Activity In Primary Somatosensory Cortex Research Articles

Pain sensitivity related to gamma oscillation of parvalbumin interneuron in primary somatosensory cortex in Dync1i1−/− mice

Cytoplasmic dynein is an important intracellular motor protein that plays an important role in neuronal growth, axonal polarity formation, dendritic differentiation, and dendritic spine development among others. The intermediate chain of dynein, encoded by Dync1i1, plays a vital role in the dynein complex. Therefore, we assessed the behavioral and related neuronal activities in mice with dync1i1 gene knockout. Neuronal activities in primary somatosensory cortex were recorded by in vivo electrophysiology and manipulated by optogenetic and chemogenetics. Nociception of mechanical, thermal, and cold pain in Dync1i1−/− mice were impaired. The activities of parvalbumin (PV) interneurons and gamma oscillation in primary somatosensory were also impaired when exposed to mechanical nociceptive stimulation. This neuronal dysfunction was rescued by optogenetic activation of PV neurons in Dync1i1−/− mice, and mimicked by suppressing PV neurons using chemogenetics in WT mice. Impaired pain sensations in Dync1i1−/− mice were correlated with impaired gamma oscillations due to a loss of interneurons, especially the PV type. This genotype-driven approach revealed an association between impaired pain sensation and cytoplasmic dynein complex.

Thalamic bursting and the role of timing and synchrony in thalamocortical signaling in the awake mouse

The thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior-medial thalamus in the vibrissa pathway of the awake mouse and measured spiking activity in the thalamus and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting; however, surprisingly, the S1 cortical response was not amplified, but instead, timing precisionwas significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to the cortex.

Graded motor imagery modifies movement pain, cortical excitability and sensorimotor function in complex regional pain syndrome.

Patients with complex regional pain syndrome suffer from chronic neuropathic pain and also show a decrease in sensorimotor performance associated with characteristic central and peripheral neural system parameters. In the brain imaging domain, these comprise altered functional sensorimotor representation for the affected hand side. With regard to neurophysiology, a decrease in intracortical inhibition for the sensorimotor cortex contralateral to the affected hand has been repetitively verified, which might be related to increased primary somatosensory cortex functional activation for the affected limb. Rare longitudinal intervention studies in randomized controlled trials have demonstrated that a decrease in primary somatosensory cortex functional MRI activation coincided with pain relief and recovery in sensorimotor performance. By applying a randomized wait-list control crossover study design, we tested possible associations of clinical, imaging and neurophysiology parameters in 21 patients with complex regional pain syndrome in the chronic stage (>6 months). In more detail, we applied graded motor imagery over 6 weeks to relieve movement pain of the affected upper limb. First, baseline parameters were tested between the affected and the non-affected upper limb side and age-matched healthy controls. Second, longitudinal changes in clinical and testing parameters were associated with neurophysiological and imaging parameters. During baseline short intracortical inhibition, as assessed with transcranial magnetic stimulation, was decreased only for hand muscles of the affected hand side. During movement of the affected limb, primary somatosensory cortex functional MRI activation was increased. Hand representation area size for somatosensory stimulation in functional MRI was smaller on the affected side with longer disease duration. Graded motor imagery intervention but not waiting, resulted in a decrease of movement pain. An increase of somatosensory hand representation size over graded motor imagery intervention was related to movement pain relief. Over graded motor imagery intervention, pathological parameters like the increased primary somatosensory cortex activation during fist movement or decreased short intracortical inhibition were modified in the same way as movement pain and hand performance improved. No such changes were observed during the waiting period. Overall, we demonstrated characteristic changes in clinical, behaviour and neuropathology parameters applying graded motor imagery in patients with upper limb complex regional pain syndrome, which casts light on the effects of graded motor imagery intervention on biomarkers for chronic neuropathic pain.

Rapid Cortical Adaptation and the Role of Thalamic Synchrony during Wakefulness.

