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1.  Electrophysiological Mapping of Rat Sensorimotor Lumbosacral Spinal Networks after Complete Paralysis 
Progress in brain research  2015;218:199-212.
Stimulation of the spinal cord has been shown to have great potential for improving function after motor deficits caused by injury or pathological conditions. Using a wide range of animal models, many studies have shown that stimulation applied to the neural networks intrinsic to the spinal cord can result in a dramatic improvement of motor ability, even allowing an animal to step and stand after a complete spinal cord transection. Clinical use of this technology, however, has been slow to develop due to the invasive nature of the implantation procedures and the difficulty of ascertaining specific sites of stimulation that would provide optimal amelioration of the motor deficits. Moreover, the development of tools available to control precise stimulation chronically via biocompatible electrodes has been limited. In this paper, we outline the use of a multisite electrode array in the spinal rat model to identify and stimulate specific sites of the spinal cord to produce discrete motor behaviors in spinal rats. The results demonstrate that spinal rats can stand and step when the spinal cord is stimulated tonically via electrodes located at specific sites on the spinal cord. The quality of stepping and standing was dependent on the location of the electrodes on the spinal cord, the specific stimulation parameters, and the orientation of the cathode and anode. The spinal motor evoked potentials (sMEP) in selected muscles during standing and stepping are shown to be critical tools to study selective activation of interneuronal circuits via responses of varying latencies. The present results provide further evidence that the assessment of functional networks in the background of behaviorally relevant functional states is likely to be a physiological tool of considerable importance in developing strategies to facilitate recovery of motor function after a number of neuromotor disorders.
PMCID: PMC4512743  PMID: 25890138
Spinal cord epidural stimulation; spinal motor evoked potentials; electrode array; electric enabling motor control (eEmc); locomotion; neurorehabilitation
2.  Physiological and pathophysiological interactions between the respiratory central pattern generator and the sympathetic nervous system 
Progress in brain research  2014;212:1-23.
Respiratory modulation seen in the sympathetic nerve activity (SNA) implies that the respiratory and sympathetic networks interact. During hypertension elicited by chronic intermittent hypoxia (CIH), the SNA displays an enhanced respiratory modulation reflecting strengthened interactions between the networks. In this chapter, we review a series of experimental and modeling studies that help elucidate possible mechanisms of sympatho-respiratory coupling. We conclude that this coupling significantly contributes to both the sympathetic baroreflex and the augmented sympathetic activity after exposure to CIH. This conclusion is based on the following findings. (1) Baroreceptor activation results in perturbation of the respiratory pattern via transient activation of postinspiratory neurons in the Bötzinger complex (BötC). The same BötC neurons are involved in the respiratory modulation of SNA, and hence provide an additional pathway for the sympathetic baroreflex. (2) Under hypercapnia, phasic activation of abdominal motor nerves (AbN) is accompanied by synchronous discharges in SNA due to the common source of this rhythmic activity in the retrotrapezoid nucleus (RTN). CIH conditioning increases the CO2 sensitivity of central chemoreceptors in the RTN which results in the emergence of AbN and SNA discharges under normocapnic conditions similar to those observed during hypercapnia in naïve animals. Thus, respiratory–sympathetic interactions play an important role in defining sympathetic output and significantly contribute to the sympathetic activity and hypertension under certain physiological or pathophysiological conditions, and the theoretical framework presented may be instrumental in understanding of malfunctioning control of sympathetic activity in a variety of disease states.
PMCID: PMC4512751  PMID: 25194190
respiratory–sympathetic interactions; baroreflex; chronic intermittent hypoxia; hypertension; modeling
3.  The mammillary bodies and memory: more than a hippocampal relay 
Progress in brain research  2015;219:163-185.
