Prenatal stress exposure (PSE) has been observed to exert a programming effect on the developing infant brain, possibly with long-lasting consequences on temperament, cognitive functions and the risk for developing psychiatric disorders. Several prior studies have revealed that PSE associates with alterations in neonate functional connectivity in the prefrontal regions and amygdala. In this study, we explored whether maternal psychological symptoms measured during the 24th gestational week had associations with neonate resting-state network metrics. 21 neonates (9 female) underwent resting-state fMRI scanning (mean gestation-corrected age at scan 26.95 days) to assess fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). The ReHO/fALFF maps were used in multiple regression analysis to investigate whether maternal self-reported anxiety and/or depressive symptoms associate with neonate functional brain features. Maternal psychological distress (composite score of depressive and anxiety symptoms) was positively associated with fALFF in the neonate medial prefrontal cortex (mPFC). Anxiety and depressive symptoms, assessed separately, exhibited similar but weaker associations. Post hoc seed-based connectivity analyses further showed that distal connectivity of mPFC covaried with PSE. No associations were found between neonate ReHo and PSE. These results offer preliminary evidence that PSE may affect functional features of the developing brain during gestation.
The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioral responses to standardized sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behavior-based diagnoses. One of these is Akinetic Mutism (AM), a rare neurological syndrome characterized by the inability to initiate volitional motor responses, sometimes associated with clinical presentations overlapping with those of DoC. Here we describe the case of a patient with large bilateral mesial frontal lesions showing a prolonged behavioral unresponsiveness and a severe disorganization of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented battery of multimodal longitudinal measurements encompassing spontaneous EEG, evoked potentials, event-related potentials, transcranial magnetic stimulation-evoked potentials, and structural and functional MRI, we provide (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of a complete AM, (ii) a plausible neurophysiological explanation of behavioral unresponsiveness and of its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case provides proof-of-principle evidence supporting the clinical utility of a multimodal hierarchical workflow combining conventional and advanced techniques to detect covert signs of consciousness in unresponsive patients.
Millions of people suffer from dopamine-related disorders spanning disturbances in movement, cognition and emotion, often attributed to changes in striatal dopamine function. Understanding how dopamine signaling in the striatum and basal ganglia shapes human behavior is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large scale brain networks and many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico-striatal loops sparks the question, whether dopamine signals in the basal ganglia serve an overarching computational principle which could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing, or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson’s disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition, as defined by the sequence effect or decrement of movement. Finally, we speculate on how therapeutic interventions such as deep brain stimulation (DBS) may be able to reinstate reinforcement signals and thereby improve treatment strategies of PD in the future.
Auditory processing and the complexity of neural activity can both indicate residual conscious-ness levels and differentiate between states of arousal. However, how measures of neural signal diversity, or complexity, manifest in evoked activity, and, more generally, how the electrophys-iological characteristics of auditory responses change in states of reduced consciousness, re-main under-explored. Here, we tested the hypothesis that measures of neural complexity and the spectral slope would discriminate stages of sleep not only in spontaneous EEG, but also in auditory-evoked responses. High-density EEG was recorded in 21 participants to determine the spatial relationship between these measures, and between spontaneous and auditory-evoked signals. Results showed that the complexity and the spectral slope in the 2-20 Hz range dis-criminated between sleep stages and had a high correlation in sleep. In wakefulness, complexity was strongly correlated to the 20-40 Hz spectral slope. Auditory stimulation resulted in reduced complexity in sleep compared to spontaneous activity and modulated the spectral slope in wake-fulness. These findings demonstrate the persistence of electrophysiological markers of arousal during both spontaneous and evoked EEG activity and have direct applications to studies using auditory stimulation to probe neural functions in states of reduced consciousness.