Rapid sensory adaptation is observed across all sensory systems, and strongly shapes sensory percepts in complex sensory environments. Yet despite its ubiquity and likely necessity for survival, the mechanistic basis is poorly understood. A wide range of primarily in vitro and anesthetized studies have demonstrated the emergence of adaptation at the level of primary sensory cortex, with only modest signatures in earlier stages of processing. The nature of rapid adaptation and how it shapes sensory representations during wakefulness, and thus the potential role in perceptual adaptation, is underexplored, as are the mechanisms that underlie this phenomenon. To address these knowledge gaps, we recorded spiking activity in primary somatosensory cortex (S1) and the upstream ventral posteromedial (VPm) thalamic nucleus in the vibrissa pathway of awake male and female mice, and quantified responses to whisker stimuli delivered in isolation and embedded in an adapting sensory background. We found that cortical sensory responses were indeed adapted by persistent sensory stimulation; putative excitatory neurons were profoundly adapted, and inhibitory neurons only modestly so. Further optogenetic manipulation experiments and network modeling suggest this largely reflects adaptive changes in synchronous thalamic firing combined with robust engagement of feedforward inhibition, with little contribution from synaptic depression. Taken together, these results suggest that cortical adaptation in the regime explored here results from changes in the timing of thalamic input, and the way in which this differentially impacts cortical excitation and feedforward inhibition, pointing to a prominent role of thalamic gating in rapid adaptation of primary sensory cortex.SIGNIFICANCE STATEMENT Rapid adaptation of sensory activity strongly shapes representations of sensory inputs across all sensory pathways over the timescale of seconds, and has profound effects on sensory perception. Despite its ubiquity and theoretical role in the efficient encoding of complex sensory environments, the mechanistic basis is poorly understood, particularly during wakefulness. In this study in the vibrissa pathway of awake mice, we show that cortical representations of sensory inputs are strongly shaped by rapid adaptation, and that this is mediated primarily by adaptive gating of the thalamic inputs to primary sensory cortex and the differential way in which these inputs engage cortical subpopulations of neurons.

Use of Functional MRI to Assess Effects of Deep Brain Stimulation Frequency Changes on Brain Activation in Parkinson Disease.

Models have been developed for predicting ideal contact and amplitude for subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Pulse-width is generally varied to modulate the size of the energy field produced. Effects of varying frequency in humans have not been systematically evaluated. To examine how altered frequencies affect blood oxygen level-dependent activation in PD. PD subjects with optimized DBS programming underwent functional magnetic resonance imaging (fMRI). Frequency was altered and fMRI scans/Unified Parkinson Disease Rating Scale motor subunit (UPDRS-III) scores were obtained. Analysis using DBS-OFF data was used to determine which regions were activated during DBS-ON. Peak activity utilizing T-values was obtained and compared. At clinically optimized settings (n=14 subjects), thalamic, globus pallidum externa (GPe), and posterior cerebellum activation were present. Activation levels significantly decreased in the thalamus, anterior cerebellum, and the GPe when frequency was decreased (P <.001). Primary somatosensory cortex activation levels significantly decreased when frequency was increased by 30Hz, but not 60Hz. Sex, age, disease/DBS duration, and bilaterality did not significantly affect the data. Retrospective analysis of fMRI activation patterns predicted optimal frequency in 11/14 subjects. We show the first data with fMRI of STN DBS-ON while synchronizing cycling with magnetic resonance scanning. At clinically optimized settings, an fMRI signature of thalamic, GPe, and posterior cerebellum activation was seen. Reducing frequency significantly decreased thalamic, GPe, and anterior cerebellum activation. Current standard-of-care programming can take up to 6 mo using UPDRS-III testing alone. We provide preliminary evidence that using fMRI signature of frequency may have clinical utility and feasibility.

Neural Stimulation In Vitro and In Vivo by Photoacoustic Nanotransducers

Summary Neuromodulation is an invaluable approach for the study of neural circuits and clinical treatment of neurological diseases. Here, we report semiconducting polymer nanoparticles based photoacoustic nanotransducers (PANs) for neural stimulation in vitro and in vivo. Our PANs strongly absorb the nanosecond pulsed laser in the near-infrared second window (NIR-II) and generate localized acoustic waves. PANs are shown to be surface modified and selectively bind onto neurons. PAN-mediated activation of primary neurons in vitro is achieved with ten 3-ns laser pulses at 1,030 nm over a 3-ms duration. In vivo neural modulation of mouse brain activities and motor activities is demonstrated by PANs directly injected into brain cortex. With submillimeter spatial resolution and negligible heat deposition, PAN stimulation is a new non-genetic method for precise control of neuronal activities, opening up potentials in non-invasive brain modulation.

