Insights into brain development from neurogenetic syndromes: evidence from fragile X syndrome,Williams syndrome,Turner syndrome and velocardiofacial syndrome

Over the past few decades, behavioral, neuroimaging and molecular studies of neurogenetic conditions, such as Williams, fragile X, Turner and velocardiofacial (22q11.2 deletion) syndromes, have led to important insights regarding brain development. These investigations allow researchers to examine “experiments of nature” in which the deletion or alteration of one gene or a contiguous set of genes can be linked to aberrant brain structure or function. Converging evidence across multiple imaging modalities has now begun to highlight the abnormal neural circuitry characterizing many individual neurogenetic syndromes. Furthermore, there has been renewed interest in combining analyses across neurogenetic conditions in order to search for common organizing principles in development. In this review, we highlight converging evidence across syndromes from multiple neuroimaging modalities, with a particular emphasis on functional imaging. In addition, we discuss the commonalities and differences pertaining to selective deficits in visuospatial processing that occur across four neurogenetic syndromes. We suggest avenues for future exploration, with the goal of achieving a deeper understanding of the neural abnormalities in these affected populations.     

Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation

Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications.     

Molecular imaging in neuroscience research with small-animal PET in rodents

Cognitive neuroscience, which studies the biological basis of mental processes, widely uses neuroimaging technologies like functional magnetic resonance imaging and positron emission tomography (PET) to study the human brain. Small laboratory animals, like rodents, are commonly used in brain research and provide abundant models of human brain diseases. The development of high-resolution small-animal PET and various radiotracers together with sophisticated methods for analyzing functional brain imaging data have accelerated research on brain function and neurotransmitter release during behavioral tasks in rodents. In this review, we first summarize advances in the methodology of cognitive research brought about by the development of sophisticated methods for whole-brain imaging analysis and improvements in neuroimaging protocols. Then, we discuss basic mechanisms related to metabolic changes and the expression of neurotransmitters in various brain areas during task-induced neural activity. In particular, we discuss glucose metabolism imaging and brain receptor imaging for various receptor systems. Finally, we discuss the current status and future perspectives. Mechanisms of neurotransmitter expression will probably become an increasingly important field of study in the future, leading to more collaboration between investigators in fields such as computational and theoretical neuroscience.     

The organisation of conceptual knowledge in the brain: The future's past and some future directions

We review the development and current status of theories of the organisation and representation of conceptual knowledge in the human brain. The currently known facts from optic aphasia, category-specific semantic deficits, and functional neuroimaging are consistent with a framework in which the first-order constraint on the organisation of conceptual knowledge is domain. Data from functional neuroimaging suggests additionally a framework characterised by both domain- and modality-specific constraints. Work in congenital disorders and in apraxia indicate that the content of conceptual knowledge is not exhausted by modality-specific input/output processes. It is concluded that future empirical and theoretical work on the organisation and representation of conceptual knowledge will profit from a reorientation of the problem from the organisation of distinct processing systems to the content of information represented internal to such systems.     

Imaging the genetics of executive function

Recent advances in neuroimaging technologies have allowed ever more detailed studies of the human brain. The combination of neuroimaging techniques with genetics may provide a more sensitive measure of the influence of genetic variants on cognitive function than behavioural measures alone. Here we present a review of functional magnetic resonance imaging (fMRI) studies of genetic links to executive functions, focusing on sustained attention, working memory and response inhibition. In addition to studies in the normal population, we also address findings from three clinical populations: schizophrenia, ADHD and autism spectrum disorders. While the findings in the populations studied do not always converge, they all point to the usefulness of neuroimaging techniques such as fMRI as potential endophenotypes for parsing the genetic aetiology of executive function.     

