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1.  Visual homeostatic processing in V1: when probability meets dynamics 
doi:10.3389/fnsys.2015.00006
PMCID: PMC4315031
visual cortex; predictive coding; homeostasis; information transmission; orientation difference detection; natural image processing
2.  Multifaceted effects of noisy galvanic vestibular stimulation on manual tracking behavior in Parkinson’s disease 
Parkinson’s disease (PD) is a neurodegenerative movement disorder that is characterized clinically by slowness of movement, rigidity, tremor, postural instability, and often cognitive impairments. Recent studies have demonstrated altered cortico-basal ganglia rhythms in PD, which raises the possibility of a role for non-invasive stimulation therapies such as noisy galvanic vestibular stimulation (GVS). We applied noisy GVS to 12 mild-moderately affected PD subjects (Hoehn and Yahr 1.5–2.5) off medication while they performed a sinusoidal visuomotor joystick tracking task, which alternated between 2 task conditions depending on whether the displayed cursor position underestimated the actual error by 30% (‘Better’) or overestimated by 200% (‘Worse’). Either sham or subthreshold, noisy GVS (0.1–10 Hz, 1/f-type power spectrum) was applied in pseudorandom order. We used exploratory (linear discriminant analysis with bootstrapping) and confirmatory (robust multivariate linear regression) methods to determine if the presence of GVS significantly affected our ability to predict cursor position based on target variables. Variables related to displayed error were robustly seen to discriminate GVS in all subjects particularly in the Worse condition. If we considered higher frequency components of the cursor trajectory as “noise,” the signal-to-noise ratio of cursor trajectory was significantly increased during the GVS stimulation. The results suggest that noisy GVS influenced motor performance of the PD subjects, and we speculate that they were elicited through a combination of mechanisms: enhanced cingulate activity resulting in modulation of frontal midline theta rhythms, improved signal processing in neuromotor system via stochastic facilitation and/or enhanced “vigor” known to be deficient in PD subjects. Further work is required to determine if GVS has a selective effect on corrective submovements that could not be detected by the current analyses.
doi:10.3389/fnsys.2015.00005
PMCID: PMC4313776
Parkinson’s disease; vestibular system; GVS; manual tracking; discriminant analysis
3.  Functions of delay-period activity in the prefrontal cortex and mnemonic scotomas revisited 
Working memory (WM) is one of key concepts to understand functions of the prefrontal cortex. Delay-period activity is an important neural correlate to understand the role of WM in prefrontal functions. The importance of delay-period activity is that this activity can encode not only visuospatial information but also a variety of information including non-spatial visual features, auditory and tactile stimuli, task rules, expected reward, and numerical quantity. This activity also participates in a variety of information processing including sensory-to-motor information transformation. These mnemonic features of delay-period activity enable to perform various important operations that the prefrontal cortex participates in, such as executive controls, and therefore, support the notion that WM is an important function to understand prefrontal functions. On the other hand, although experiments using manual versions of the delayed-response task had revealed many important findings, an oculomotor version of this task enabled us to use multiple cue positions, exclude postural orientation during the delay period, and further prove the importance of mnemonic functions of the prefrontal cortex. In addition, monkeys with unilateral lesions exhibited specific impairment only in the performance of memory-guided saccades directed toward visual cues in the visual field contralateral to the lesioned hemisphere. This result indicates that memories for visuospatial coordinates in each hemifield are processed primarily in the contralateral prefrontal cortex. This result further strengthened the idea of mnemonic functions of the prefrontal cortex. Thus, the mnemonic functions of the prefrontal cortex and delay-period activity may not need to be reconsidered, but should be emphasized.
doi:10.3389/fnsys.2015.00002
PMCID: PMC4318271
prefrontal cortex; working memory; mnemonic scotoma; delay-period activity; delayed-response task; spatial-information processing
4.  Enhancing multiple object tracking performance with noninvasive brain stimulation: a causal role for the anterior intraparietal sulcus 
Multiple object tracking (MOT) is a complex task recruiting a distributed network of brain regions. There are also marked individual differences in MOT performance. A positive causal relationship between the anterior intraparietal sulcus (AIPS), an integral region in the MOT attention network and inter-individual variation in MOT performance has not been previously established. The present study used transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation, in order to examine such a causal link. Active anodal stimulation was applied to the right AIPS and the left dorsolateral prefrontal cortex (DLPFC) (and sham stimulation), an area associated with working memory (but not MOT) while participants completed a MOT task. Stimulation to the right AIPS significantly improved MOT accuracy more than the other two conditions. The results confirm a causal role of the AIPS in the MOT task and illustrate that tDCS has the ability to improve MOT performance.