Sevoflurane induces neuronal activation and behavioral hyperactivity in young mice

Sevoflurane, a commonly used anesthetic, may cause agitation in patients. However, the mechanism underlying this clinical observation remains largely unknown. We thus assessed the effects of sevoflurane on neuronal activation and behaviors in mice. Ten-day-old mice received 2% sevoflurane, 1% isoflurane, or 6% desflurane for 10 minutes. The behavioral activities were recorded and evaluated at one minute after the loss of righting reflex in the mice, which was about two minutes after the anesthetic administration. The neuronal activation was evaluated by c-Fos expression and calcium imaging at one minute after the anesthetic administration. Propofol, which reduces neuronal activation, was used to determine the cause-and-effect of sevoflurane. We found that sevoflurane caused an increase in neuronal activation in primary somatosensory cortex of young mice and behavioral hyperactivity in the mice at one minute after the loss of righting reflex. Desflurane did not induce behavioral hyperactivity and isoflurane only caused behavioral hyperactivity with borderline significance. Finally, propofol attenuated the sevoflurane-induced increase in neuronal activation and behavioral hyperactivity in young mice. These results demonstrate an unexpected sevoflurane-induced increase in neuronal activation and behavioral hyperactivity in young mice. These findings suggest the potential mechanisms underlying the sevoflurane-induced agitation and will promote future studies to further determine whether anesthetics can induce behavioral hyperactivity via increasing neuronal activation.

Functional Localization of an Attenuating Filter within Cortex for a Selective Detection Task in Mice.

An essential feature of goal-directed behavior is the ability to selectively respond to the diverse stimuli in one's environment. However, the neural mechanisms that enable us to respond to target stimuli while ignoring distractor stimuli are poorly understood. To study this sensory selection process, we trained male and female mice in a selective detection task in which mice learn to respond to rapid stimuli in the target whisker field and ignore identical stimuli in the opposite, distractor whisker field. In expert mice, we used widefield Ca2+ imaging to analyze target-related and distractor-related neural responses throughout dorsal cortex. For target stimuli, we observed strong signal activation in primary somatosensory cortex (S1) and frontal cortices, including both the whisker region of primary motor cortex (wMC) and anterior lateral motor cortex (ALM). For distractor stimuli, we observed strong signal activation in S1, with minimal propagation to frontal cortex. Our data support only modest subcortical filtering, with robust, step-like attenuation in distractor processing between mono-synaptically coupled regions of S1 and wMC. This study establishes a highly robust model system for studying the neural mechanisms of sensory selection and places important constraints on its implementation.SIGNIFICANCE STATEMENT Responding to task-relevant stimuli while ignoring task-irrelevant stimuli is critical for goal-directed behavior. However, the neural mechanisms involved in this selection process are poorly understood. We trained mice in a detection task with both target and distractor stimuli. During expert performance, we measured neural activity throughout cortex using widefield imaging. We observed responses to target stimuli in multiple sensory and motor cortical regions. In contrast, responses to distractor stimuli were abruptly suppressed beyond sensory cortex. Our findings localize the sites of attenuation when successfully ignoring a distractor stimulus and provide essential foundations for further revealing the neural mechanism of sensory selection and distractor suppression.

Comparison of transcranial electrical stimulation regimens for effects on inhibitory circuit activity in primary somatosensory cortex and tactile spatial discrimination performance