Sentence processing in the cerebral cortex

Human language is a unique faculty of the mind. It has been the ultimate mystery throughout the history of neuroscience. Despite many aphasia and functional imaging studies, the exact correlation between cortical language areas and subcomponents of the linguistic system has not been established. One notable drawback is that most functional imaging studies have tested language tasks at the word level, such as lexical decision and word generation tasks, thereby neglecting the syntactic aspects of the language faculty. As proposed by Chomsky, the critical knowledge of language involves universal grammar (UG), which governs the syntactic structure of sentences. In this article, we will review recent advances made by functional neuroimaging studies of language, focusing especially on sentence processing in the cerebral cortex. We also present the recent results of our functional magnetic resonance imaging (fMRI) study intended to identify cortical areas specifically involved in syntactic processing. A study of sentence processing that employs a newly developed technique, optical topography (OT), is also presented. Based on these findings, we propose a modular specialization of Broca's area, Wernicke's area, and the angular gyrus/supramarginal gyrus. The current direction of research in neuroscience is beginning to establish the existence of distinct modules responsible for our knowledge of language.     

High-resolution spatio-temporal functional neuroimaging of brain activity

The past decades have shown extraordinary progress in our ability to noninvasively image the functions of the human brain. Of particular interest is the recent trend in combining information from electrophysiological and magnetic resonance imaging, which we termed eMRI, to achieve high-resolution functional neuroimaging in both space and time domains. In this article, we review the recent progress in high-resolution functional neuroimaging, in particular the multimodal integration of electroencephalography (EEG) and magnetic resonance imaging (MRI). The state-of-the-art EEG inverse solutions based on different brain electric source models and various approaches to integrate the information from MRI are reviewed. The remaining challenges, future trends, and potential applications of the high-resolution functional neuroimaging research are discussed.     

Structural and functional neural correlates of music perception

This review article highlights state-of-the-art functional neuroimaging studies and demonstrates the novel use of music as a tool for the study of human auditory brain structure and function. Music is a unique auditory stimulus with properties that make it a compelling tool with which to study both human behavior and, more specifically, the neural elements involved in the processing of sound. Functional neuroimaging techniques represent a modern and powerful method of investigation into neural structure and functional correlates in the living organism. These methods have demonstrated a close relationship between the neural processing of music and language, both syntactically and semantically. Greater neural activity and increased volume of gray matter in Heschl's gyrus has been associated with musical aptitude. Activation of Broca's area, a region traditionally considered to subserve language, is important in interpreting whether a note is on or off key. The planum temporale shows asymmetries that are associated with the phenomenon of perfect pitch. Functional imaging studies have also demonstrated activation of primitive emotional centers such as ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex in listeners of moving musical passages. In addition, studies of melody and rhythm perception have elucidated mechanisms of hemispheric specialization. These studies show the power of music and functional neuroimaging to provide singularly useful tools for the study of brain structure and function.     

The use of functional neuroimaging to evaluate psychological and other non-pharmacological treatments for clinical pain

A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings from neuroimaging studies that evaluated the neural response to distraction-based techniques, cognitive behavioral therapy (CBT), clinical hypnosis, mental imagery, physical therapy/exercise, biofeedback, and mirror therapy. To date, the results from studies that used neuroimaging to evaluate these methods have not been conclusive and the experimental methods have been suboptimal for assessing clinical pain. Still, several different psychological and non-pharmacological treatment modalities were associated with increased pain-related activations of executive cognitive brain regions, such as the ventral- and dorsolateral prefrontal cortex. There was also evidence for decreased pain-related activations in afferent pain regions and limbic structures. If future studies will address the technical and methodological challenges of today's experiments, neuroimaging might have the potential of segregating the neural mechanisms of different treatment interventions and elucidate predictive and mediating factors for successful treatment outcomes. Evaluations of treatment-related brain changes (functional and structural) might also allow for sub-grouping of patients and help to develop individualized treatments.     

Cortico-limbic circuitry and the airways: Insights from functional neuroimaging of respiratory afferents and efferents

After nearly two decades of active research, functional neuroimaging has demonstrated utility in the identification of cortical, limbic, and paralimbic (cortico-limbic) brain regions involved in respiratory control and respiratory perception. Before the recent boon of human neuroimaging studies, the location of the principal components of respiratory-related cortico-limbic circuitry had been unknown and their function had been poorly understood. Emerging neuroimaging evidence in both healthy and patient populations suggests that cognitive and emotional/affective processing within cortico-limbic circuitry modulates respiratory control and respiratory perception. This paper will review functional neuroimaging studies of respiration with a focus on whole brain investigations of sensorimotor pathways that have identified respiratory-related neural circuitry known to overlap emotional/affective cortico-limbic circuitry. To aid the interpretation of present and future findings, the complexities and challenges underlying neuroimaging methodologies will also be reviewed as applied to the study of respiration physiology.     

