Alpha/beta-gamma decoupling in methylphenidate medicated ADHD patients.

There is much interest to understand how different neural rhythms function, interact and are regulated. Here, we focus on WM delay gamma to investigate its coupling with alpha/beta rhythms and its neuromodulation by methylphenidate. We address this through the use of human EEG conducted in healthy and ADHD subjects which revealed ADHD-specific electrophysiological deficits and MPH-induced normalization of gamma amplitude and its coupling with alpha/beta rhythms. Decreased alpha/beta-gamma coupling is known to facilitate memory representations via disinhibition of gamma ensembles coding the maintained stimuli. Here, we present EEG evidence which suggests that these dynamics are sensitive to catecholaminergic neuromodulation. MPH decreased alpha/beta-gamma coupling and this was related to the increase in delay-relevant gamma activity evoked by the same drug. These results add further to the neuromodulatory findings that reflect an electrophysiological dimension to the well-known link between WM delay and catecholaminergic transmission.

Occipital Intralobar fasciculi: a description, through tractography, of three forgotten tracts.

Diffusion MRI paired with tractography has facilitated a non-invasive exploration of many association, projection, and commissural fiber tracts. However, there is still a scarcity of research studies related to intralobar association fibers. The Dejerines' (two of the most notable neurologists of 19th century France) gave an in-depth description of the intralobar fibers of the occipital lobe. Unfortunately, their exquisite work has since been sparsely cited in the modern literature. This work gives a modern description of many of the occipital intralobar lobe fibers described by the Dejerines. We perform a virtual dissection and reconstruct the tracts using diffusion MRI tractography. The dissection is guided by the Dejerines' treatise, Anatomie des Centres Nerveux. As an accompaniment to this article, we provided a French-to-English translation of the treatise portion concerning five intra-occipital tracts, namely: the stratum calcarinum, the stratum proprium cunei, the vertical occipital fasciculus of Wernicke, the transverse fasciculus of the cuneus and the transverse fasciculus of the lingual lobule of Vialet. It was possible to reconstruct all but one of these tracts. For completeness, the recently described sledge runner fasciculus, although not one of the Dejerines' tracts, was identified and successfully reconstructed.

A tutorial and tool for exploring feature similarity gradients with MRI data.

There has been an increasing interest in examining organisational principles of the cerebral cortex (and subcortical regions) using different MRI features such as structural or functional connectivity. Despite the widespread interest, introductory tutorials on the underlying technique targeted for the novice neuroimager are sparse in the literature. Articles that investigate various "neural gradients" (for example based on region studied "cortical gradients," "cerebellar gradients," "hippocampal gradients" etc … or feature of interest "functional gradients," "cytoarchitectural gradients," "myeloarchitectural gradients" etc …) have increased in popularity. Thus, we believe that it is opportune to discuss what is generally meant by "gradient analysis". We introduce basics concepts in graph theory, such as graphs themselves, the degree matrix, and the adjacency matrix. We discuss how one can think about gradients of feature similarity (the similarity between timeseries in fMRI, or streamline in tractography) using graph theory and we extend this to explore such gradients across the whole MRI scale; from the voxel level to the whole brain level. We proceed to introduce a measure for quantifying the level of similarity in regions of interest. We propose the term "the Vogt-Bailey index" for such quantification to pay homage to our history as a brain mapping community. We run through the techniques on sample datasets including a brain MRI as an example of the application of the techniques on real data and we provide several appendices that expand upon details. To maximise intuition, the appendices contain a didactic example describing how one could use these techniques to solve a particularly pernicious problem that one may encounter at a wedding. Accompanying the article is a tool, available in both MATLAB and Python, that enables readers to perform the analysis described in this article on their own data. We refer readers to the graphical abstract as an overview of the analysis pipeline presented in this work.