Although the mammillary bodies were one of the first neural structures to be implicated in memory, it has long been assumed that their main function was to act primarily as a hippocampal relay, passing information on to the anterior thalamic nuclei and from there to the cingulate cortex. This view not only afforded the mammillary bodies no independent role in memory, it also neglected the potential significance of other, nonhippocampal, inputs to the mammillary bodies. Recent advances have transformed the picture, revealing that projections from the tegmental nuclei of Gudden, and not the hippocampal formation, are critical for sustaining mammillary body function. By uncovering a role for the mammillary bodies that is independent of its subicular inputs, this work signals the need to consider a wider network of structures that form the neural bases of episodic memory.
PMCID: PMC4498492  PMID: 26072239
Anterograde amnesia; Fornix; Mammillothalamic tract; Medial diencephalon; Papez circuit
4.  Sleep–Wake Control of the Upper Airway by Noradrenergic Neurons, with and without Intermittent Hypoxia 
Progress in brain research  2014;209:255-274.
Hypoglossal (XII) motoneurons innervate muscles of the tongue whose tonic and inspiratory modulated activity protects the upper airway from collapse in patients affected by the obstructive sleep apnea (OSA) syndrome. Both norepinephrine and serotonin provide wakefulness-related excitatory drives that maintain activity in XII motoneurons, with the noradrenergic system playing a particularly prominent role in rats. When noradrenergic and serotonergic drives are antagonized, no further decline of XII nerve activity occurs during pharmacologically induced rapid eye movement (REM) sleep-like state. This is the best evidence to date that, at least in this model, the entire REM sleep-related decline of upper airway muscle tone results from withdrawal of these two excitatory inputs. A major component of noradrenergic input to XII motoneurons originates from pontine noradrenergic neurons that have state-dependent patterns of activity, maximal during wakefulness, and minimal, or absent during REM sleep. Our data suggest that not all ventrolateral medullary catecholaminergic neurons follow this pattern, with adrenergic C1 neurons probably increasing their activity during REM sleep. When rats are subjected to chronic-intermittent hypoxia, noradrenergic drive to XII motoneurons is increased by mechanisms that include sprouting of noradrenergic terminals in the XII nucleus, and increased expression of α1-adrenoceptors; an outcome that may underlie the elevated baseline activity of upper airway muscles during wakefulness in OSA patients.
PMCID: PMC4498577  PMID: 24746052
adrenergic receptors; atonia; norepinephrine; genioglossus; obstructive sleep apnea; REM sleep
5.  Serotonin Neurons and Central Respiratory Chemoreception: Where are we now? 
Progress in brain research  2014;209:207-233.
Serotonin (5-hydroxytryptamine; 5-HT) neurons are widely considered to play an important role in central respiratory chemoreception. Although many studies in the past decades have supported this hypothesis, there had been concerns about its validity until recently. One recurring claim had been that 5-HT neurons are not consistently sensitive to hypercapnia in vivo. Another belief was that 5-HT neurons do not stimulate breathing; instead, they inhibit or modulate respiratory output. It was also believed by some that 5-HT neuron chemosensitivity is dependent on TASK channels, but mice with genetic deletion of TASK-1 & TASK-3 have a normal hypercapnic ventilatory response (HCVR). This review explains why these principal arguments against the hypothesis are not supported by existing data. Despite repeated challenges, a large body of evidence now supports the conclusion that at least a subset of 5-HT neurons are central chemoreceptors.
PMCID: PMC4486262  PMID: 24746050
5-HT neurons; chemoreceptors; control of breathing; hypercapnia; acidosis; raphé
6.  Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility 
Progress in brain research  2010;186:77-95.
There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders.
PMCID: PMC4465286  PMID: 21094887
DNA methylation; Epigenetics; Histone modifications; MicroRNAs; Non-coding RNAs; Sex differences; X chromosome inactivation
7.  The Impact of Genetic Research on Our Understanding of Parkinson’s Disease 
Progress in brain research  2010;183:21-41.