doi:10.3389/fnsys.2015.00003
PMCID: PMC4318277
tDCS; brain stimulation; multiple object tracking; anterior intraparietal sulcus; spatial attention
5.  Systems neuroscience in focus: from the human brain to the global brain? 
doi:10.3389/fnsys.2015.00007
PMCID: PMC4319389
global brain; complex adaptive systems; human longevity; techno-cultural society; noeme; systems neuroscience
6.  Screening and personalizing nootropic drugs and cognitive modulator regimens in silico 
The go-to cognitive enhancers of today are those that are widely available rather than optimal for the user, including drugs typically prescribed for treatment of ADHD (e.g., methylphenidate) and sleep disturbances such as narcolepsy (modafinil). While highly effective in their intended therapeutic role, performance gains in healthy populations are modest at best and profoundly inconsistent across subgroups and individuals. We propose a method for in silico screening of possible novel cognitive enhancers followed by high-throughput in vivo and in vitro validation. The proposed method uses gene expression data to evaluate the the collection of activated or suppressed signaling pathways in tissues or neurons of the cognitively enhanced brain. An algorithm maps expression data onto signaling pathways and quantifies their individual activation strength. The collective pathways and their activation form what we term the signaling pathway cloud, a biological fingerprint of cognitive enhancement (or any other condition of interest). Drugs can then be screened and ranked based on their ability to minimize, mimic, or exaggerate pathway activation or suppression within that cloud. Using this approach, one may predict the efficacy of many drugs that may enhance various aspects of cognition before costly preclinical studies and clinical trials are undertaken.
doi:10.3389/fnsys.2015.00004
PMCID: PMC4319391
nootropic; cognitive enhancement; personalized medicine; drug repositioning; oncofinder; in silico medicine; signalome; signalome profiling
7.  DC-shifts in amplitude in-field generated by an oscillatory interference model of grid cell firing 
Oscillatory interference models propose a mechanism by which the spatial firing pattern of grid cells can arise from the interaction of multiple oscillators that shift in relative phase. These models produce aspects of the physiological data such as the phase precession dynamics observed in grid cells. However, existing oscillatory interference models did not predict the in-field DC shifts in the membrane potential of grid cells that have been observed during intracellular recordings in navigating animals. Here, we demonstrate that DC shifts can be generated in an oscillatory interference model when half-wave rectified oscillatory inputs are summed by a leaky integrate-and-fire neuron with a long membrane decay constant (100 ms). The non-linear mean of the half-wave rectified input signal is reproduced in the grid cell's membrane potential trace producing the DC shift within field. For shorter values of the decay constant integration is more effective if the input signal, comprising input from 6 head direction selective populations, is temporally spread during in-field epochs; this requires that the head direction selective populations act as velocity controlled oscillators with baseline oscillations that are phase offset from one another. The resulting simulated membrane potential matches several properties of the empirical intracellular recordings, including: in-field DC-shifts, theta-band oscillations, phase precession of both membrane potential oscillations and grid cell spiking activity relative to network theta and a stronger correlation between DC-shift amplitude and firing-rate than between theta-band oscillation amplitude and firing-rate. This work serves to demonstrate that oscillatory interference models can account for the DC shifts in the membrane potential observed during intracellular recordings of grid cells without the need to appeal to attractor dynamics.
doi:10.3389/fnsys.2014.00001
PMCID: PMC3901010  PMID: 24478639
grid cells; theta phase precession; oscillatory interference model; leaky-integrate-and-fire neuron; oscillations
8.  Transcranial direct current stimulation: five important issues we aren't discussing (but probably should be) 
Transcranial Direct Current Stimulation (tDCS) is a neuromodulatory device often publicized for its ability to enhance cognitive and behavioral performance. These enhancement claims, however, are predicated upon electrophysiological evidence and descriptions which are far from conclusive. In fact, a review of the literature reveals a number of important experimental and technical issues inherent with this device that are simply not being discussed in any meaningful manner. In this paper, we will consider five of these topics. The first, inter-subject variability, explores the extensive between- and within-group differences found within the tDCS literature and highlights the need to properly examine stimulatory response at the individual level. The second, intra-subject reliability, reviews the lack of data concerning tDCS response reliability over time and emphasizes the importance of this knowledge for appropriate stimulatory application. The third, sham stimulation and blinding, draws attention to the importance (yet relative lack) of proper control and blinding practices in the tDCS literature. The fourth, motor and cognitive interference, highlights the often overlooked body of research that suggests typical behaviors and cognitions undertaken during or following tDCS can impair or abolish the effects of stimulation. Finally, the fifth, electric current influences, underscores several largely ignored variables (such as hair thickness and electrode attachments methods) influential to tDCS electric current density and flow. Through this paper, we hope to increase awareness and start an ongoing dialog of these important issues which speak to the efficacy, reliability, and mechanistic foundations of tDCS.