Beta band oscillatory deficits during working memory encoding in adolescents with attention-deficit hyperactive disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder, characterized by symptoms of inattention and/or hyperactivity/impulsivity, in addition to various cognitive deficits, including working memory impairments. This pathology arises from a complex constellation of genetic, structural and neurotransmission abnormalities, which give rise to the aberrant electrophysiological patterns evident in patients with ADHD. Among such, findings have consistently provided support in favour of weaker power across the beta frequency range. Evidence has also emerged that beta rhythmic decrements are linked to working memory encoding. The catecholaminergic modulation of both working memory and beta oscillations may suggest that the link between the two might be rooted at the neurotransmission level. Studies have consistently shown that ADHD involves significant catecholaminergic dysregulation, which is also supported by other clinical studies that demonstrate stimulant-induced amelioration of ADHD symptomology. In this study, we explore the possible ways that might relate ADHD, working memory, beta rhythms and catecholaminergic signalling altogether by investigating the integrity of encoding-relevant electroencephalographic beta rhythms in medication-naïve and stimulant-medicated adolescent patients. The aberrant parietal and frontal encoding-related beta rhythm revealed in the ADHD patients together with a working memory (WM) deficit as observed herein was reversed by methylphenidate in the latter case but not with regard to the beta rhythm. This finding per se raises the issue of the role played by beta rhythms in the WM deficits associated with ADHD.

Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding.

To facilitate scalable profiling of single cells, we developed split-pool ligation-based transcriptome sequencing (SPLiT-seq), a single-cell RNA-seq (scRNA-seq) method that labels the cellular origin of RNA through combinatorial barcoding. SPLiT-seq is compatible with fixed cells or nuclei, allows efficient sample multiplexing, and requires no customized equipment. We used SPLiT-seq to analyze 156,049 single-nucleus transcriptomes from postnatal day 2 and 11 mouse brains and spinal cords. More than 100 cell types were identified, with gene expression patterns corresponding to cellular function, regional specificity, and stage of differentiation. Pseudotime analysis revealed transcriptional programs driving four developmental lineages, providing a snapshot of early postnatal development in the murine central nervous system. SPLiT-seq provides a path toward comprehensive single-cell transcriptomic analysis of other similarly complex multicellular systems.

Working memory alpha-beta band oscillatory signatures in adolescents and young adults.

The timing of neural activity is an intriguing way of exposing behaviorally relevant neural activity, as neural populations exploit transient windows of synchronized activations to exchange dynamic communications in the service of various cognitive operations. The link between neural synchrony and working memory (WM) has been supported at the theoretical and empirical level. However, findings have also shown that WM encoding is also related to significant alpha-beta desynchronization. These findings have been primarily recorded during subsequent memory effect paradigms that compare correct with incorrect encoding trials. The dissociable contribution imparted by various processes to WM performance suggests that incorrect performance may not be directly translatable to unsuccessful encoding. Here, we address the relationship between alpha-beta desynchronization and encoding through the use of an alternative paradigm design by contrasting frontal and parietal human scalp electroencephalography activity during the encoding interval of a delayed matching-to-sample task with that recorded during a control task. The additional use of non-verbal/semantic visual stimulation and recruitment of typically developing adolescent subjects has led us to the conclusion that encoding-relevant alpha-beta decrements can be replicated via a non-verbal/semantic delayed matching-to-sample task and these are also evident in typically developing adolescents, in addition to adults, as has been previously demonstrated. The identification of encoding-related alpha-beta decrements in adolescent subjects performing such WM tasks may open new avenues to explore whether such a rhythmic signature may explain WM and electrophysiological deficits that emerge in various adolescent neuropsychiatric disorders such as attention deficit hyperactivity disorder.

A spatially localized architecture for fast and modular DNA computing.

Cells use spatial constraints to control and accelerate the flow of information in enzyme cascades and signalling networks. Synthetic silicon-based circuitry similarly relies on spatial constraints to process information. Here, we show that spatial organization can be a similarly powerful design principle for overcoming limitations of speed and modularity in engineered molecular circuits. We create logic gates and signal transmission lines by spatially arranging reactive DNA hairpins on a DNA origami. Signal propagation is demonstrated across transmission lines of different lengths and orientations and logic gates are modularly combined into circuits that establish the universality of our approach. Because reactions preferentially occur between neighbours, identical DNA hairpins can be reused across circuits. Co-localization of circuit elements decreases computation time from hours to minutes compared to circuits with diffusible components. Detailed computational models enable predictive circuit design. We anticipate our approach will motivate using spatial constraints for future molecular control circuit designs.

Brain Symmetry Index in Healthy and Stroke Patients for Assessment and Prognosis.