Sentence processing is uniquely human

In this article, we will focus on three fundamental issues concerning language processing in the human brain, and update recent advances made by functional neuroimaging and magnetic stimulation studies of language. First, we will provide the first experimental evidence that the neural basis of sentence comprehension is indeed specialized. Specifically, our recent functional magnetic resonance imaging (fMRI) study has clarified that the human left prefrontal cortex (PFC) is more specialized in the syntactic processes of sentence comprehension than other domain-general processes such as short-term memory. Second, the distinction between explicit and implicit syntactic processes will be clarified, based on our fMRI studies that elucidate syntactic specialization in the left PFC. Third, we will advance a hypothesis stating that distinct subregions of the left PFC are recruited for the syntactic integration of lexico-semantic information. The current direction of research in the neuroscience of language is beginning to reveal the uniqueness of the human mind.     

Structural MRI studies of language function in the undamaged brain

In recent years, the demonstration that structural changes can occur in the human brain beyond those associated with development, ageing and neuropathology has revealed a new approach to studying the neural basis of behaviour. In this review paper, we focus on structural imaging studies of language that have utilised behavioural measures in order to investigate the neural correlates of language skills in the undamaged brain. We report studies that have used two different techniques: voxel-based morphometry of whole brain grey or white matter images and diffusion tensor imaging. At present, there are relatively few structural imaging studies of language. We group them into those that investigated (1) the perception of novel speech sounds, (2) the links between speech sounds and their meaning, (3) speech production, and (4) reading. We highlight the validity of the findings by comparing the results to those from functional imaging studies. Finally, we conclude by summarising the novel contribution of these studies to date and potential directions for future research.     

语言文字加工神经机制的fMRI研究进展

应用血氧合水平依赖功能磁共振成像技术(BOLD-fMRI)进行语言文字加工研究发现,大脑左侧梭状回中部皮质对语言文字视觉加工的任务具有稳定和明显的反应,但是在语言文字加工中该区域的激活是由何种因素引起尚存在不一致的看法。一些研究认为该区域的激活主要由于文字的构词规则、语音和语义的加工等因素所致;但是另外一些研究则认为该区域是通过对语言文字的广泛经验和专业知识构建了专门处理文字视觉加工的皮层模块。作者对最近的相关研究进展进行了综述和分析,同时对今后可能的研究方向进行了探讨。     

Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer’s disease (AD), where both widespread atrophy and ‘signature’ brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.     

Neuroimaging studies of priming

This article reviews functional neuroimaging studies of priming, a behavioural change associated with the repeated processing of a stimulus. Using the haemodynamic techniques of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), priming-related effects have been observed in numerous regions of the human brain, with the specific regions depending on the type of stimulus and the manner in which it is processed. The most common finding is a decreased haemodynamic response for primed versus unprimed stimuli, though priming-related response increases have been observed. Attempts have been made to relate these effects to a form of implicit or "unconscious" memory. The priming-related decrease has also been used as a tool to map the brain regions associated with different stages of stimulus-processing, a method claimed to offer superior spatial resolution. This decrease has a potential analogue in the stimulus repetition effects measured with single-cell recording in the non-human primate. The paradigms reviewed include word-stem completion, masked priming, repetition priming of visual objects and semantic priming. An attempt is made to relate the findings within a "component process" framework, and the relationship between behavioural, haemodynamic and neurophysiological data is discussed. Interpretation of the findings is not always clear-cut, however, given potential confounding factors such as explicit memory, and several recommendations are made for future neuroimaging studies of priming.     

