使用非侵入的神经影像方法解码人类思维

随着神经影像技术的发展,“读脑机器”在不久的将来可能会变成现实。在众多实现“读脑机器”的技术中,使用基于血氧水平依赖的脑功能磁共振技术的神经解码方法则是非常有希望的一种技术。在本报告中,我们结合我们实验室最近开展的两个研究工作,说明了使用功能磁共振技术进行神经解码的一般方法及其应用。本领域的发展很快,所有的这些工作让我们对发明“读脑机器”充满了期待。但是,与此同时,我们也应该看到目前还存在着很多技术的局限和挑战。本报告的最后,我们也对这些局限和挑战进行了一些讨论。     

NMR structural characterization of the penta-peptide calpain inhibitor

Calpains are ubiquitous intracellular calcium- and thiol-dependent proteases. Their over activation, resulting in the degradation of various substrates, has been implicated in a number of cardiovascular and neurological disorders. Here, we present the first structural characterization of LSEAL penta-peptide, a potent calpain inhibitor, bound to the calmodulin-like domain of calpain. Our in vitro binding data supports the idea that domains other than calpain’s active site may be suitable targets for future development of therapeutic agents to be used to treat heart attack, traumatic brain injuries or a variety of neurodegenerative conditions, such as ischemic stroke.     

Relative Changes from Prior Reward Contingencies Can Constrain Brain Correlates of Outcome Monitoring

It is well-known that the affective value of an environment can be relative to whether it reflects an improvement or a worsening from a previous state. A potential explanation for this phenomenon suggests that relative changes from previous reward contingencies can constrain how brain monitoring systems form predictions about future events. In support of this idea, we found that changes per se relative to previous states of learned reward contingencies modulated the Feedback-Related Negativity (FRN), a human brain potential known to index discrepancies between predictions and affective outcomes. Specifically, we observed that environments with a 50% reward probability yielded different FRN patterns according to whether they reflected an improvement or a worsening from a previous environment. Further, we also found that this pattern of results was driven mainly by variations in the amplitude of ERPs to positive outcomes. Overall, these results suggest that relative changes in reward probability from previous learned environments can constrain how neural systems of outcome monitoring formulate predictions about the likelihood of future rewards and nonrewards.     

Samuel Butler and human long term memory: Is the cupboard bare?

Memory studies in biological systems distinguish three informational processes that are generally sequential—production/acquisition, storage, and retrieval/use. Identification of DNA as a storage form for hereditary information accelerated progress in that field. Assuming the path of successful elucidation in one memory field (heredity) to be heuristic for elucidation in another (brain), then progress in neuroscience should accelerate when a storage form is identified. In the 19th century Ewald Hering and Samuel Butler held that heredity and brain memory both involved the storage of information and that the two forms of storage were the same. Hering specified storage as ‘molecular vibrations’ but, while making a fuller case, Butler was less committal. In the 20th century, the ablation studies of Karl Lashley failed to identify unique sites for storage of brain information, and Donald Hebb's ‘synaptic plasticity’ hypothesis of distributed storage over a neuronal network won favor. In the 21st century this has come under attack, and the idea that brain and hereditary information are stored as DNA is advocated. Thus, albeit without attribution, Butler's idea is reinstated. Yet, while the case is still open, the synaptic plasticity and DNA hypotheses have problems. Two broad alternatives remain on the table. Long term memory is located: (1) in the brain, either in some other macromolecular form (e.g. protein, lipid) or in some sub-molecular form (e.g. quantum computing and ‘brain as holograph’ hypotheses) or (2) outside the brain. The suggestion of the medieval physician Avicenna that the brain ‘cupboard’ is bare—i.e. the brain is a perceptual, not storage, organ—is consistent with a mysterious ‘universe as holograph’ model. Understanding how Butler came to contribute could be heuristic for future progress in a field fraught with ‘fractionation and disunity’.     