Until recently, genetics was thought to play a minor role in the development of Parkinson’s disease (PD). Over the last decade, a number of genes that definitively cause PD have been identified, which has led to the generation of disease models based on pathogenic gene variants that recapitulate many features of the disease. These genetic studies have provided novel insight into potential mechanisms underlying the etiology of PD. This chapter will provide a profile of the genes conclusively linked to PD and will outline the mechanisms of PD pathogenesis implicated by genetic studies. Mitochondrial dysfunction, oxidative stress and impaired ubiquitin-proteasome system function are disease mechanisms that are particularly well supported by genetic studies and are therefore the focus of this chapter.
PMCID: PMC4451604  PMID: 20696313
8.  The role of dopamine in modulating the structure and function of striatal circuits 
Progress in brain research  2010;183:149-167.
Dopamine (DA) is a key regulator of action selection and associative learning. The striatum has long been thought to be a major locus of DA action in this process. Although all striatal cell types express G protein-coupled receptors for DA, the effects of DA on principal medium spiny neurons (MSNs) understandably have received the most attention. In the two principal classes of MSN, DA receptor expression diverges, with striatonigral MSNs robustly expressing D1 receptors and striatopallidal MSNs expressing D2 receptors. In the last couple of years, our understanding of how these receptors and the intracellular signalling cascades that they couple to modulate dendritic physiology and synaptic plasticity has rapidly expanded, fuelled in large measure by the development of new optical and genetic tools. These tools also have enabled a rapid expansion of our understanding of the striatal adaptations in models of Parkinson's disease. This chapter highlights some of the major advances in these areas.
PMCID: PMC4431764  PMID: 20696319
Striatum; Dopamine; Synaptic plasticity; Dendritic excitability; Dendritic spines; Parkinson's Disease
9.  Musicians and music making as a model for the study of brain plasticity 
Progress in brain research  2015;217:37-55.
Playing a musical instrument is an intense, multisensory, and motor experience that usually commences at an early age and requires the acquisition and maintenance of a range of sensory and motor skills over the course of a musician’s lifetime. Thus, musicians offer an excellent human model for studying behavioral-cognitive as well as brain effects of acquiring, practicing, and maintaining these specialized skills. Research has shown that repeatedly practicing the association of motor actions with specific sound and visual patterns (musical notation), while receiving continuous multisensory feedback will strengthen connections between auditory and motor regions (e.g., arcuate fasciculus) as well as multimodal integration regions. Plasticity in this network may explain some of the sensorimotor and cognitive enhancements that have been associated with music training. Furthermore, the plasticity of this system as a result of long term and intense interventions suggest the potential for music making activities (e.g., forms of singing) as an intervention for neurological and developmental disorders to learn and relearn associations between auditory and motor functions such as vocal motor functions.
PMCID: PMC4430083  PMID: 25725909
brain plasticity; diffusion tensor imaging; morphometry; motor; auditory; Melodic Intonation Therapy; Auditory–Motor Mapping Training (AMMT)
10.  The Integrative Role of the Sigh in Psychology, Physiology, Pathology, and Neurobiology 
Progress in brain research  2014;209:91-129.
“Sighs, tears, grief, distress” expresses Johann Sebastian Bach in a musical example for the relationship between sighs and deep emotions. This review explores the neurobiological basis of the sigh and its relationship with psychology, physiology, and pathology. Sighs monitor changes in brain states, induce arousal, and reset breathing variability. These behavioral roles homeostatically regulate breathing stability under physiological and pathological conditions. Sighs evoked in hypoxia evoke arousal and thereby become critical for survival. Hypoarousal and failure to sigh have been associated with sudden infant death syndrome. Increased breathing irregularity may provoke excessive sighing and hyperarousal, a behavioral sequence that may play a role in panic disorders. Essential for generating sighs and breathing is the pre-Bötzinger complex. Modulatory and synaptic interactions within this local network and between networks located in the brainstem, cerebellum, cortex, hypothalamus, amygdala, and the periaqueductal gray may govern the relationships between physiology, psychology, and pathology. Unraveling these circuits will lead to a better understanding of how we balance emotions and how emotions become pathological.