Objective. Quantitative neurophysiological signal parameters are of value in predicting motor recovery after stroke. The novel role of EEG-derived brain symmetry index for motor function prognostication in the subacute phase after stroke is explored. Methods. Ten male stroke patients and ten matched healthy controls were recruited. Motor function was first assessed clinically using the MRC score, its derivative Motricity Index, and the Fugl-Meyer assessment score. EEG was subsequently recorded first with subjects at rest and then during hand grasping motions, triggered by visual cues. Brain symmetry index (BSI) was used to identify the differences in EEG-quantified interhemispheric cortical power asymmetry observable in healthy versus cortical and subcortical stroke patients. Subsequently, any correlation between BSI and motor function was explored. Results. BSI was found to be significantly higher in stroke subjects compared to healthy controls (p = 0.023). The difference in BSI was more pronounced in the cortical stroke subgroup (p = 0.016). BSI showed only a mild general decrease on repeated monthly recording. Notably, a statistically significant correlation was observed between early BSI and Fugl-Meyer score later in recovery (p < 0.050). Conclusions. Brain symmetry index is increased in the subacute poststroke phase and correlates with motor function 1-2 months after stroke.

An autonomous molecular assembler for programmable chemical synthesis.

Molecular machines that assemble polymers in a programmed sequence are fundamental to life. They are also an achievable goal of nanotechnology. Here, we report synthetic molecular machinery made from DNA that controls and records the formation of covalent bonds. We show that an autonomous cascade of DNA hybridization reactions can create oligomers, from building blocks linked by olefin or peptide bonds, with a sequence defined by a reconfigurable molecular program. The system can also be programmed to achieve combinatorial assembly. The sequence of assembly reactions and thus the structure of each oligomer synthesized is recorded in a DNA molecule, which enables this information to be recovered by PCR amplification followed by DNA sequencing.

DNA nanotechnology from the test tube to the cell.

The programmability of Watson-Crick base pairing, combined with a decrease in the cost of synthesis, has made DNA a widely used material for the assembly of molecular structures and dynamic molecular devices. Working in cell-free settings, researchers in DNA nanotechnology have been able to scale up system complexity and quantitatively characterize reaction mechanisms to an extent that is infeasible for engineered gene circuits or other cell-based technologies. However, the most intriguing applications of DNA nanotechnology - applications that best take advantage of the small size, biocompatibility and programmability of DNA-based systems - lie at the interface with biology. Here, we review recent progress in the transition of DNA nanotechnology from the test tube to the cell. We highlight key successes in the development of DNA-based imaging probes, prototypes of smart therapeutics and drug delivery systems, and explore the future challenges and opportunities for cellular DNA nanotechnology.

Acute nicotine induces anxiety and disrupts temporal pattern organization of rat exploratory behavior in hole-board: a potential role for the lateral habenula.

Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic-like effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.

The central role of aquaporins in the pathophysiology of ischemic stroke.

Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

Hsp60 response in experimental and human temporal lobe epilepsy.

The mitochondrial chaperonin Hsp60 is a ubiquitous molecule with multiple roles, constitutively expressed and inducible by oxidative stress. In the brain, Hsp60 is widely distributed and has been implicated in neurological disorders, including epilepsy. A role for mitochondria and oxidative stress has been proposed in epileptogenesis of temporal lobe epilepsy (TLE). Here, we investigated the involvement of Hsp60 in TLE using animal and human samples. Hsp60 immunoreactivity in the hippocampus, measured by Western blotting and immunohistochemistry, was increased in a rat model of TLE. Hsp60 was also increased in the hippocampal dentate gyrus neurons somata and neuropil and hippocampus proper (CA3, CA1) of the epileptic rats. We also determined the circulating levels of Hsp60 in epileptic animals and TLE patients using ELISA. The epileptic rats showed circulating levels of Hsp60 higher than controls. Likewise, plasma post-seizure Hsp60 levels in patients were higher than before the seizure and those of controls. These results demonstrate that Hsp60 is increased in both animals and patients with TLE in affected tissues, and in plasma in response to epileptic seizures, and point to it as biomarker of hippocampal stress potentially useful for diagnosis and patient management.

Cerebral white matter injuries following a hypoxic/ischemic insult during the perinatal period: pathophysiology, prognostic factors, and future strategy of treatment approach. A minireview.

Recent advances in medical care have significantly improved the survival rate of neonates who suffer a hypoxic/ ischemic event, before, during, or after birth. These infants are extremely vulnerable to brain injury and are at high risk of developing motor and cognitive abnormalities later on in life. The regional distribution of perinatal brain injury varies, and depends primarily on; the severity, pattern and type of insult, the metabolic status, and on the gestational age. The principal neuropathological substrate that is affected in the premature infant is cerebral white matter. The aim of this article is to re-examine the current knowledge on the ischemic pathophysiology of all cellular components that comprise the white matter, pred ict the consequences of the long-term neurological outcome, and analyze possible therapeutic strategies. Although oligodendrocytes have long been regarded as the hallmark of perinatal white matter injury, axons, astrocytes and microglia, all contribute to the complex pattern of brain injury that occurs in this cohort of individuals. It is hoped that a better understanding of the pathophysiology of white matter injury and its underlying prognostic factors, may lead to the development of new therapeutic strategies for such a complex and debilitating condition.