Transcranial electrical stimulation (tES) can be used to modulate inhibitory circuits in primary somatosensory cortex, resulting in improved somatosensory function. However, efficacy may depend on the specific stimulus modality and patterns. For instance, transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), and transcranial pulsed current stimulation (tPCS) were found to stably and effectively modulate neuronal excitability, while anodal transcranial direct current stimulation (tDCS) appeared less effective overall but with substantial response heterogeneity among subjects. Therefore, we compared the effects of tES applied to primary somatosensory cortex on somatosensory evoked potential paired-pulse depression (SEP-PPD) and tactile discrimination performance in 17 neurologically healthy subjects. In Experiment 1, somatosensory evoked potential N20/P25_SEP-PPD, N20_SEP-PPD, and P25_SEP-PPD responses were assessed before and immediately after anodal tDCS, tACS (stimulation frequency, 140 Hz), tRNS (stimulation frequency, 0.1–640 Hz), anodal tPCS (pulse width, 50 ms; inter-pulse interval, 5 ms), and sham stimulation applied to primary somatosensory cortex. In Experiment 2, a grating orientation task (GOT) was performed before and immediately after the same anodal tDCS, tRNS, anodal tPCS, and sham stimulation regimens. Anodal tDCS and anodal tPCS decreased N20_SEP-PPD, and tRNS increased the first N20 SEP amplitude. Furthermore, tRNS and anodal tPCS decreased GOT discrimination threshold (improved performance). These results suggest that tRNS and anodal tPCS can improve sensory perception by modulating neuronal activity in primary somatosensory cortex.

Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo

Objective. The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam’s focus. Approach. To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory-evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca2+ responses. Main results. Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm−2 (Isppa), the onset of sensory-evoked cortical responses occurred 3.0 ± 0.7 ms earlier and altered the surface spatial morphology of Ca2+ responses. Significance. These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex.

TrpM8-mediated somatosensation in mouse neocortex.

Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well-defined somatosensory modality, cool sensation mediated by peripheral TrpM8-receptors, to investigate the neural substrate for cool perception in the mouse neocortex. Using activation of cutaneous TrpM8 receptor-expressing neurons, we identify candidate neocortical areas responsive for cool sensation. Initially, we optimized TrpM8 stimulation and determined that menthol, a selective TrpM8 agonist, was more effective than cool stimulation at inducing expression of the immediate-early gene c-fos in the spinal cord. We developed a broad-scale brain survey method for identification of activated brain areas, using automated methods to quantify c-fos immunoreactivity (fos-IR) across animals. Brain areas corresponding to the posterior insular cortex and secondary somatosensory (S2) show elevated fos-IR after menthol stimulation, in contrast to weaker activation in primary somatosensory cortex (S1). In addition, menthol exposure triggered fos-IR in piriform cortex, the amygdala, and the hypothalamus. Menthol-mediated activation was absent in TrpM8-knock-out animals. Our results indicate that cool somatosensory input broadly drives neural activity across the mouse brain, with neocortical signal most elevated in the posterior insula, as well as S2 and S1. These findings are consistent with data from humans indicating that the posterior insula is specialized for somatosensory information encoding temperature, pain, and gentle touch.

Temporal dynamics of brain activation during 40 minutes of pleasant touch

IntroductionTouch is important for individuals' subjective well-being, is typically rewarding, and is one of few sensory stimuli which are experienced as pleasant for a rather long time. This study tracked brain activation during slow stroking stimulation of the arm that was applied continuously for 40min - a much longer time than what previous studies have investigated. Methods25 subjects were stroked for 40min with a soft brush while they were scanned with functional Magnetic Resonance Imaging, and rated the perceived pleasantness of the brush stroking. Two resting baselines were included. Whole brain-based analyses investigated the neural response to long-lasting stroking. ResultsStroking was perceived as pleasant throughout scanning and activated areas that were previously found to be involved in the processing of pleasant touch. Activation in primary somatosensory cortex (S1) and S2, subdivision OP1, decreased over time, whereas activation in orbito-frontal gyrus (OFC) and putamen strongly increased until reaching a plateau after approximately 20min. Similarly, functional connectivity of posterior insula with middle cingulate and striatal regions increased over time. DiscussionLong-lasting stroking was processed in similar areas as shorter-lasting stroking. The decreased activation in somatosensory cortices over time may represent stimulus habituation, whereas increased activation in OFC and putamen may relate to the stimulation's subjective reward value. This involvement of reward-related brain circuits can facilitate maintenance of long-lasting social touch interactions.

Discrepancies between cortical and behavioural long-term readouts of hyperalgesia in awake freely moving rats.