Astrocytes, glial cells in the central nervous system, perform a multitude of homeostatic functions and are in constant bidirectional communication with neuronal cells, a concept named the tripartite synapse, however their role in the dopamine homeostasis remains unexplored. The aim of this study was to clarify the pharmacological and molecular characteristics of dopamine transport in cultured cortical astrocytes of adult rats. In addition, we were interested in the expression of mRNA of dopamine transporters as well as dopamine receptors D1 and D2 and in the effect of dopaminergic drugs on the expression of these transporters and receptors. We have found that astrocytes possess both Na+-dependent and Na+-independent transporters. Uptake of radiolabelled dopamine was time-, temperature- and concentration-dependent and was inhibited by decynium-22, a plasma membrane monoamine transporter inhibitor, tricyclic antidepressants desipramine and nortriptyline, both inhibitors of the norepinephrine transporter. Results of transporter mRNA expression indicate that the main transporters involved in cortical astrocyte dopamine uptake are the norepinephrine transporter and plasma membrane monoamine transporter. Both dopamine receptor subtypes were identified in cortical astrocyte cultures. 24-hour treatment of astrocyte cultures with apomorphine, a D1/D2 agonist, induced upregulation of D1 receptor, norepinephrine transporter and plasma membrane monoamine transporter, whereas the latter was downregulated by haloperidol and L-DOPA. Astrocytes take up dopamine by multiple transporters and express dopamine receptors, which are sensitive to dopaminergic drugs. The findings of this study could open a promising area of research for the fine-tuning of existing therapeutic strategies.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. miR-221 is also implicated in promoting neuronal survival against oxidative stress and in promoting neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of this study; 1) miR-221 protects against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2) miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3) miR-221 has moderate predictive power for PD; 4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by manipulating the Akt signaling pathway, performs in controlling cell viability and apoptosis in PD. This review study suggests that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.
DYT1 dystonia is a form of generalized dystonia associated with abnormalities in striatal dopamine release in mouse models and likely in humans. In the present study, we examined the possibility that ultrastructural changes in the morphology of nigrostriatal dopamine terminals could contribute to this neurochemical imbalance using a Serial-Block Face/Scanning Electron Microscope (SBF/SEM) and three-dimensional reconstruction approach to analyze striatal tyrosine hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a DYT1(ΔE) Knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to study possible changes in vesicle packaging capacity of dopamine, we used transmission electron microscopy to assess possible changes in the size of synaptic vesicles in striatal dopamine terminals between wild type (WT) and the DYT1-KI mice. Quantitative analysis of 80 fully reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate: 1) No significant difference in the volume of TH-IR terminals between WT and DYT1-KI mice, 2) No major change in the proportion of axo-spinous vs axo-dendritic synapses formed by TH-IR terminals between the two groups, 3) No significant change in the post-synaptic density (PSD) area of axo-dendritic synapses, while the PSDs of axo-spinous synapses were significantly smaller in DYT1-KI mice, 4) No significant difference in the mean volume of mitochondria between WT mice and 5) No significant difference in the surface area of synaptic vesicles between the two groups. Altogether, these findings suggest that abnormal morphometric changes of nigrostriatal dopamine terminals and their post-synaptic targets are unlikely to be a major source of reduced striatal dopamine release in DYT1 dystonia.
Consciousness is one of final questions for humans to tackle in neuroscience. Due to the lack of understanding of the basic brain network and mechanisms of functions, our knowledge of consciousness remains at the theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal a basic brain network for consciousness. The projection from the thalamus to different cortical regions form a network of activities to maintain consciousness in human and animals. These feedback and feedforward circuits maintain the consciousness even in certain brain injury conditions. Proteins and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness, such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall, modify circuits and contribute to a high level of consciousness in certain populations.
Listening effort can be defined as a measure of cognitive resources used by listeners to perform a listening task. Several methods have been proposed to assess listening effort, but the reliability of these methods has not yet been thoroughly established, which is necessary before using them in research or clinical settings. This study included 32 participants who performed speech-in-noise tasks in two sessions (separated approx. 1 week apart) by listening to Sentences and Word lists presented at different signal-to-noise ratios (-9, -6, -3, and 0 dB). We assessed the test-retest reliability of the self-reported measure of listening effort and frontal midline theta (Fmθ) power, which has been proposed as a neural correlate of listening effort. The reliability of the percentage of correct words was also examined. Relative and absolute reliability was evaluated using intraclass correlation coefficients (ICC) and Bland-Altman analysis, respectively. The standard error of measurement (SEM) and the smallest detectable change (SDC) were also assessed. Overall, the reliability analysis revealed an acceptable between-session variability for the correct words and effort rating. However, Fmθ power showed high variability, which brings into question its use as a reliable correlate of listening effort.