PMCID: PMC4427060  PMID: 24746045
anxiety; panic; arousal; cardiorespiratory; PAG; rhythm generation; SIDS; breathing; pre-Bötzinger complex
11.  Apollo’s gift: new aspects of neurologic music therapy 
Progress in brain research  2015;217:237-252.
Music listening and music making activities are powerful tools to engage multisensory and motor networks, induce changes within these networks, and foster links between distant, but functionally related brain regions with continued and life-long musical practice. These multimodal effects of music together with music’s ability to tap into the emotion and reward system in the brain can be used to facilitate and enhance therapeutic approaches geared toward rehabilitating and restoring neurological dysfunctions and impairments of an acquired or congenital brain disorder. In this article, we review plastic changes in functional networks and structural components of the brain in response to short- and long-term music listening and music making activities. The specific influence of music on the developing brain is emphasized and possible transfer effects on emotional and cognitive processes are discussed. Furthermore, we present data on the potential of using musical tools and activities to support and facilitate neurorehabilitation. We will focus on interventions such as melodic intonation therapy and music-supported motor rehabilitation to showcase the effects of neurologic music therapies and discuss their underlying neural mechanisms.
PMCID: PMC4425943  PMID: 25725918
brain plasticity; melodic intonation therapy; music-supported training; neurologic music therapy; neurorehabilitation
12.  The Role of Dopamine in Huntington’s Disease 
Progress in brain research  2014;211:235-254.
Alterations in dopamine (DA) neurotransmission in Parkinson’s disease are well-known and widely studied. Much less is known about DA changes that accompany and underlie some of the symptoms of Huntington’s disease (HD), a dominant inherited neurodegenerative disorder characterized by chorea, cognitive deficits and psychiatric disturbances. The cause is an expansion in CAG (glutamine) repeats in the HTT gene. The principal histopathology of HD is the loss of medium-sized spiny neurons (MSNs) and, to a lesser degree, neuronal loss in cerebral cortex, thalamus, hippocampus and hypothalamus. Neurochemical, electrophysiological and behavioral studies in HD patients and genetic mouse models suggest biphasic changes in DA neurotransmission. In the early stages DA neurotransmission is increased leading to hyperkinetic movements that can be alleviated by depleting DA stores. In contrast, in the late stages DA deficits produce hypokinesia that can be treated by increasing DA function. Alterations in DA neurotransmission affect glutamate receptor modulation and could contribute to excitotoxicity. The mechanisms of DA dysfunction, in particular the increased DA tone in the early stages of the disease, are presently unknown but may include initial upregulation of DA neuron activity caused by the genetic mutation, reduced inhibition resulting from striatal MSN loss, increased excitation from cortical inputs, and DA autoreceptor dysfunction. Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms.
PMCID: PMC4409123  PMID: 24968783
Huntington’s disease; dopamine; neurotransmission; receptors; glutamate; medium-sized spiny neurons
13.  A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common denominator for multiple features of Down syndrome 
Progress in brain research  2012;197:223-236.
The hedgehog (HH) family of growth factors is involved in many aspects of growth and development, from the establishment of left-right axes at gastrulation to the patterning and formation of multiple structures in essentially every tissue and the maintenance and regulation of stem cell populations in adults. Sonic hedgehog (Shh) in particular acts as a mitogen, regulating proliferation of target cells, a growth factor that triggers differentiation in target populations, and a morphogen causing cells to respond differently based on their positions along a spatial and temporal concentration gradient. Given its very broad range of effects in development, it is not surprising that many of the structures affected by a disruption in Shh signaling are also affected in Down syndrome (DS). However, recent studies have shown that trisomic cerebellar granule cell precursors have a deficit, compared to their euploid counterparts, in their response to the mitogenic effects of Shh. This deficit substantially contributes to the hypocellular cerebellum in mouse models that parallels the human DS phenotype, and can be corrected in early development by a single exposure to a small molecule agonist of the Shh pathway.
PMCID: PMC4405118  PMID: 22541295
14.  Respiration and Autonomic Regulation and Orexin 
Progress in brain research  2012;198:25-46.
Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles including the modulation of breathing and autonomic function. That orexin activity is fundamentally dependent on sleep-wake state and circadian cycle requires consideration of orexin function in physiological control systems in respect to these two state-related activity patterns. Both transgenic mouse studies and focal orexin receptor antagonism support a role for orexins in respiratory chemosensitivity to CO2 predominantly in wakefulness, with further observations limiting this role to the dark period. In addition, orexin neurons participate in the regulation of sympathetic activity, including effects on blood pressure and thermoregulation. Orexin is also essential in physiological responses to stress. Orexin-mediated processes may operate at two levels: 1) in sleep-wake and circadian states; and 2) in stress, e.g., the defense or “fight or flight” response and panic anxiety syndrome.
PMCID: PMC4405125  PMID: 22813968
orexin; Almorexant; chemoreception; CO2; blood pressure
15.  Changes in plasticity across the lifespan: Cause of disease and target for intervention 
Progress in brain research  2013;207:91-120.
We conceptualize brain plasticity as an intrinsic property of the nervous system enabling rapid adaptation in response to changes in an organism's internal and external environment. In prenatal and early postnatal development, plasticity allows for the formation of organized nervous system circuitry and the establishment of functional networks. As the individual is exposed to various sensory stimuli in the environment, brain plasticity allows for functional and structural adaptation and underlies learning and memory. We argue that the mechanisms of plasticity change over the lifespan with different slopes of change in different individuals. These changes play a key role in the clinical phenotype of neurodevelopmental disorders like autism and schizophrenia, as well as neurodegenerative disorders such as Alzheimer's disease. Altered plasticity can trigger maladaptive cascades and be the cause of deficits and disability, but also offers opportunities for novel therapeutic interventions. In this chapter, we discuss the importance of brain plasticity across the lifespan and how neuroplasticity based therapies offer promise for disorders with otherwise limited effective treatment.
PMCID: PMC4392917  PMID: 24309252
Plasticity; Aging; Lifespan; Transcranial Magnetic Stimulation; Autism Spectrum Disorders; Schizophrenia; Alzheimer's Disease
16.  Contributions of the Pre-Bötzinger Complex and the Kölliker-Fuse Nuclei to Respiratory Rhythm and Pattern Generation in Awake and Sleeping Goats 
Progress in brain research  2014;209:73-89.
We investigated in three groups of awake and sleeping goats whether there are differences in ventilatory responses after injections of Ibotenic acid (IA, glutamate receptor agonist and neurotoxin) into the pre-Bötzinger complex (preBötC), lateral parabrachial (LPBN), medial (MPBN) parabrachial, or Kölliker-Fuse nuclei (KFN). In one group, within minutes after bilateral injection of 10 µl IA (50 mM) into the preBötC, there was a 10-fold increase in breathing frequency, but 1.5 h later, the goats succumbed to terminal apnea. These data are consistent with findings in reduced preparations that the preBötC is critical to sustaining normal breathing. In a second group, increasing volumes (0.5–10 µl) of IA injected at weekly intervals into the preBötC elicited a near-dose-dependent tachypnea and irregular breathing that lasted at least 5 h. There were apneas restricted to wakefulness, but none were terminal. Postmortem histology revealed that the preBötC was 90% destroyed, but there was a 25–40% above normal number of neurons in the presumed parafacial respiratory group that may have contributed to maintenance of arterial blood gas homeostasis. In a third group, bilateral injections (1 and 10 µl) of IA into the LPBN, MPBN, or KFN did not significantly increase breathing in any group, and there were no terminal apneas. However, 3–5 h after the injections into the KFN, breathing frequency was decreased and the three-phase eupneic breathing pattern was eliminated. Between 10 and 15 h after the injections, the eupneic breathing pattern was not consistently restored to normal, breathing frequency remained attenuated, and there were apneas during wakefulness. Our findings during wakefulness and NREM sleep warrant concluding that (a) the preBötC is a primary site of respiratory rhythm generation; (b) the preBötC and the KFN are determinants of respiratory pattern generation; (c) after IA-induced lesions, there is time-dependent plasticity within the respiratory control network; and (d) ventilatory control mechanisms are state dependent.