doi:10.3389/fnsys.2014.00002
PMCID: PMC3901383  PMID: 24478640
transcranial direct current stimulation (tDCS); variability; reliability; efficacy; mechanisms of action
9.  Neural signal for counteracting pre-action bias in the centromedian thalamic nucleus 
Most of our daily actions are selected and executed involuntarily under familiar situations by the guidance of internal drives, such as motivation. The behavioral tendency or biasing towards one over others reflects the action-selection process in advance of action execution (i.e., pre-action bias). Facing unexpected situations, however, pre-action bias should be withdrawn and replaced by an alternative that is suitable for the situation (i.e., counteracting bias). To understand the neural mechanism for the counteracting process, we studied the neural activity of the thalamic centromedian (CM) nucleus in monkeys performing GO-NOGO task with asymmetrical or symmetrical reward conditions. The monkeys reacted to GO signal faster in large-reward condition, indicating behavioral bias toward large reward. In contrast, they responded slowly in small-reward condition, suggesting a conflict between internal drive and external demand. We found that neurons in the CM nucleus exhibited phasic burst discharges after GO and NOGO instructions especially when they were associated with small reward. The small-reward preference was positively correlated with the strength of behavioral bias toward large reward. The small-reward preference disappeared when only NOGO action was requested. The timing of activation predicted the timing of action opposed to bias. These results suggest that CM signals the discrepancy between internal pre-action bias and external demand, and mediates the counteracting process—resetting behavioral bias and leading to execution of opposing action.
doi:10.3389/fnsys.2014.00003
PMCID: PMC3904122  PMID: 24478641
reward; thalamus; basal ganglia; attention; monkey; action-selection
10.  Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands 
Cerebellar ataxias represent a very heterogeneous group of disabling disorders for which we lack effective symptomatic therapies in most cases. There is currently an intense interest in the use of non-invasive transcranial DC stimulation (tDCS) to modulate the activity of the cerebellum in ataxic disorders. We performed a detailed laboratory assessment of the effects of transcranial cerebello-cerebral DC stimulation (tCCDCS, including a sham procedure) on upper limb tremor and dysmetria in 2 patients presenting a dominant spinocerebellar ataxia (SCA) type 2, one of the most common SCAs encountered during practice. Both patients had a very similar triplet expansion size in the ATXN2 gene (respectively, 39 and 40 triplets). tCCDCS reduced both postural tremor and action tremor, as confirmed by spectral analysis. Quadratical PSD (power spectral density) of postural tremor dropped to 38.63 and 41.42% of baseline values in patient 1 and 2, respectively. The integral of the subband 4–20 Hz dropped to 46.9 and 62.3% of baseline values, respectively. Remarkably, tCCDCS canceled hypermetria and reduced dramatically the onset latency of the antagonist EMG activity associated with fast goal-directed movements toward 3 aimed targets (0.2, 0.3, and 0.4 rad). Following tCCDCS, the latency dropped from 108–98 to 63–57 ms in patient 1, and from 74–87 to 41–46 ms in patient 2 (mean control values ± SD: 36 ± 8 to 45 ± 11 ms), corresponding to a major drop of z scores for the 2 patients from 7.12 ± 0.69 to 1.28 ± 1.27 (sham procedure: 6.79 ± 0.71). This is the first demonstration that tCCDCS improves upper limb tremor and hypermetria in SCA type 2. In particular, this is the first report of a favorable effect on the onset latency of the antagonist EMG activity, a neurophysiological marker of the defect in programming of timing of motor commands. Our results indicate that tCCDCS should be considered in the symptomatic management of upper limb motor deficits in cerebellar ataxias. Future studies addressing a tDCS-based neuromodulation to improve motor control of upper limbs are required (a) in a large group of cerebellar disorders, and (b) in different subgroups of ataxic patients. The anatomical location of the cerebellum below the skull is particularly well suited for such studies.