BackgroundIt is still unclear to what extent the most common animal models of pain and analgesia, based on indirect measures such as nocifensive behaviours, provide valid measures of pain perception.MethodsTo address this issue, we developed a novel animal model comprising a more direct readout via chronically (>1 month) implanted multichannel electrodes (MCE) in rat primary somatosensory cortex (S1; known to be involved in pain perception in humans) and compared this readout to commonly used behavioural pain‐related measures during development of hyperalgesia. A translational method to induce hyperalgesia, UVB irradiation of the skin, was used. Localized CO 2 laser stimulation was made of twenty skin sites (20 stimulations/site/observation day) on the plantar hind paw, before and during the time period when enhanced pain perception is reported in humans after UVB irradiation.ResultsWe demonstrate a 2–10 fold significant enhancement of cortical activity evoked from both irradiated and adjacent skin and a time course that corresponds to previously reported enhancement of pain magnitude during development of primary and secondary hyperalgesia in humans. In contrast, withdrawal reflexes were only significantly potentiated from the irradiated skin area and this potentiation was significantly delayed as compared to activity in S1.ConclusionsThe present findings provide direct evidence that chronic recordings in S1 in awake animals can offer a powerful, and much sought for, translational model of the perception of pain magnitude during hyperalgesia.What does this study add? In a novel animal model, chronic recordings of nociceptive activity in primary somatosensory cortex (S1) in awake freely moving rats are compared to behavioural readouts during UVB‐induced hyperalgesia. Evoked activity in rat S1 replicates altered pain perception in humans during development of hyperalgesia, but withdrawal reflexes do not.

Neural activity related to discrimination and vocal production of consonant and dissonant musical intervals

Background: Relationships between musical pitches are described as either consonant, when associated with a pleasant and harmonious sensation, or dissonant, when associated with an inharmonious feeling. The accurate singing of musical intervals requires communication between auditory feedback processing and vocal motor control (i.e. audio-vocal integration) to ensure that each note is produced correctly. The objective of this study is to investigate the neural mechanisms through which trained musicians produce consonant and dissonant intervals.Methodology: We utilized 4 musical intervals (specifically, an octave, a major seventh, a fifth, and a tritone) as the main stimuli for auditory discrimination testing, and we used the same interval tasks to assess vocal accuracy in a group of musicians (11 subjects, all female vocal students at conservatory level). The intervals were chosen so as to test for differences in recognition and production of consonant and dissonant intervals, as well as narrow and wide intervals. The subjects were studied using fMRI during performance of the interval tasks; the control condition consisted of passive listening.Results: Singing dissonant intervals as opposed to singing consonant intervals led to an increase in activation in several regions, most notably the primary auditory cortex, the primary somatosensory cortex, the amygdala, the left putamen, and the right insula. Singing wide intervals as opposed to singing narrow intervals resulted in the activation of the right anterior insula. Moreover, we also observed a correlation between singing in tune and brain activity in the premotor cortex, and a positive correlation between training and activation of primary somatosensory cortex, primary motor cortex, and premotor cortex during singing. When singing dissonant intervals, a higher degree of training correlated with the right thalamus and the left putamen.Conclusions/Significance: Our results indicate that singing dissonant intervals requires greater involvement of neural mechanisms associated with integrating external feedback from auditory and sensorimotor systems than singing consonant intervals, and it would then seem likely that dissonant intervals are intoned by adjusting the neural mechanisms used for the production of consonant intervals. Singing wide intervals requires a greater degree of control than singing narrow intervals, as it involves neural mechanisms which again involve the integration of internal and external feedback.

Optogenetic Synthesis of Touch Perception via Biomimetic Photo Stimulation of S1

Accurate decision-making requires the precisely timed input of sensory information to yield a functional percept that can inform behavioral choices. Touch perception requires neural activity in primary somatosensory cortex (S1). Here, we determine optimal laser power and shape to optogenetically drive precise spiking activity recorded via electrophysiology in layer IV of mouse S1, for the purpose of biasing sensation and thereby behavior in a multi-whisker two alternative forced-choice task. Our results indicate that power values between 500 µW and 2 mW at the skull were best suited for driving barrel-specific firing for a given stimulation location, with most powers in this range evoking ∼50% lower driven firing rates when laser stimulation was applied 500 µm from the recording region and no above-baseline firing for stimulations occurring 1 mm from the recording region. Additionally, characterization of the laser's beam profile illustrated that the width of the laser (250 µm) corresponded with the average width of a barrel of the barrel cortex, indicating that the laser was tightly focused on a single barrel throughout stimulation sessions. With this high level of spatial specificity for our stimulation trials, we were able to bias perception of an object's location (near whisker C1) to a more anterior location (near whisker C4) while a mouse was performing the two alternative forced-choice task. This effect was not observed when laser-stimulating layer IV of either C1 or C4 when an object was in range of the whisker corresponding to the barrel being stimulated. These results indicate that a laser using low-power settings with a tight beam width is ideal for driving highly specific spiking activity to influence behavior.