PMCID: PMC4341960  PMID: 24746044
respiratory rhythm and pattern generation; pre-Bötzinger complex; pontine respiratory group; neural plasticity; wakefulness; NREM sleep
17.  Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior 
Progress in brain research  2014;211:13-30.
Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat co-morbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here we summarize recent studies in juvenile rats on the molecular effects in the mid- and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH+FLX treatments can produce similar molecular changes as seen after cocaine exposure, while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood.
PMCID: PMC4331026  PMID: 24968775
19.  Molecular mechanisms of clinical concentrating and diluting disorders 
Progress in brain research  2008;170:539-550.
Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, hypothyroidism, glucocorticoid and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the non-osmotic stimulation of arginine vasopressin release with upregulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin-resistant. They may involve several factors, such as impaired counter-current concentration secondary to downregulation of Na-K-2Cl co-transporter. Vasopressin-resistant downregulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
PMCID: PMC4319677  PMID: 18655907
vasopressin; water channels; hyponatremia; V2 receptor antagonists; aquaretics
20.  Making the lifetime connection between brain and machine for restoring and enhancing function 
Progress in brain research  2011;194:1-25.
A reliable neural interface that lasts a lifetime will lead to the development of neural prosthetic devices as well as the possibility that brain function can be enhanced. Our data demonstrate that a reliable neural interface is best achieved when the surrounding neuropil grows into the electrode tip where it is held securely, allowing myelinated axons to be recorded using implanted amplifiers. Stable single and multiunits were recorded from three implanted subjects and classified according to amplitudes and firing rates. In one paralyzed and mute subject implanted for over 5 years with a double electrode in the speech motor cortex, the single units allowed recognition of over half the 39 English language phonemes detected using a variety of decoding methods. These single units were used by the subject in a speech task where vowel phonemes were recognized and fed back to the subject using audio output. Weeks of training resulted in an 80% success rate in producing four vowels in an adaptation of the classic center-out task used in motor control studies. The importance of using single units was shown in a different task using pure tones that the same subject heard and then sung or hummed in his head. Feedback was associated with smoothly coordinated unit firings. The plasticity of the unit firings was demonstrated over several sessions first without, and then with, feedback. These data suggest that units can be reliably recorded over years, that there is an inverse relationship between single unit firing rate and amplitude, that pattern recognition decoding paradigms can allow phoneme recognition, that single units appear more important than multiunits when precision is important, and that units are plastic in their functional relationships. These characteristics of a reliable neural interface are essential for the development of neural prostheses and also for the future enhancement of human brain function.
PMCID: PMC4305334  PMID: 21867791
brain computer interfacing; brain machine interfacing; neurotrophic electrode; long-term human recording; speech prosthesis; single unit recording; multi-unit recording; local field potentials
21.  Cortical Plasticity, Excitatory–Inhibitory Balance, and Sensory Perception 
Progress in brain research  2013;207:65-90.
Experience shapes the central nervous system throughout life. Structural and functional plasticity confers a remarkable ability on the brain, allowing neural circuits to adequately adapt to dynamic environments. This process can require selective adjustment of many excitatory and inhibitory synapses in an organized manner, in such a way as to enhance representations of behaviorally important sensory stimuli while preserving overall network excitability. The rules and mechanisms that orchestrated these changes across different synapses and throughout neuronal ensembles are beginning to be understood. Here, we review the evidence connecting synaptic plasticity to functional plasticity and perceptual learning, focusing on the roles of various neuromodulatory systems in enabling plasticity of adult neural circuits. However, the challenge remains to appropriately leverage these systems and forms of plasticity to persistently improve perceptual abilities and behavioral performance.