doi:10.3389/fnsys.2014.00009
PMCID: PMC3906576  PMID: 24523678
DC stimulation; cerebellum; ataxia; tremor; hypermetria; antagonist; EMG; timing
11.  The thalamostriatal system in normal and diseased states 
Because of our limited knowledge of the functional role of the thalamostriatal system, this massive network is often ignored in models of the pathophysiology of brain disorders of basal ganglia origin, such as Parkinson’s disease (PD). However, over the past decade, significant advances have led to a deeper understanding of the anatomical, electrophysiological, behavioral and pathological aspects of the thalamostriatal system. The cloning of the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) has provided powerful tools to differentiate thalamostriatal from corticostriatal glutamatergic terminals, allowing us to carry out comparative studies of the synaptology and plasticity of these two systems in normal and pathological conditions. Findings from these studies have led to the recognition of two thalamostriatal systems, based on their differential origin from the caudal intralaminar nuclear group, the center median/parafascicular (CM/Pf) complex, or other thalamic nuclei. The recent use of optogenetic methods supports this model of the organization of the thalamostriatal systems, showing differences in functionality and glutamate receptor localization at thalamostriatal synapses from Pf and other thalamic nuclei. At the functional level, evidence largely gathered from thalamic recordings in awake monkeys strongly suggests that the thalamostriatal system from the CM/Pf is involved in regulating alertness and switching behaviors. Importantly, there is evidence that the caudal intralaminar nuclei and their axonal projections to the striatum partly degenerate in PD and that CM/Pf deep brain stimulation (DBS) may be therapeutically useful in several movement disorders.
doi:10.3389/fnsys.2014.00005
PMCID: PMC3906602  PMID: 24523677
thalamus; Parkinson’s disease; intralaminar nuclei; glutamate; vesicular glutamate transporter; attention; striatum; Tourette’s syndrome
12.  Effects of age-related hearing loss and background noise on neuromagnetic activity from auditory cortex 
Aging is often accompanied by hearing loss, which impacts how sounds are processed and represented along the ascending auditory pathways and within the auditory cortices. Here, we assess the impact of mild binaural hearing loss on the older adults’ ability to both process complex sounds embedded in noise and to segregate a mistuned harmonic in an otherwise periodic stimulus. We measured auditory evoked fields (AEFs) using magnetoencephalography while participants were presented with complex tones that had either all harmonics in tune or had the third harmonic mistuned by 4 or 16% of its original value. The tones (75 dB sound pressure level, SPL) were presented without, with low (45 dBA SPL), or with moderate (65 dBA SPL) Gaussian noise. For each participant, we modeled the AEFs with a pair of dipoles in the superior temporal plane. We then examined the effects of hearing loss and noise on the amplitude and latency of the resulting source waveforms. In the present study, results revealed that similar noise-induced increases in N1m were present in older adults with and without hearing loss. Our results also showed that the P1m amplitude was larger in the hearing impaired than in the normal-hearing adults. In addition, the object-related negativity (ORN) elicited by the mistuned harmonic was larger in hearing impaired listeners. The enhanced P1m and ORN amplitude in the hearing impaired older adults suggests that hearing loss increased neural excitability in auditory cortices, which could be related to deficits in inhibitory control.
doi:10.3389/fnsys.2014.00008
PMCID: PMC3907769  PMID: 24550790
aging; MEG; hearing loss; auditory cortex; inhibition (psychology)
13.  Back to front: cerebellar connections and interactions with the prefrontal cortex 
Although recent neuroanatomical evidence has demonstrated closed-loop connectivity between prefrontal cortex and the cerebellum, the physiology of cerebello-cerebral circuits and the extent to which cerebellar output modulates neuronal activity in neocortex during behavior remain relatively unexplored. We show that electrical stimulation of the contralateral cerebellar fastigial nucleus (FN) in awake, behaving rats evokes distinct local field potential (LFP) responses (onset latency ~13 ms) in the prelimbic (PrL) subdivision of the medial prefrontal cortex. Trains of FN stimulation evoke heterogeneous patterns of response in putative pyramidal cells in frontal and prefrontal regions in both urethane-anesthetized and awake, behaving rats. However, the majority of cells showed decreased firing rates during stimulation and subsequent rebound increases; more than 90% of cells showed significant changes in response. Simultaneous recording of on-going LFP activity from FN and PrL while rats were at rest or actively exploring an open field arena revealed significant network coherence restricted to the theta frequency range (5–10 Hz). Granger causality analysis indicated that this coherence was significantly directed from cerebellum to PrL during active locomotion. Our results demonstrate the presence of a cerebello-prefrontal pathway in rat and reveal behaviorally dependent coordinated network activity between the two structures, which could facilitate transfer of sensorimotor information into ongoing neocortical processing during goal directed behaviors.