Gating of tactile information through gamma band during passive arm movement in awake primates.

To make precise and prompt action in a dynamic environment, the sensorimotor system needs to integrate all related information. The inflow of somatosensory information to the cerebral cortex is regulated and mostly suppressed by movement, which is commonly referred to as sensory gating or gating. Sensory gating plays an important role in preventing redundant information from reaching the cortex, which should be considered when designing somatosensory neuroprosthetics. Gating can occur at several levels within the sensorimotor pathway, while the underlying mechanism is not yet fully understood. The average sensory evoked potential is commonly used to assess sensory information processing, however the assumption of a stereotyped response to each stimulus is still an open question. Event related spectral perturbation (ERSP), which is the power spectrum after time-frequency decomposition on single trial evoked potentials (total power), could overcome this limitation of averaging and provide additional information for understanding the underlying mechanism. To this aim, neural activities in primary somatosensory cortex (S1), primary motor cortex (M1), and ventral posterolateral (VPL) nucleus of thalamus were recorded simultaneously in two areas (S1 and M1 or S1 and VPL) during passive arm movement and rest in awake monkeys. Our results showed that neural activity at different recording areas demonstrated specific and unique response frequency characteristics. Tactile input induced early high frequency responses followed by low frequency oscillations within sensorimotor circuits, and passive movement suppressed these oscillations either in a phase-locked or non-phase-locked manner. Sensory gating by movement was non-phase-locked in M1, and complex in sensory areas. VPL showed gating of non-phase-locked at gamma band and mix of phase-locked and non-phase-locked at low frequency, while S1 showed gating of phase-locked and non-phase-locked at gamma band and an early phase-locked elevation followed by non-phase-locked gating at low frequency. Granger causality (GC) analysis showed bidirectional coupling between VPL and S1, while GC between M1 and S1 was not responsive to tactile input. Thus, these results suggest that tactile input is dominantly transmitted along the ascending direction from VPL to S1, and the sensory input is suppressed during movement through a bottom-up strategy within the gamma-band during passive movement.

Sensory encoding in Neuregulin 1 mutants.

Schizophrenic patients show altered sensory perception as well as changes in electrical and magnetic brain responses to sustained, frequency-modulated sensory stimulation. Both the amplitude and temporal precision of the neural responses differ in patients as compared to control subjects, and these changes are most pronounced for stimulation at gamma frequencies (20-40Hz). In addition, patients display enhanced spontaneous gamma oscillations, which has been interpreted as 'neural noise' that may interfere with normal stimulus processing. To investigate electrophysiological markers of aberrant sensory processing in a model of schizophrenia, we recorded neuronal activity in primary somatosensory cortex of mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1. Sensory responses to sustained 20-70Hz whisker stimulation were analyzed with respect to firing rates, spike precision (phase locking) and gamma oscillations, and compared to baseline conditions. The mutants displayed elevated spontaneous firing rates, a reduced gain in sensory-evoked spiking and gamma activity, and reduced spike precision of 20-40Hz responses. These findings present the first in vivo evidence of the linkage between a genetic marker and altered stimulus encoding, thus suggesting a novel electrophysiological endophenotype of schizophrenia.