Neuroimaging biomarkers of epileptogenesis

Much progress has been made in the field studying the process of epileptogenesis via neuroimaging techniques. Conventional imaging methods include magnetic resonance imaging with morphometric analysis, magnetic resonance spectroscopy and positron emission tomography. Newer network-based methods such as diffusion tensor imaging and functional magnetic resonance imaging with resting functional connectivity are being developed and applied to clinical use. This review provides a brief summary of the major human and animal studies in both partial and generalized epilepsies that demonstrate the potential of these imaging modalities to serve as biomarkers of epileptogenesis.     

Neuroimaging-based markers of bipolar disorder: evidence from two meta-analyses

Background

Bipolar disorder (BD) is often misdiagnosed or tardily detected, leading to inadequate treatment and devastating consequences. The identification of objective biomarkers, such as functional and structural brain abnormalities of BD might improve diagnosis and help elucidate its pathophysiology.

Methods

To identify neurobiological markers of BD, two meta-analyses, one of functional neuroimaging studies related to emotional processing and a second of structural whole-brain neuroimaging studies in BD were conducted in the present study. Conducting a literature search on studies published up to September 2009 we identified 28 studies that were eligible for the meta-analyses: 13 functional magnetic resonance imaging studies, related to emotional processing and 15 structural imaging studies using whole-brain voxel-based morphometry. Only studies comparing patients with bipolar disorder to healthy controls were considered. Data were extracted or converted to a single anatomical reference (Talairach space). The activation likelihood estimation technique was used to assess the voxel-wise correspondence of results between studies.

Results

In patients with BD, decreased activation and diminution of gray matter were identified in a cortical-cognitive brain network that has been associated with the regulation of emotions. By contrast, patients with BD exhibited increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses. The present study provides evidence for functional and anatomical alterations in BD in brain networks associated with the experience and regulation of emotions.

Conclusions

These alterations support previously proposed neurobiological models of BD and might represent valid neurobiological markers of the disorder. The specificity of these results to unipolar depression remains to be explored.     

Combining structural and functional neuroimaging data for studying brain connectivity: a review

Different brain areas are thought to be integrated into large-scale networks to support cognitive function. Recent approaches for investigating structural organization and functional coordination within these networks involve measures of connectivity among brain areas. We review studies combining in vivo structural and functional brain connectivity data, where (a) structural connectivity analysis, mostly based on diffusion tensor imaging is paired with voxel-wise analysis of functional neuroimaging data or (b) the measurement of functional connectivity based on covariance analysis is guided/aided by structural connectivity data. These studies provide insights into the relationships between brain structure and function. Promising trends involve (a) studies where both functional and anatomical connectivity data are collected using high-resolution neuroimaging methods and (b) the development of advanced quantitative models of integration.     

Somato-motor inhibitory processing in humans: evidence from neurophysiology and neuroimaging

Motor execution processing has been examined using an index of behavioral performance such as reaction times, kinetics, and kinematics. However, difficulties have been associated with the study of motor inhibitory processing because of the absence of actual behavioral performance. Therefore, non-invasive neurophysiological and neuroimaging methods including electroencephalography, magnetoencephalography, transcranial magnetic stimulation, and functional magnetic resonance imaging have been used to investigate neural processes in the central nervous system. We mainly reviewed research on somato-motor inhibitory processing based on data obtained by using these techniques, which can examine ‘when’, ‘where, and ‘how’ motor inhibition occurs in the brain. Although to date a number of studies have used these techniques separately, few studies have utilized them in a comprehensive manner. In this review, we provide evidence that combining neurophysiological and neuroimaging methods should contribute to our understanding of how executive and inhibitory functions are implemented.     

What does neuroimaging tell us about the role of prefrontal cortex in memory retrieval?

The past five years have seen an outpouring of neuroimaging studies of memory — using both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These studies have convincingly demonstrated that neuroimaging can be used to study the functional anatomy of normal human memory and that neuroimaging can precisely localize memory related brain activations within small areas of cortex. As one illustration of the application of neuroimaging in the study of memory, this review shows how several laboratories have produced data that converge on the notion that specific areas in the prefrontal cortex are active during long-term memory retrieval. Moreover, the data further suggest that distinct prefrontal brain areas might make differential contributions to different kinds of long-term memory retrieval.