doi:10.3389/fnsys.2014.00004
PMCID: PMC3912388  PMID: 24550789
cerebellum; fastigial nucleus; prefrontal cortex; prelimbic cortex; theta; coherence
14.  Oscillatory motor network activity during rest and movement: an fNIRS study 
Coherent network oscillations (<0.1 Hz) linking distributed brain regions are commonly observed in the brain during both rest and task conditions. What oscillatory network exists and how network oscillations change in connectivity strength, frequency and direction when going from rest to explicit task are topics of recent inquiry. Here, we study network oscillations within the sensorimotor regions of able-bodied individuals using hemodynamic activity as measured by functional near-infrared spectroscopy (fNIRS). Using spectral interdependency methods, we examined how the supplementary motor area (SMA), the left premotor cortex (LPMC) and the left primary motor cortex (LM1) are bound as a network during extended resting state (RS) and between-tasks resting state (btRS), and how the activity of the network changes as participants execute left, right, and bilateral hand (LH, RH, and BH) finger movements. We found: (i) power, coherence and Granger causality (GC) spectra had significant peaks within the frequency band (0.01–0.04 Hz) during RS whereas the peaks shifted to a bit higher frequency range (0.04–0.08 Hz) during btRS and finger movement tasks, (ii) there was significant bidirectional connectivity between all the nodes during RS and unidirectional connectivity from the LM1 to SMA and LM1 to LPMC during btRS, and (iii) the connections from SMA to LM1 and from LPMC to LM1 were significantly modulated in LH, RH, and BH finger movements relative to btRS. The unidirectional connectivity from SMA to LM1 just before the actual task changed to the bidirectional connectivity during LH and BH finger movement. The uni-directionality could be associated with movement suppression and the bi-directionality with preparation, sensorimotor update and controlled execution. These results underscore that fNIRS is an effective tool for monitoring spectral signatures of brain activity, which may serve as an important precursor before monitoring the recovery progress following brain injury.
doi:10.3389/fnsys.2014.00013
PMCID: PMC3912434  PMID: 24550793
fNIR; slow oscillations; resting state; motor networks; Granger causality; brain connectivity
15.  When is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics 
The enhancement debate in neuroscience and biomedical ethics tends to focus on the augmentation of certain capacities or functions: memory, learning, attention, and the like. Typically, the point of contention is whether these augmentative enhancements should be considered permissible for individuals with no particular “medical” disadvantage along any of the dimensions of interest. Less frequently addressed in the literature, however, is the fact that sometimes the diminishment of a capacity or function, under the right set of circumstances, could plausibly contribute to an individual's overall well-being: more is not always better, and sometimes less is more. Such cases may be especially likely, we suggest, when trade-offs in our modern environment have shifted since the environment of evolutionary adaptation. In this article, we introduce the notion of “diminishment as enhancement” and go on to defend a welfarist conception of enhancement. We show how this conception resolves a number of definitional ambiguities in the enhancement literature, and we suggest that it can provide a useful framework for thinking about the use of emerging neurotechnologies to promote human flourishing.
doi:10.3389/fnsys.2014.00012
PMCID: PMC3912453  PMID: 24550792
enhancement; neuroenhancement; welfare; well-being; neuroethics; bioethics; diminishment; empathy
16.  The effect of mild-to-moderate hearing loss on auditory and emotion processing networks 
We investigated the impact of hearing loss (HL) on emotional processing using task- and rest-based functional magnetic resonance imaging. Two age-matched groups of middle-aged participants were recruited: one with bilateral high-frequency HL and a control group with normal hearing (NH). During the task-based portion of the experiment, participants were instructed to rate affective stimuli from the International Affective Digital Sounds (IADS) database as pleasant, unpleasant, or neutral. In the resting state experiment, participants were told to fixate on a “+” sign on a screen for 5 min. The results of both the task-based and resting state studies suggest that NH and HL patients differ in their emotional response. Specifically, in the task-based study, we found slower response to affective but not neutral sounds by the HL group compared to the NH group. This was reflected in the brain activation patterns, with the NH group employing the expected limbic and auditory regions including the left amygdala, left parahippocampus, right middle temporal gyrus and left superior temporal gyrus to a greater extent in processing affective stimuli when compared to the HL group. In the resting state study, we observed no significant differences in connectivity of the auditory network between the groups. In the dorsal attention network (DAN), HL patients exhibited decreased connectivity between seed regions and left insula and left postcentral gyrus compared to controls. The default mode network (DMN) was also altered, showing increased connectivity between seeds and left middle frontal gyrus in the HL group. Further targeted analysis revealed increased intrinsic connectivity between the right middle temporal gyrus and the right precentral gyrus. The results from both studies suggest neuronal reorganization as a consequence of HL, most notably in networks responding to emotional sounds.
