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1.  Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis 
Brain  2013;136(6):1692-1707.
The uncinate fasciculus is a bidirectional, long-range white matter tract that connects lateral orbitofrontal cortex and Brodmann area 10 with the anterior temporal lobes. Although abnormalities in the uncinate fasciculus have been associated with several psychiatric disorders and previous studies suggest it plays a putative role in episodic memory, language and social emotional processing, its exact function is not well understood. In this review we summarize what is currently known about the anatomy of the uncinate, we review its role in psychiatric and neurological illnesses, and we evaluate evidence related to its putative functions. We propose that an overarching role of the uncinate fasciculus is to allow temporal lobe-based mnemonic associations (e.g. an individual’s name + face + voice) to modify behaviour through interactions with the lateral orbitofrontal cortex, which provides valence-based biasing of decisions. The bidirectionality of the uncinate fasciculus information flow allows orbital frontal cortex-based reward and punishment history to rapidly modulate temporal lobe-based mnemonic representations. According to this view, disruption of the uncinate may cause problems in the expression of memory to guide decisions and in the acquisition of certain types of learning and memory. Moreover, uncinate perturbation should cause problems that extend beyond memory to include social–emotional problems owing to people and objects being stripped of personal value and emotional history and lacking in higher-level motivational value.
doi:10.1093/brain/awt094
PMCID: PMC3673595  PMID: 23649697
diffusion tensor imaging; episodic memory; orbitofrontal cortex; schizophrenia; anterior temporal lobe
2.  A landmark publication in movement disorders 
Brain  2013;136(2):682-684.
doi:10.1093/brain/aws329
PMCID: PMC3572933
3.  Prions and the like 
Brain  2013;137(1):301-305.
doi:10.1093/brain/awt179
PMCID: PMC3891441
4.  The non-motor syndrome of primary dystonia: clinical and pathophysiological implications 
Brain  2011;135(6):1668-1681.
Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications.
doi:10.1093/brain/awr224
PMCID: PMC3359748  PMID: 21933808
primary dystonia; non-motor; sensory; depression; endophenotypes; pathophysiology; quality of life
5.  Is SOD1 loss of function involved in amyotrophic lateral sclerosis? 
Brain  2013;136(8):2342-2358.
Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a—still unknown—toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1–amyotrophic lateral sclerosis. From analysing published data from patients with SOD1–amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1–amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.
doi:10.1093/brain/awt097
PMCID: PMC3722346  PMID: 23687121
amyotrophic lateral sclerosis; motor neuron disease; superoxide dismutase 1; loss of function
6.  The fantastic organ 
Brain  2013;136(4):1328-1332.
doi:10.1093/brain/awt038
PMCID: PMC3613716
7.  Pathophysiological distortions in time perception and timed performance 
Brain  2011;135(3):656-677.
Distortions in time perception and timed performance are presented by a number of different neurological and psychiatric conditions (e.g. Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder and autism). As a consequence, the primary focus of this review is on factors that define or produce systematic changes in the attention, clock, memory and decision stages of temporal processing as originally defined by Scalar Expectancy Theory. These findings are used to evaluate the Striatal Beat Frequency Theory, which is a neurobiological model of interval timing based upon the coincidence detection of oscillatory processes in corticostriatal circuits that can be mapped onto the stages of information processing proposed by Scalar Timing Theory.
doi:10.1093/brain/awr210
PMCID: PMC3491636  PMID: 21921020
time perception; timing; striatum; frontal lobe; Parkinson's disease
8.  Neurological perspectives on voltage-gated sodium channels 
Brain  2012;135(9):2585-2612.
The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors.
doi:10.1093/brain/aws225
PMCID: PMC3437034  PMID: 22961543
ion channel; genetics; pain; epilepsy; SCN1A
9.  Ingredients for a brain 
Brain  2011;134(12):3772-3774.
doi:10.1093/brain/awr112
PMCID: PMC3235553
10.  Harnessing neuroplasticity for clinical applications 
Brain  2011;134(6):1591-1609.
Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.
doi:10.1093/brain/awr039
PMCID: PMC3102236  PMID: 21482550
neuroplasticity; retraining; therapeutics; clinical assessment
11.  Reorganization of cerebral networks after stroke: new insights from neuroimaging with connectivity approaches 
Brain  2011;134(5):1264-1276.