Congenital amusia: all the songs sound the same

Recent evidence from individuals born with a profound musical impairment suggests that the ability to process pitch information is normally present from birth. This finding supports the idea that the perception and appreciation of music, both of which critically depend on pitch processing, have a biological basis in the brain.     

Probabilistic Clustering of the Human Connectome Identifies Communities and Hubs

A fundamental assumption in neuroscience is that brain function is constrained by its structural properties. This motivates the idea that the brain can be parcellated into functionally coherent regions based on anatomical connectivity patterns that capture how different areas are interconnected. Several studies have successfully implemented this idea in humans using diffusion weighted MRI, allowing parcellation to be conducted in vivo. Two distinct approaches to connectivity-based parcellation can be identified. The first uses the connection profiles of brain regions as a feature vector, and groups brain regions with similar connection profiles together. Alternatively, one may adopt a network perspective that aims to identify clusters of brain regions that show dense within-cluster and sparse between-cluster connectivity. In this paper, we introduce a probabilistic model for connectivity-based parcellation that unifies both approaches. Using the model we are able to obtain a parcellation of the human brain whose clusters may adhere to either interpretation. We find that parts of the connectome consistently cluster as densely connected components, while other parts consistently result in clusters with similar connections. Interestingly, the densely connected components consist predominantly of major cortical areas, while the clusters with similar connection profiles consist of regions that have previously been identified as the ‘rich club’; regions known for their integrative role in connectivity. Furthermore, the probabilistic model allows quantification of the uncertainty in cluster assignments. We show that, while most clusters are clearly delineated, some regions are more difficult to assign. These results indicate that care should be taken when interpreting connectivity-based parcellations obtained using alternative deterministic procedures.     

Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo

Experience-dependent regulation of synaptic strength has been suggested as a physiological mechanism by which memory storage occurs in the brain. Although modifications in postsynaptic glutamate receptor levels have long been hypothesized to be a molecular basis for long-lasting regulation of synaptic strength, direct evidence obtained in the intact brain has been lacking. Here we show that in the adult brain in vivo, synaptic glutamate receptor trafficking is bidirectionally, and reversibly, modified by NMDA receptor-dependent synaptic plasticity and that changes in glutamate receptor protein levels accurately predict changes in synaptic strength. These findings support the idea that memories can be encoded by the precise experience-dependent assignment of glutamate receptors to synapses in the brain.     

Detection of a specific mitochondrial DNA deletion in tissues of older humans.

Using PCR, we found that normal heart muscle and brain from adult human individuals contain low levels of a specific mitochondrial DNA deletion, previously found only in patients affected with certain types of neuromuscular disease. This deletion was not observed in fetal heart or brain. Experimental tests support the idea that the deletion exists in vivo in adult mitochondria and is not an in vitro artifact of PCR. Our data provide direct experimental support for the idea that accumulation of mitochondrial DNA deletions may be important in aging.     

Binding of laminin to brain gangliosides and inhibition of laminin-neuron interaction by the gangliosides

Binding of laminin to glycolipids of neuronal membranes was studied with a thin-layer chromatography overlay assay. The major brain ganglioside GD1A was the main binding component, when chromatograms containing the same molar amount of the different brain gangliosides and the brain sulfatide were incubated with laminin at physiological ionic strength. The possible role of laminin binding to brain gangliosides in laminin-neuron interactions was studied with adhesion assays. It was found that binding of rat brain neurons to laminin is blocked by 10-40 microM brain gangliosides but not by sulfatide. The inhibition by the gangliosides is suggested to be due to competition with the cell surface interaction sites of laminin and not to binding of the gangliosides to the cells. Our findings support the idea that the adhesive and neurite-promoting effect of laminin is dependent on its interaction with gangliosides at the neuronal cell surfaces.     