doi:10.3389/fnsys.2014.00010
PMCID: PMC3912518  PMID: 24550791
fMRI; hearing loss; resting-state fMRI; functional connectivity; emotion; IADS
17.  Volitional enhancement of firing synchrony and oscillation by neuronal operant conditioning: interaction with neurorehabilitation and brain-machine interface 
In this review, we focus on neuronal operant conditioning in which increments in neuronal activities are directly rewarded without behaviors. We discuss the potential of this approach to elucidate neuronal plasticity for enhancing specific brain functions and its interaction with the progress in neurorehabilitation and brain-machine interfaces. The key to-be-conditioned activities that this paper emphasizes are synchronous and oscillatory firings of multiple neurons that reflect activities of cell assemblies. First, we introduce certain well-known studies on neuronal operant conditioning in which conditioned enhancements of neuronal firing were reported in animals and humans. These studies demonstrated the feasibility of volitional control over neuronal activity. Second, we refer to the recent studies on operant conditioning of synchrony and oscillation of neuronal activities. In particular, we introduce a recent study showing volitional enhancement of oscillatory activity in monkey motor cortex and our study showing selective enhancement of firing synchrony of neighboring neurons in rat hippocampus. Third, we discuss the reasons for emphasizing firing synchrony and oscillation in neuronal operant conditioning, the main reason being that they reflect the activities of cell assemblies, which have been suggested to be basic neuronal codes representing information in the brain. Finally, we discuss the interaction of neuronal operant conditioning with neurorehabilitation and brain-machine interface (BMI). We argue that synchrony and oscillation of neuronal firing are the key activities required for developing both reliable neurorehabilitation and high-performance BMI. Further, we conclude that research of neuronal operant conditioning, neurorehabilitation, BMI, and system neuroscience will produce findings applicable to these interrelated fields, and neuronal synchrony and oscillation can be a common important bridge among all of them.
doi:10.3389/fnsys.2014.00011
PMCID: PMC3915778  PMID: 24567704
operant conditioning; synchrony; oscillation; neurorehabilitation; brain-machine interface
18.  Electrophysiological characterization of entopeduncular nucleus neurons in anesthetized and freely moving rats 
The EntoPeduncular nucleus (EP), which is homologous to the internal segment of the Globus Pallidus (GPi) in primates, is one of the two basal ganglia (BG) output nuclei. Despite their importance in cortico-BG information processing, EP neurons have rarely been investigated in rats and there is no available electrophysiological characterization of EP neurons in vivo. We recorded and analyzed the activity of EP neurons in freely moving as well as anesthetized rats, and compared their activity patterns. Examination of neuronal firing statistics during wakefulness suggested that similar to neurons recorded in the primate GPi, EP neurons are a single population characterized by Poisson-like firing. Under isoflurane anesthesia the firing rate of EP neurons decreased substantially and their coefficient of variation and relative duration of quiescence periods increased. Investigation of the relationship between firing rate and depth of anesthesia revealed two distinct neuronal groups: one that decreased its firing rate with the increase in anesthesia level, and a second group where the firing rate was independent of anesthesia level. Post-hoc examination of the firing properties of the two groups showed that they were statistically distinct. These results may thus help reconcile in vitro studies in rats and primates which have reported two distinct neuronal populations, and in vivo studies in behaving primates indicating one homogeneous population. Our data support the existence of two distinct neuronal populations in the rat EP that can be distinguished by their characteristic firing response to anesthesia.