MicroRNA-based single-gene circuits buffer protein synthesis rates against perturbations.

Achieving precise control of mammalian transgene expression has remained a long-standing, and increasingly urgent, challenge in biomedical science. Despite much work, single-cell methods have consistently revealed that mammalian gene expression levels remain susceptible to fluctuations (noise) and external perturbations. Here, we show that precise control of protein synthesis can be realized using a single-gene microRNA (miRNA)-based feed-forward loop (sgFFL). This minimal autoregulatory gene circuit consists of an intronic miRNA that targets its own transcript. In response to a step-like increase in transcription rate, the network generated a transient protein expression pulse before returning to a lower steady state level, thus exhibiting adaptation. Critically, the steady state protein levels were independent of the size of the stimulus, demonstrating that this simple network architecture effectively buffered protein production against changes in transcription. The single-gene network architecture was also effective in buffering against transcriptional noise, leading to reduced cell-to-cell variability in protein synthesis. Noise was up to 5-fold lower for a sgFFL than for an unregulated control gene with equal mean protein levels. The noise buffering capability varied predictably with the strength of the miRNA-target interaction. Together, these results suggest that the sgFFL single-gene motif provides a general and broadly applicable platform for robust gene expression in synthetic and natural gene circuits.

Oligodendrocyte pathophysiology and treatment strategies in cerebral ischemia.

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia-ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult-onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OLs, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OLs in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.

High dose of 8-OH-DPAT decreases maximal dentate gyrus activation and facilitates granular cell plasticity in vivo.

Although several studies have emphasized a crucial role for the serotonergic system in the control of hippocampal excitability, the role of serotonin (5-HT) and its receptors in normal and pathologic conditions, such as temporal lobe epilepsy (TLE), is still unclear. The present study was therefore designed firstly to investigate the acute effect of 8-OH-DPAT, a mixed 5-HT1A/7 receptor agonist, at a high dose (1 mg/kg, i.p.) known to have antiepileptic properties, in a model of acute partial epilepsy in rats. For this purpose, a maximal dentate activation (MDA) protocol was used to measure electrographic seizure onset and duration. In addition, the effect of 8-OH-DPAT on in vivo dentate gyrus cell reactivity and short- and long-term plasticity was studied. Rats injected with 8-OH-DPAT exhibited a significant reduction in MDA and epileptic discharges, a decrease in paired-pulse facilitation and an increase in long-term potentiation. This study suggests that 8-OH-DPAT or in general 5-HT1A/7 agonists might be useful for the treatment of TLE and also have some beneficial effects on the comorbid cognitive disorders seen in epileptic patients.

Small molecule signals that direct the route of a molecular cargo.

The route taken by a DNA cargo on a branched track can be controlled by the small molecule adenosine using a pair of aptamers that reciprocally block and unblock branches of the track in response to adenosine binding.

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature.

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K(+) channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1(V408A/+)). Here, we investigated the neuromuscular transmission of Kv1.1(V408A/+) ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve-muscle from Kv1.1(+/+) and Kv1.1(V408A/+) mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca(2+) signals that occurred abnormally only in preparations dissected from Kv1.1(V408A/+) mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca(2+) homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K(+) channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult.

Investigating linear superposition of multi-species neurotransmitter voltammetric measurements in-vitro.

Fast-Scan Cyclic Voltammetry (FSCV) is frequently used to monitor the concentrations of neurotransmitters in real-time. However, few studies have examined the issue of monitoring the concentration of multiple neurotransmitters at the same time, despite their coexistence at brain synapses. This stems from the fact that some neurotransmitters have relatively similar electrochemical profiles. In this work we use Factor Spaces to analyze the current signals obtained using FSCV for both individual and mixed solutions of neurotransmitters. It is shown that the behavior of the current signals during the interaction between the neurotransmitter species approaches the principle of superposition. This potentially results in a significant simplification in the way combined voltammetric data is interpreted. The performance of Principal Component Analysis in extracting suitable Factor Spaces is evaluated.