Effect of mineralocorticoids on the Na, K-ATPase activity of the rat brain

The effect of desoxycorticosterone (DOC) on Na, K-ATPase activity was studied in vivo and in vitro on microsomal rat brain fractions. An hour after intramuscular administration of DOC a noticeable increase in the enzyme activity was observed. Preincubation of microsomal brain fractions with 5 and 15 mkg/ml of DOC caused a decrease in Na, K-ATPase activity, with the results evident 3-5 minutes after the addition of the hormone into the incubation medium. The idea of a two-phase hormonal effect is suggested. It is likely that desoxycorticosterone effect is realized both by the direct influence, on Na, K-ATPase of the brain plasma membrane and by the influence on the biosynthesis.     

Motor and Linguistic Linking of Space and Time in the Cerebellum

Background

Recent literature documented the presence of spatial-temporal interactions in the human brain. The aim of the present study was to verify whether representation of past and future is also mapped onto spatial representations and whether the cerebellum may be a neural substrate for linking space and time in the linguistic domain. We asked whether processing of the tense of a verb is influenced by the space where response takes place and by the semantics of the verb.

Principal Findings

Responses to past tense were facilitated in the left space while responses to future tense were facilitated in the right space. Repetitive transcranial magnetic stimulation (rTMS) of the right cerebellum selectively slowed down responses to future tense of action verbs; rTMS of both cerebellar hemispheres decreased accuracy of responses to past tense in the left space and to future tense in the right space for non-verbs, and to future tense in the right space for state verbs.

Conclusions

The results suggest that representation of past and future is mapped onto spatial formats and that motor action could represent the link between spatial and temporal dimensions. Right cerebellar, left motor brain networks could be part of the prospective brain, whose primary function is to use past experiences to anticipate future events. Both cerebellar hemispheres could play a role in establishing the grammatical rules for verb conjugation.     

The depletion of tryptophan and serotonin in the brain of developing hyperphenylalaninemic rats is abolished by the additional administration of lysine

In suckling hyperphenylalaninemic (hyper-Phe) rats, all essential amino acids including tryptophan are depleted in the blood. The inadequate supply of Trp to the developing brain leads to a decline of Trp, of serotonin, and of 5-hydroxyindoleacetic acid. The exhaustion of amino acids in both blood and brain can be restored by administration of Lys. Even though Phe is still elevated in blood and brain, Trp, serotonin and 5-hydroxyindoleacetic acid, are no longer depleted in the brain. This observation contradicts the idea that the serotonin deficit in the developing hyper-Phe brain is caused by competitive uptake inhibition of tryptophan or by the interference of Phe metabolites with the formation of serotonin. Increased accumulation of all large neutral amino acids in peripheral tissues and an impeded intestinal amino acid transport in suckling hyper-Phe rats appear to be responsible for the deficient supply of other amino acids, including Trp, to the developing brain. The availability of Lys for developing extraintestinal tissues seems to be involved in the regulation of intestinal amino acid transport.     

The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system

Several studies support the idea that the polypeptides belonging to the family of insulin and insulin-like growth factors (IGFs) play an important role in brain development and continue to be produced in discrete areas of the adult brain. In numerous neuronal populations within the olfactory bulb, the cerebral and cerebellar cortex, the hippocampus, some diencephalic and brainstem nuclei, the spinal cord and the retina, specific insulin and IGF receptors, as well as crucial components of the intracellular receptor signaling pathway have been demonstrated. Thus, mature neurons are endowed with the cellular machinery to respond to insulin and IGF stimulation. Studies in vitro and in vivo, using normal and transgenic animals, have led to the hypothesis that, in the adult brain, IGF-I not only acts as a trophic factor, but also as a neuromodulator of some higher brain functions, such as long-term potentiation and depression. Furthermore, a trophic effect on certain neuronal populations becomes clearly evident in the ischemic brain or neurodegenerative disorders. Thus, the analysis of the early intracellular signaling pathway for the insulin/IGF receptor family in the brain is providing us with new intriguing findings on the way the mammalian brain is sculpted and operates.     