doi:10.3389/fnsys.2014.00007
PMCID: PMC3918587  PMID: 24574980
basal ganglia; electrophysiology; anesthesia; extracellular recording; firing patterns; neuronal population
19.  Spike sorting for polytrodes: a divide and conquer approach 
In order to determine patterns of neural activity, spike signals recorded by extracellular electrodes have to be clustered (sorted) with the aim of ensuring that each cluster represents all the spikes generated by an individual neuron. Many methods for spike sorting have been proposed but few are easily applicable to recordings from polytrodes which may have 16 or more recording sites. As with tetrodes, these are spaced sufficiently closely that signals from single neurons will usually be recorded on several adjacent sites. Although this offers a better chance of distinguishing neurons with similarly shaped spikes, sorting is difficult in such cases because of the high dimensionality of the space in which the signals must be classified. This report details a method for spike sorting based on a divide and conquer approach. Clusters are initially formed by assigning each event to the channel on which it is largest. Each channel-based cluster is then sub-divided into as many distinct clusters as possible. These are then recombined on the basis of pairwise tests into a final set of clusters. Pairwise tests are also performed to establish how distinct each cluster is from the others. A modified gradient ascent clustering (GAC) algorithm is used to do the clustering. The method can sort spikes with minimal user input in times comparable to real time for recordings lasting up to 45 min. Our results illustrate some of the difficulties inherent in spike sorting, including changes in spike shape over time. We show that some physiologically distinct units may have very similar spike shapes. We show that RMS measures of spike shape similarity are not sensitive enough to discriminate clusters that can otherwise be separated by principal components analysis (PCA). Hence spike sorting based on least-squares matching to templates may be unreliable. Our methods should be applicable to tetrodes and scalable to larger multi-electrode arrays (MEAs).
doi:10.3389/fnsys.2014.00006
PMCID: PMC3918743  PMID: 24574979
spike sorting; polytrodes; clustering; tetrodes; multichannel electrodes
20.  Asymmetric pallidal neuronal activity in patients with cervical dystonia 
The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD) is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct vs. indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP) activity from the external (GPe) and internal pallidal segment (GPi) of 13 CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA) with those obtained in CD patients operated under general anaesthesia (GA). In awake patients, mean GPe discharge rate (52 Hz) was lower than that of GPi (72 Hz). Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe– and GPi–LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology.
doi:10.3389/fnsys.2014.00015
PMCID: PMC3920073  PMID: 24574981
cervical dystonia; GPi; GPe; microelectrode recording; LFP; oscillations; coherence; phase–amplitude coupling
21.  Book review: “Glial physiology and pathophysiology” by Alexei Verkhratsky and Arthur Butt, Wiley-Blackwell, 2013 
doi:10.3389/fnsys.2014.00017
PMCID: PMC3920112
astrocytes; glial diseases; microglia; NG2 cells; oligodendrocytes; peripheral glia
22.  How age and linguistic competence alter the interplay of perceptual and cognitive factors when listening to conversations in a noisy environment 
Multi-talker conversations challenge the perceptual and cognitive capabilities of older adults and those listening in their second language (L2). In older adults these difficulties could reflect declines in the auditory, cognitive, or linguistic processes supporting speech comprehension. The tendency of L2 listeners to invoke some of the semantic and syntactic processes from their first language (L1) may interfere with speech comprehension in L2. These challenges might also force them to reorganize the ways in which they perceive and process speech, thereby altering the balance between the contributions of bottom-up vs. top-down processes to speech comprehension. Younger and older L1s as well as young L2s listened to conversations played against a babble background, with or without spatial separation between the talkers and masker, when the spatial positions of the stimuli were specified either by loudspeaker placements (real location), or through use of the precedence effect (virtual location). After listening to a conversation, the participants were asked to answer questions regarding its content. Individual hearing differences were compensated for by creating the same degree of difficulty in identifying individual words in babble. Once compensation was applied, the number of questions correctly answered increased when a real or virtual spatial separation was introduced between babble and talkers. There was no evidence that performance differed between real and virtual locations. The contribution of vocabulary knowledge to dialog comprehension was found to be larger in the virtual conditions than in the real whereas the contribution of reading comprehension skill did not depend on the listening environment but rather differed as a function of age and language proficiency. The results indicate that the acoustic scene and the cognitive and linguistic competencies of listeners modulate how and when top-down resources are engaged in aid of speech comprehension.