Conventional transcranial direct-current stimulation (tDCS) delivered to the primary motor cortex (M1) has been shown to enhance implicit motor sequence learning (IMSL). Conventional tDCS targets M1 but also the motor association cortices (MAC), making the precise contribution of M1 to IMSL presently unclear. We aimed to address the roles of these areas by comparing conventional tDCS of M1 and MAC to High-Definition (HD) tDCS, which more focally targets M1. In this sham-controlled, crossover study in 89 healthy adults, we used mixed-effects models to analyze sequence-specific and general learning effects in the acquisition, short- and long-term consolidation phases of IMSL, as measured by the serial reaction time task. Conventional tDCS did not influence general learning, improved sequence-specific learning during acquisition (anodal: M=42.64 ms, sham: M=32.87 ms, p=.041) and deteriorated it at long-term consolidation (anodal: M=75.37 ms, sham: M=86.63 ms, p=.019). HD tDCS did not influence general learning, slowed performance specifically in sequential blocks across all learning phases (all p’s<.050), and consequently deteriorated sequence-specific learning during acquisition (anodal: M=24.13 ms, sham: M=35.67 ms, p=.014) and long-term consolidation (anodal: M=60.03 ms, sham: M=75.01 ms, p=.002). Our findings indicate that generalized stimulation of M1 and MAC enhanced acquisition, but hindered consolidation of IMSL. In contrast, focal M1 stimulation by HD tDCS worsened overall performance, likely due to cathodal inhibition of MAC as induced by the return electrodes. Consequently, this disruption of performance supports the notion that these areas fundamentally contribute to IMSL as an integral part in the cortico-basal ganglia-thalamo-cortical network.
Early life adversities alter the development of a still maturing nervous system and can have long-term consequences on its function at adult age. This include nociceptive circuits that are critical to shape an adaptive pain response to protect our organism from potentially damaging insults. As such, adult rats with a history of neonatal maternal separation (NMS) display a visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anesthetized adult rat during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat hindpaws. This nicely explains the hypernociceptive behaviors seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e. TRPV1, TRPM8, TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevated of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS is associated with a reduced spinal cord inhibition favoring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites as other NMS-associated symptoms include also excessive anxiety and impaired sociability.
Psychopathy is characterized by glibness and superficial charm, as well as a lack of empathy, guilt, and remorse, and is often accompanied by antisocial behavior. The cerebral bases of this syndrome have been mostly studied in violent subjects or those with a criminal history. However, the antisocial component of psychopathy is not central to its conceptualization and, in fact, psychopathic traits are present in well-adjusted, non-criminal individuals within the general population. Interestingly, certain psychopathy characteristics appear to be particularly pronounced in some groups or professions. Importantly, as these so-called adaptive or successful psychopaths do not show antisocial tendencies or have significant psychiatric comorbidities, they may represent an ideal population to study this trait. Here we investigated such a group, specifically elite female judo athletes, and compared them to matched non-athletes. Participants completed psychopathy, anger, perspective-taking and empathic concern questionnaires and underwent structural magnetic resonance imaging (MRI). Grey matter density (GMD) was computed using voxel-based morphometry from the T1-weighted images. Athletes scored significantly higher in primary psychopathy and anger, and lower in empathy and perspective taking. They also exhibited smaller GMD in the right Temporal Pole, left Occipital Cortex, and left Amygdala/Hippocampus. GMD values for the latter cluster significantly correlated with primary psychopathy scores across both groups. These results confirm and extend previous findings to a little-studied population and provide support for the conceptualization of psychopathy as a dimensional personality trait which, not only is not necessarily associated with antisocial behavior, but may potentially have adaptive value.
Schizophrenia and Autism Spectrum Disorder (ASD) can disrupt cognition and consequently behaviour. Traits of ASD and the subclinical manifestation of schizophrenia, schizotypy, have been studied in healthy populations with overlap found in trait profiles linking ASD social deficits to negative schizotypy, and ASD attention to detail to positive schizotypy. Here, we probed the relationship between sub-trait profiles, cognition and behaviour, using a predictive tracking task to measure individual eye movements under three gravity conditions. 48 healthy participants tracked an on-screen bouncing ball under familiar gravity, inverted antigravity and horizontal gravity control conditions while eye movements were recorded and dynamic performance quantified. Participants completed ASD and Schizotypy inventories generating highly correlated scores, r = 0.73. All tracked best under the gravity condition, producing anticipatory downward responses from stimulus onset under gravity which were delayed upwards under antigravity. Tracking performance was not associated with overall ASD or schizotypy trait levels. Combining measures using Principal Components Analysis (PCA), we decomposed the inventories into sub-traits unveiling interesting patterns. Positive Schizotypy was associated with ASD dimensions of rigidity, odd behaviour and face processing, and which all linked to anticipatory tracking responses under atypical antigravity. In contrast, negative schizotypy was associated with ASD dimensions of social interactions and rigidity, and to early stimulus-driven tracking under gravity. There was also substantial nonspecific overlap between ASD and Schizotypy dissociated from tracking. Our work links positive-odd traits with anticipatory tracking when physics rules are violated, and negative-social traits with the application of expected physics.
Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was however a significant increase in the amplitude of synaptically-induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 hours). Group 1 mGluR priming of LTP was abolished in ArckR mice, which could also potentially contribute to a depression of LTP. Although high frequency-stimulation (HFS)-induced LTP was not significantly different in ArcKR compared to WT mice (after 1 hour) there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses.
Alcohol abuse is not only responsible for 5.3% of the total deaths in the world, but also has a substantial impact on neurological and memory disabilities throughout the population. One extensively studied brain area involved in cognitive functions is the hippocampus. Evidence in several rodent models has shown that ethanol produces cognitive impairment in hippocampal-dependent tasks and that the damage is varied according to the stage of development at which the rodent was exposed to ethanol and the dose. To the authors’ knowledge, there is a biomarker for cognitive processes in the hippocampus that has not been evaluated in association with memory impairment by alcohol administration. This biomarker is called Sharp Wave Ripples which are synchronous neuronal population events that are well known to be involved in memory consolidation. Methodologies for facilitation or automatic identification of ripples and their analysis have been reported for a wider bandwidth than Sharp Wave Ripples. This review is focused on communicating the state-of-the art about the relationship between alcohol, memory consolidation and ripple activity as well as the use of the main methodologies to identify SWRs automatically.
It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signaling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. The cognitive ability was assessed by novel object recognition task (NORT) and Morris water maze (MWM) test. Immunofluorescence, Golgi-cox staining were used to observe dendritic synaptic. Gamma oscillation in hippocampus CA1 was performed by Tetrode in-vivo recording. Prostaglandins were measured by HPLC/mass spectrometry. We observed the expressions of cyclic adenosine monophosphate (cAMP)/ brain-derived neurotrophic factor (BDNF) pathway proteins in hippocampus and N2a cells by Elisa and western blot. We found COX-2 gene knockout (KO) could significantly impact the learning and memory ability; reduce the expression of postsynaptic density protein 95 (PSD95) in the neuron; cause synaptic disorder; influence gamma oscillation and reduce the expression prostaglandin (PG) E2, cAMP, phosphorylated protein kinase A (p-PKA), phosphorylated cAMP response element binding protein (p-CREB) and BDNF in the hippocampus. It suggested COX-2 might play a critical role in learning, regulating synaptic plasticity and gamma oscillation in the hippocampus CA1 by regulating COX-2/BDNF signaling pathway.
Sepsis is a life-threatening organ dysfunction that results from dysregulated host response to infection. Multiple organ system dysfunction syndromes are prevalent among septic patients and are essential hallmarks of sepsis diagnosis. These syndromes involve failure of the pulmonary, hepatic, circulatory, renal, gastrointestinal and central nervous systems. Neurological dysfunction is part of this syndrome and has gained research attention recently . Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioral deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioral impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective eﬀects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+-dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO) which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective eﬀects of SIRT1 in neuroinﬂammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.
Multimodal studies evaluating associations between specific for Parkinson’s disease (PD) neuroimaging and neurophysiological biomarkers in revealing executive dysfunction mechanisms are scarce and needed to be validated. Hence, our study aimed to evaluate associations between electroencephalographic power spectral density (PSD-EEG), striatal [18F]Fluorodopa uptake and neuropsychological testing parameters in PD. Additional aim was to estimate PD diagnostic accuracy of the PSD-EEG parameters. We compared resting PSD-EEG, striatal [18F]Fluorodopa uptake ratio with positron emission computed tomography ([18F]FDOPA PET/CT), and neuropsychological test outcomes between PD patients and healthy controls, and then calculated correlations among these outcomes. Additionally we estimated PD diagnostic sensitivity and specificity (with the receiver operating characteristic curves) of the PSD-EEG parameters in reference to the gold diagnostic standard of the striatal [18F]FDOPA PET/CT uptake ratio.PD patients exhibited (i) increased power of the EEG theta and lower-alpha bands in the frontal lobe areas, (ii) decreased putaminal and caudate nuclei [18F]FDOPA PET/CT uptake ratios and (iii) longer performance times of part A and B of the Trail Making Test (TMT-A and TMT-B). Most of the PSD-EEG parameters negatively correlated with striatal [18F]FDOPA PET/CT uptake ratios and positively correlated with TMT-A and TMT-B. Furthermore, [18F]FDOPA PET/CT uptake ratios positively correlated with TMT-A and TMT-B. Theta and lower-alpha bands PSD-EEG were found to have high diagnostic accuracy. Our findings showed that slowing of EEG waves in the frontal lobe was correlated with striatal dopaminergic deficiency and executive dysfunction in mild PD patients, and appears to be a promising biomarker of PD-related executive dysfunction.