTSD, mainly characterized by higher levels of depersonalization and derealization. D-PTSD profile sometimes presented other dissociative symptoms, such as gaps in awareness and memory, other comorbid disorders, and a history of abuse. Despite some limitations, this review supports the existence of a dissociative subgroup of individuals among those with PTSD. More rigorous studies are needed to clarify these findings and their clinical implications.
Metacognition encompasses the capability to monitor and control one's cognitive processes, with metamemory and metadecision configuring among the most studied higher order functions. Although imaging ...experiments evaluated the role of disparate brain regions, neural substrates of metacognitive judgments remain undetermined. The aim of this systematic review is to summarize and discuss the available evidence concerning the neural bases of metacognition which has been collected by assessing the effects of noninvasive brain stimulation (NIBS) on human subjects' metacognitive capacities. Based on such literature analysis, our goal is, at first, to verify whether prospective and retrospective second‐order judgments are localized within separate brain circuits and, subsequently, to provide compelling clues useful for identifying new targets for future NIBS studies. The search was conducted following the preferred reporting items for systematic reviews and meta‐analyses guidelines among PubMed, PsycINFO, PsycARTICLES, PSYNDEX, MEDLINE, and ERIC databases. Overall, 25 studies met the eligibility criteria, yielding a total of 36 experiments employing transcranial magnetic stimulation and 16 ones making use of transcranial electrical stimulation techniques, including transcranial direct current stimulation and transcranial alternating current stimulation. Importantly, we found that both perspective and retrospective judgments about both memory and perceptual decision‐making performances depend on the activation of the anterior and lateral portions of the prefrontal cortex, as well as on the activity of more caudal regions such as the premotor cortex and the precuneus. Combining this evidence with results from previous imaging and lesion studies, we advance ventromedial prefrontal cortex as a promising target for future NIBS studies.
We summarized the available evidence on neural correlates of metacognition gathered by assessing the effects of noninvasive brain stimulation on humans. Both perspective and retrospective second‐order judgments require an activation of anterior and lateral portions of the prefrontal cortex, as well as more caudal regions such as premotor cortex and precuneus.
Mitochondria and their dynamics fuel most cellular processes both in physiological and pathological conditions. In the central nervous system, mitochondria sustain synaptic transmission and ...plasticity via multiple mechanisms which include their redistribution and/or expansion to higher energy demanding sites, sustaining activity changes and promoting morphological circuit adaptations.
To be able to evaluate changes in mitochondrial number and protein phenotype, we propose a novel methodological approach where the simultaneous analysis of both mitochondrial DNA and protein content is performed on each individual microsample, avoiding non-homogeneous loss of material.
We validated this method on neuronal-like cells and tissue samples and obtained estimates for the mitochondrial/genomic DNA ratio as well as for the abundance of protein counterparts. When the mitochondrial content per cell was evaluated in different brain areas, our results matched the known regional variation in aerobic-anaerobic metabolism. When long-term potentiation (LTP) was induced on hippocampal neurons, we detected increases in the abundance of mitochondria that correlated with the degree of synaptic enhancement.
Our approach can be effectively used to study the mitochondrial content andits changes in different brain cells and tissues.
•Simultaneous analysis of mtDNA and proteins in brain cells and tissues is presented.•Mitochondrial content can be related to regional metabolic variations.•Synaptic potentiation drives mitochondrial rearrangement.