doi:10.3389/fnsys.2014.00021
PMCID: PMC3933794  PMID: 24578684
age; nonnative listeners; speech comprehension; spatial separation; hearing; multitalker discourse; auditory-cognitive interaction; hearing loss
23.  Cognitive-motor interactions of the basal ganglia in development 
Neural circuits linking activity in anatomically segregated populations of neurons in subcortical structures and the neocortex throughout the human brain regulate complex behaviors such as walking, talking, language comprehension, and other cognitive functions associated with frontal lobes. The basal ganglia, which regulate motor control, are also crucial elements in the circuits that confer human reasoning and adaptive function. The basal ganglia are key elements in the control of reward-based learning, sequencing, discrete elements that constitute a complete motor act, and cognitive function. Imaging studies of intact human subjects and electrophysiologic and tracer studies of the brains and behavior of other species confirm these findings. We know that the relation between the basal ganglia and the cerebral cortical region allows for connections organized into discrete circuits. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia. Neuronal activity within the basal ganglia associated with motor areas of the cerebral cortex is highly correlated with parameters of movement. Neuronal activity within the basal ganglia and cerebellar loops associated with the prefrontal cortex is related to the aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Damage to the basal ganglia of circuits with motor areas of the cortex leads to motor symptoms, whereas damage to the subcortical components of circuits with non-motor areas of the cortex causes higher-order deficits. In this report, we review some of the anatomic, physiologic, and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex and apply it in clinical applications to attention deficit/hyperactivity disorder (ADHD) with biomechanics and a discussion of retention of primitive reflexes being highly associated with the condition.
doi:10.3389/fnsys.2014.00016
PMCID: PMC3923298  PMID: 24592214
basal ganglia; frontal lobe; cognition; autism; ADHD; posture
24.  Noise-induced hearing loss increases the temporal precision of complex envelope coding by auditory-nerve fibers 
While changes in cochlear frequency tuning are thought to play an important role in the perceptual difficulties of people with sensorineural hearing loss (SNHL), the possible role of temporal processing deficits remains less clear. Our knowledge of temporal envelope coding in the impaired cochlea is limited to two studies that examined auditory-nerve fiber responses to narrowband amplitude modulated stimuli. In the present study, we used Wiener-kernel analyses of auditory-nerve fiber responses to broadband Gaussian noise in anesthetized chinchillas to quantify changes in temporal envelope coding with noise-induced SNHL. Temporal modulation transfer functions (TMTFs) and temporal windows of sensitivity to acoustic stimulation were computed from 2nd-order Wiener kernels and analyzed to estimate the temporal precision, amplitude, and latency of envelope coding. Noise overexposure was associated with slower (less negative) TMTF roll-off with increasing modulation frequency and reduced temporal window duration. The results show that at equal stimulus sensation level, SNHL increases the temporal precision of envelope coding by 20–30%. Furthermore, SNHL increased the amplitude of envelope coding by 50% in fibers with CFs from 1–2 kHz and decreased mean response latency by 0.4 ms. While a previous study of envelope coding demonstrated a similar increase in response amplitude, the present study is the first to show enhanced temporal precision. This new finding may relate to the use of a more complex stimulus with broad frequency bandwidth and a dynamic temporal envelope. Exaggerated neural coding of fast envelope modulations may contribute to perceptual difficulties in people with SNHL by acting as a distraction from more relevant acoustic cues, especially in fluctuating background noise. Finally, the results underscore the value of studying sensory systems with more natural, real-world stimuli.
doi:10.3389/fnsys.2014.00020
PMCID: PMC3925834  PMID: 24596545
amplitude modulation; auditory nerve; sensorineural hearing loss; temporal envelope; temporal resolution; Wiener-kernel analysis
25.  Procedural-based category learning in patients with Parkinson's disease: impact of category number and category continuity 
Previously we found that Parkinson's disease (PD) patients are impaired in procedural-based category learning when category membership is defined by a nonlinear relationship between stimulus dimensions, but these same patients are normal when the rule is defined by a linear relationship (Maddox and Filoteo, 2001; Filoteo et al., 2005a,b). We suggested that PD patients' impairment was due to a deficit in recruiting “striatal units” to represent complex nonlinear rules. In the present study, we further examined the nature of PD patients' procedural-based deficit in two experiments designed to examine the impact of (1) the number of categories, and (2) category discontinuity on learning. Results indicated that PD patients were impaired only under discontinuous category conditions but were normal when the number of categories was increased from two to four. The lack of impairment in the four-category condition suggests normal integrity of striatal medium spiny cells involved in procedural-based category learning. In contrast, and consistent with our previous observation of a nonlinear deficit, the finding that PD patients were impaired in the discontinuous condition suggests that these patients are impaired when they have to associate perceptually distinct exemplars with the same category. Theoretically, this deficit might be related to dysfunctional communication among medium spiny neurons within the striatum, particularly given that these are cholinergic neurons and a cholinergic deficiency could underlie some of PD patients' cognitive impairment.
doi:10.3389/fnsys.2014.00014
PMCID: PMC3928591  PMID: 24600355
Parkinson's disease; category learning; implicit processes; procedural learning; striatum; basal ganglia

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