A dynamical systems model of the effect of Locus Coeruleus firing on single trial cortical state dynamics

Activity of sensory areas continuously varies reflecting both changes in external sensory stimuli and in internal states of the organism that do not necessarily always have a precise relationship to sensory inputs. An important aim in systems neuroscience is to develop quantitative models that may explain how state-dependent representations are generated and how they can be best interpreted. Statedependent modulations of cortical activity are in part mediated by changes in activity of various subcortical neuromodulatory nuclei. A prominent example is the Locus Coeruleus (LC), which can modulate both ongoing changes of cortical states and their responses to sensory inputs. However, a quantitative model of how the temporal fluctuations of LC firing affect ongoing and stimulus-driven primary cortical dynamics is currently missing. Here we investigated how LC modulates the ongoing cortical states and the sensory information carried by cortical firing using a combination of neurophysiological experiments and data-driven dynamic-system models of cortical state changes. We performed simultaneous recordings of neural activity in primary somatosensory cortex and both ipsilateral and contralateral LC in urethane anaesthetized rats during spontaneous activity and during electrical stimulation of the contralateral hind paw. On the basis of this data, we have constructed a novel data-driven dynamical system model of cortical states dynamics. This model extends and generalizes recent simple effective models [1] by including the effect of firing of LC noradrenergic neurons. We first fitted dynamic systems models of cortical states that either did or did not contain LC-cortical interactions. We found that models omitting the LC noradrenergic input to cortex tend to describe the dynamics of spontaneous activity of S1 cortex reasonably well. However, including ipsilateral (and to a lesser extent contralateral) LC activity as input to the models make the prediction of cortical states and of single trials responses much better. We then investigated which aspects of the LC dynamics help the model to increase cortical state predictability. We found that ipsilateral LC firing activity at low frequencies (< 10 Hz) correlated positively with slow (1-6 Hz) fluctuations of cortical power. The insertion of ipsilateral LC input to the model captured this dynamics by creating additional low frequency (1-6 Hz) state variation of model activity that correlated, both in power and phase, to those observed in real cortical activity. We finally investigated how these dynamical systems models can be used to predict single trial sensory evoked responses and to understand how this dynamics shapes the information representation of sensory stimuli. We derived an explicit mathematical rule predicting the trial-by-trial variability of cortical responses to stimuli arising from LC-modulated cortical state dynamics, and found that subtracting this variability from single trial cortical responses approximately doubles the amount of mutual information about the somatosensory stimuli that could be extracted from cortical responses.

Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans

Improved methods of noninvasively modulating human brain function are needed. Here we probed the influence of transcranial focused ultrasound (tFUS) targeted to the human primary somatosensory cortex (S1) on sensory-evoked brain activity and sensory discrimination abilities. The lateral and axial spatial resolution of the tFUS beam implemented were 4.9 mm and 18 mm, respectively. Electroencephalographic recordings showed that tFUS significantly attenuated the amplitudes of somatosensory evoked potentials elicited by median nerve stimulation. We also found that tFUS significantly modulated the spectral content of sensory-evoked brain oscillations. The changes produced by tFUS on sensory-evoked brain activity were abolished when the acoustic beam was focused 1 cm anterior or posterior to S1. Behavioral investigations showed that tFUS targeted to S1 enhanced performance on sensory discrimination tasks without affecting task attention or response bias. We conclude that tFUS can be used to focally modulate human cortical function.

Mirror therapy for phantom limb pain: Brain changes and the role of body representation

Phantom limb pain (PLP) is a common consequence of amputation and is difficult to treat. Mirror therapy (MT), a procedure utilizing the visual recreation of movement of a lost limb by moving the intact limb in front of a mirror, has been shown to be effective in reducing PLP. However, the neural correlates of this effect are not known. We investigated the effects of daily mirror training over 4 weeks in 13 chronic PLP patients after unilateral arm amputation. Eleven participants performed hand and lip movements during a functional magnetic resonance imaging (fMRI) measurement before and after MT. The location of neural activity in primary somatosensory cortex during these tasks was used to assess brain changes related to treatment. The treatment caused a significant reduction of PLP (average decrease of 27%). Treatment effects were predicted by a telescopic distortion of the phantom, with those patients who experienced a telescope profiting less from treatment. fMRI data analyses revealed a relationship between change in pain after MT and a reversal of dysfunctional cortical reorganization in primary somatosensory cortex. Pain reduction after mirror training was also related to a decrease of activity in the inferior parietal cortex (IPC). Experienced body appearance seems to be an important predictor of mirror treatment effectiveness. Maladaptive changes in cortical organization are reversed during mirror treatment, which also alters activity in the IPC, a region involved in painful perceptions and in the perceived relatedness to an observed limb.