PMCID: PMC4300113  PMID: 24309251
neuromodulation; sensory cortex; synaptic plasticity; excitatory–inhibitory balance; perception
22.  Cortical Odor Processing in Health and Disease 
Progress in brain research  2014;208:275-305.
The olfactory system has a rich cortical representation, including a large archicortical component present in most vertebrates, and in mammals neocortical components including the entorhinal and orbitofrontal cortices. Together, these cortical components contribute to normal odor perception and memory. They help transform the physicochemical features of volatile molecules inhaled or exhaled through the nose into the perception of odor objects with rich associative and hedonic aspects. This chapter focuses on how olfactory cortical areas contribute to odor perception and begins to explore why odor perception is so sensitive to disease and pathology. Odor perception is disrupted by a wide range of disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia, depression, autism, and early life exposure to toxins. This olfactory deficit often occurs despite maintained functioning in other sensory systems. Does the unusual network of olfactory cortical structures contribute to this sensitivity?
PMCID: PMC4284974  PMID: 24767487
piriform cortex; orbitofrontal cortex; entorhinal cortex; mediodorsal thalamus; odor perception
23.  Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006 
Progress in brain research  2007;166:525-536.
There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.
PMCID: PMC4283806  PMID: 17956816
tinnitus; standards; assessment; questionnaires; treatment; outcome; case history
24.  Affective brain areas and sleep disordered breathing 
Progress in brain research  2014;209:275-293.
The neural damage accompanying the hypoxia, reduced perfusion, and other consequences of sleep-disordered breathing found in obstructive sleep apnea, heart failure (HF), and congenital central hypoventilation syndrome (CCHS), appears in areas that serve multiple functions, including emotional drives to breathe, and involve systems that serve affective, cardiovascular, and breathing roles. The damage, assessed with structural magnetic resonance imaging (MRI) procedures, shows tissue loss or water content and diffusion changes indicative of injury, and impaired axonal integrity between structures; damage is preferentially unilateral. Functional MRI responses in affected areas also are time- or amplitude- distorted to ventilatory or autonomic challenges. Among the structures injured are the insular, cingulate, and ventral medial prefrontal cortices, as well as cerebellar deep nuclei and cortex, anterior hypothalamus, raphé, ventrolateral medulla, basal ganglia and, in CCHS, the locus coeruleus. Raphé and locus coeruleus injury may modify serotonergic and adrenergic modulation of upper airway and arousal characteristics. Since both axons and gray matter show injury, the consequences to function, especially to autonomic, cognitive, and mood regulation, are major. Several affected rostral sites, including the insular and cingulate cortices and hippocampus, mediate aspects of dyspnea, especially in CCHS, while others, including the anterior cingulate and thalamus, participate in initiation of inspiration after central breathing pauses, and the medullary injury can impair baroreflex and breathing control. The ancillary injury associated with sleep-disordered breathing to central structures can elicit multiple other distortions in cardiovascular, cognitive, and emotional functions in addition to effects on breathing regulation.
PMCID: PMC4060533  PMID: 24746053
Obstructive Sleep Apnea; Congenital Central Hypoventilation Syndrome; Heart Failure; Hypothalamus; Medulla; Brainstem; Magnetic Resonance Imaging; Dyspnea
25.  Coding odor identity and odor value in awake rodents 
Progress in brain research  2014;208:205-222.
In the last decade, drastic changes in the understanding of the role of the olfactory bulb and piriform cortex in odor detection have taken place through awake behaving recording in rodents. It is clear that odor responses in mitral and granule cells are strikingly different in the olfactory bulb of anesthetized vs. awake animals. In addition, sniff recording has evidenced that mitral cell responses to odors during the sniff can convey information on the odor identity and sniff phase. Moreover, we review studies that show that the mitral cell conveys not only information on odor identity but also on whether the odor is rewarded or not (odor value). Finally, we discuss how the substantial increase in awake behaving recording raises questions for future studies.
PMCID: PMC4131676  PMID: 24767484
olfaction; awake behaving; anesthetized; sniff; olfactory bulb; piriform cortex

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