The evolution of the cortico-cerebellar complex in primates: anatomical connections predict patterns of correlated evolution

Investigations into the evolution of the primate brain have tended to neglect the role of connectivity in determining which brain structures have changed in size, focusing instead on changes in the size of the whole brain or of individual brain structures, such as the neocortex, in isolation. We show that the primate cerebellum, neocortex, vestibular nuclei and relays between them exhibit correlated volumetric evolution, even after removing the effects of change in other structures. The patterns of correlated evolution among individual nuclei correspond to their known patterns of connectivity. These results support the idea that the brain evolved by mosaic size change in arrays of functionally connected structures. Furthermore, they suggest that the much discussed expansion of the primate neocortex should be re-evaluated in the light of conjoint cerebellar expansion.     

Norepinephrine: A Neuromodulator That Boosts the Function of Multiple Cell Types to Optimize CNS Performance

Norepinephrine (NE) is a neuromodulator that in multiple ways regulates the activity of neuronal and non-neuronal cells. NE participates in the rapid modulation of cortical circuits and cellular energy metabolism, and on a slower time scale in neuroplasticity and inflammation. Of the multiple sources of NE in the brain, the locus coeruleus (LC) plays a major role in noradrenergic signaling. Processes from the LC primarily release NE over widespread brain regions via non-junctional varicosities. We here review the actions of NE in astrocytes, microglial cells, and neurons based on the idea that the overarching effect of signaling from the LC is to maximize brain power, which is accomplished via an orchestrated cellular response involving most, if not all cell types in CNS.     

Distribution of proglucagon mRNA and GLP-1 in the brainstem of chicks

Glucagon-like peptide-1 (GLP-1), structurally similar to glucagon, synthesized from the precursor proglucagon, is a well known anorexigenic peptide in the brain of several animal species. However, there are no previous reports concerning GLP-1-containing neurons in the chick brain. The aim of the present study was to investigate the distribution of proglucagon mRNA and GLP-1-immunoreactive (GLI) perikarya in various regions of the chick brain. We detected proglucagon mRNA in the brainstem, and to a lesser extent in the telencephalon. In the brainstem, a study using immunohistochemistry revealed that GLI perikarya were present in the nucleus motorius nervi facialis pars dosalis, nucleus motoris dorsalis nervi vagi and nucleus tractus solitarii. Furthermore, we found that proglucagon mRNA expression in the brainstem decreased after 24 h fasting. The present findings support the idea that endogenous GLP-1 is involved in feeding behavior of chicks.     

A truffle in the mouth is worth two in the bush: odor localization in the human brain

It is widely thought that locating the source of a smell is an ability best left to nonhuman members of the animal kingdom. In this issue of Neuron, two complementary articles highlight the neural mechanisms underlying the localization of an odor, either to the left or right side of the nose (Porter et al.) or to the inside or outside of the mouth (Small et al.). Together, these studies validate the idea that the human brain is equipped with the apparatus necessary to pinpoint the location of an odor source.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

Beyond the sentence given

A central and influential idea among researchers of language is that our language faculty is organized according to Fregean compositionality, which states that the meaning of an utterance is a function of the meaning of its parts and of the syntactic rules by which these parts are combined. Since the domain of syntactic rules is the sentence, the implication of this idea is that language interpretation takes place in a two-step fashion. First, the meaning of a sentence is computed. In a second step, the sentence meaning is integrated with information from prior discourse, world knowledge, information about the speaker and semantic information from extra-linguistic domains such as co-speech gestures or the visual world. Here, we present results from recordings of event-related brain potentials that are inconsistent with this classical two-step model of language interpretation. Our data support a one-step model in which knowledge about the context and the world, concomitant information from other modalities, and the speaker are brought to bear immediately, by the same fast-acting brain system that combines the meanings of individual words into a message-level representation. Underlying the one-step model is the immediacy assumption, according to which all available information will immediately be used to co-determine the interpretation of the speaker's message. Functional magnetic resonance imaging data that we collected indicate that Broca's area plays an important role in semantic unification. Language comprehension involves the rapid incorporation of information in a 'single unification space', coming from a broader range of cognitive domains than presupposed in the standard two-step model of interpretation.