The motor system comprises a network of cortical and subcortical areas interacting via excitatory and inhibitory circuits, thereby governing motor behaviour. The balance within the motor network may be critically disturbed after stroke when the lesion either directly affects any of these areas or damages-related white matter tracts. A growing body of evidence suggests that abnormal interactions among cortical regions remote from the ischaemic lesion might also contribute to the motor impairment after stroke. Here, we review recent studies employing models of functional and effective connectivity on neuroimaging data to investigate how stroke influences the interaction between motor areas and how changes in connectivity relate to impaired motor behaviour and functional recovery. Based on such data, we suggest that pathological intra- and inter-hemispheric interactions among key motor regions constitute an important pathophysiological aspect of motor impairment after subcortical stroke. We also demonstrate that therapeutic interventions, such as repetitive transcranial magnetic stimulation, which aims to interfere with abnormal cortical activity, may correct pathological connectivity not only at the stimulation site but also among distant brain regions. In summary, analyses of connectivity further our understanding of the pathophysiology underlying motor symptoms after stroke, and may thus help to design hypothesis-driven treatment strategies to promote recovery of motor function in patients.
doi:10.1093/brain/awr033
PMCID: PMC3097886  PMID: 21414995
recovery of function; motor system; functional connectivity; effective connectivity; system theory
12.  The subependymal zone neurogenic niche: a beating heart in the centre of the brain 
Brain  2009;132(11):2909-2921.
The mammalian brain is a remarkably complex organ comprising millions of neurons, glia and various other cell types. Its impressive cytoarchitecture led to the long standing belief that it is a structurally static organ and thus very sensitive to injury. However, an area of striking structural flexibility has been recently described at the centre of the brain. It is the subependymal zone of the lateral wall of the lateral ventricles. The subependymal zone—like a beating heart—continuously sends new cells to different areas of the brain: neurons to the olfactory bulbs and glial cells to the cortex and the corpus callosum. Interestingly, the generation and flow of cells changes in response to signals from anatomically remote areas of the brain or even from the external environment of the organism, therefore indicating that subependymal neurogenesis—as a system—is integrated in the overall homeostatic function of the brain. In this review, it will be attempted to describe the fundamental structural and functional characteristics of the subependymal neurogenic niche and to summarize the available evidence regarding its plasticity. Special focus is given on issues such as whether adult neural stem cells are activated after neurodegeneration, whether defects in neurogenesis contribute to neuropathological conditions and whether monitoring changes in neurogenic activity can have a diagnostic value.
doi:10.1093/brain/awp237
PMCID: PMC2768664  PMID: 19773354
adult neural stem cells; neurodegeneration; neurogenesis; subependymal zone; subventricular zone
13.  Placebo effects: clinical aspects and neurobiology 
Brain  2008;131(11):2812-2823.
Placebo effects are beneficial health outcomes not related to the relatively direct biological effects of an intervention and can be elicited by an agent that, by itself, is inert. Understanding these placebo effects will help to improve clinical trial design, especially for interventions such as surgery, CNS-active drugs and behavioural interventions which are often non-blinded. A literature review was performed to retrieve articles discussing placebo implications of clinical trials, the neurobiology of placebo effects and the implications of placebo effect for several disorders of neurological relevance. Recent research in placebo analgesia and other conditions has demonstrated that several neurotransmitter systems, such as opiate and dopamine, are involved with the placebo effect. Brain regions including anterior cingulate cortex, dorsolateral prefrontal cortex and basal ganglia have been activated following administration of placebo. A patient's expectancy of improvement may influence outcomes as much as some active interventions and this effect may be greater for novel interventions and for procedures. Maximizing this expectancy effect is important for clinicians to optimize the health of their patient. There have been many relatively acute placebo studies that are now being extended into clinically relevant models of placebo effect.
doi:10.1093/brain/awn116
PMCID: PMC2725026  PMID: 18567924
placebo effects; expectancy; cognition; clinical trials methods
14.  The complex genetics of multiple sclerosis: pitfalls and prospects 
Brain  2008;131(12):3118-3131.
The genetics of complex disease is entering a new and exciting era. The exponentially growing knowledge and technological capabilities emerging from the human genome project have finally reached the point where relevant genes can be readily and affordably identified. As a result, the last 12 months has seen a virtual explosion in new knowledge with reports of unequivocal association to relevant genes appearing almost weekly. The impact of these new discoveries in Neuroscience is incalculable at this stage but potentially revolutionary. In this review, an attempt is made to illuminate some of the mysteries surrounding complex genetics. Although focused almost exclusively on multiple sclerosis all the points made are essentially generic and apply equally well, with relatively minor addendums, to any other complex trait, neurological or otherwise.
doi:10.1093/brain/awn081
PMCID: PMC2639203  PMID: 18490360
multiple sclerosis; genetics; association; linkage
15.  Imaging of opioid receptors in the central nervous system 
Brain  2007;131(5):1171-1196.
In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.
doi:10.1093/brain/awm255
PMCID: PMC2367693  PMID: 18048446
PET; opioid receptors; pain; epilepsy; addiction

Results 1-15 (15)