Search

The posterior parietal cortex (PPC) contributes to multisensory and sensory-motor integration, as well as spatial navigation. Based on studies in primates, the PPC is composed of several subdivisions with differing connection patterns, including areas that exhibit retinotopy. In mice the exact anatomical location and composition of the PPC is poorly understood. We present a revised delineation in which we classify the higher-order visual areas RL, AM and MMA as subregions of the mouse PPC. Retrograde and anterograde tracing revealed connectivity, characteristic for primate PPC, with sensory, retrosplenial, orbitofrontal, cingulate and motor cortex, as well as with several thalamic nuclei and the superior colliculus in the mouse. Regarding cortical input, RL receives major input from the somatosensory barrel field, while AM receives more input from the trunk, whereas MMA receives strong inputs from retrosplenial, cingulate and orbitofrontal cortices. These input differences suggest that each new PPC sub-region has a distinct function. Summarized, we put forward a new refined cortical map, including a mouse PPC that contains at least 6 sub-regions, RL, AM, MMA and PtP, MPta, LPta/A. These results will facilitate a more detailed understanding about the role that the PPC and its subdivisions play in multisensory integration-based behavior in mice.HighlightsHigher-order visual areas RL, AM and MMA are part of the posterior parietal cortex (PPC) of the mouse based on connectivity.The mouse PPC contains at least 6 sub-regions, including RL, AM, MMA, PtP, LPtA/A and MPtASpecialized cortical input patterns to the new PPC subdivisions may reflect division of function.A new flattened map for mouse cortex represents refined auditory, visual, retrosplenial and PPC areas.

Introduction Source localization of interictal epileptic discharges (IEDs) is clinically useful in the presurgical workup of epilepsy patients. Recently, we have demonstrated that distributed magnetic source imaging (dMSI) has better accuracy than clinically approved equivalent current dipole method (ECD). Here, we aimed to compare the performance of four different dMSI techniques: Minimum Norm Estimate (MNE), dynamic Statistical Parametric Mapping (dSPM), standardized Low-Resolution Electromagnetic Tomography (sLORETA) and coherent Maximum Entropy on the Mean (cMEM, an entropy-based technique). Methods We analyzed dMSI results of 206 IEDs derived from MEG recordings in 28 focal epilepsy patients who had a well-defined focus determined through intracranial EEG, epileptogenic MRI lesions or surgical resection. dMSI accuracy and spatial properties were quantitatively estimated as: (a) minimum distance between the source peak and the focus; (b) within-subject reproducibility; (c) spatial dispersion of the source map outside the focus; (d) extension of cortical map; (e) effect of thresholding on map size and properties. Results Distance between the map peak and epilepsy focus as well as within subject reproducibility were clinically comparable across methods (median distance from the focus around 1 cm). Spatial dispersion was significantly lower for cMEM. cMEM maps display typically higher contrast between the source maximum and surrounding regions, being therefore less sensitive to map thresholding. Conclusions All dMSI techniques under investigation provided excellent performance in localizing the epileptic focus. cMEM provides the lowest amount of spurious activity, while obtaining similar localization accuracy compared to other techniques. dMSI techniques currently available for clinical use have the potential to significantly improve identification of intracranial EEG targets and to guide surgical planning.

Background: The precise cortical origins of the electrophysiological and behavioral effects of transcranial magnetic stimulation (TMS) remain largely unclear. Addressing this question is further impeded by substantial inter-individual response variability to TMS. Objective: We present a novel method to reliably and user-independently determine the effectively stimulated cortical site at the individual subject level. This generic approach combines physiological measurements with electric field simulations and leverages information from random coil positions, electric field estimations, and electromyography. Methods: We applied ~1000 single biphasic TMS pulses with standard TMS hardware to 13 subjects with random coil positions & orientations over the primary motor hand area. Motor evoked potentials (MEPs) of three finger muscles were recorded concurrently. We calculated the corresponding electric fields for all TMS pulses and regressed them against the elicited MEPs in each cortical element. This yields a cortical map of congruency between induced field strength and generated response. Results: We observed high congruence between the electric fields and the elicited MEPs in hotspots located primarily on the crowns and rims of the precentral gyrus. The three cortical digit representations could be distinguished at the individual subject level with a high spatial resolution. A post-hoc convergence analysis revealed a possible lower bound of only 180 pulses to obtain qualitatively identical results. Conclusions: Leveraging information from many different TMS pulses significantly reduces the number of necessary stimulations and mapping time. The protocol is easy to implement due to the realization of arbitrary coil positions & orientations and is suitable for practical and clinical use such as preoperative mapping.

Cortical maps, which are indicative of cognitive status, are shaped by the organism’s experience. Previous mapping tools, such as penetrating electrodes and imaging techniques, are limited in their ability to be used to assess high-resolution brain maps largely owing to their invasiveness and poor spatiotemporal resolution, respectively. In this study, we developed a flexible graphene-based multichannel electrode array for electrocorticography (ECoG) recording, which enabled us to assess cortical maps in a time- and labor-efficient manner. The flexible electrode array, formed by chemical vapor deposition (CVD)-grown graphene, provided low impedance and electrical noise because a good interface between the graphene and brain tissue was created, which improved the detectability of neural signals. Furthermore, cortical map remodeling was induced upon electrical stimulation at the cortical surface through a subset of graphene spots. This result demonstrated the macroscale plasticity of cortical maps, suggesting perceptual enhancement via electrical rehabilitation at the cortical surface. The spatial organization of neural networks representing sensorimotor behavior and cognition has been mapped by flexible devices placed on the cortex, the outer layer of the brain. Sensory messages from each part of the body are processed in a specific area in the brain and maps of the cortex can help understand these areas. A person’s cortical map is shaped by their early development and experiences. Study of such maps can help identify and treat sensory disorders. Existing techniques for brain mapping require placement of penetrating electrodes which is time-consuming and risks brain damage. Minseok Lee from City University of Hong Kong and colleagues made arrays of electrodes using graphene membranes and constructed sensory maps of rats and mice by placing these arrays directly on the cortical surface. The timely and continuous measurement of cortical maps is required for studying the nature and plasticity of brain maps. In this work, we developed the multichannel graphene array that enables high-resolution brain mapping, facilitating rapid and repetitive assessments of brain maps. The advanced graphene array with intervening thru-hole enables large-scale mapping simultaneously in the surface and deep of cortical areas, also improving conformality for better detection of electrocorticography signals. In a subset of the graphene array, cortical surface stimulation can remodel cortical maps, therein enhancing cortical plasticity. This technology provides potential therapeutic applications for various brain disorders by correcting brain maps.

Recent experiments in the developing mammalian visual cortex have revealed that gap junctions couple excitatory cells and potentially influence the formation of chemical synapses. In particular, cells that were coupled by a gap junction during development tend to share an orientation preference and are preferentially coupled by a chemical synapse in the adult cortex, a property that is diminished when gap junctions are blocked. In this work, we construct a simplified model of the developing mouse visual cortex including spike-timing-dependent plasticity of both the feedforward synaptic inputs and recurrent cortical synapses. We use this model to show that synchrony among gap-junction-coupled cells underlies their preference to form strong recurrent synapses and develop similar orientation preference; this effect decreases with an increase in coupling density. Additionally, we demonstrate that gap-junction coupling works, together with the relative timing of synaptic development of the feedforward and recurrent synapses, to determine the resulting cortical map of orientation preference., Author summary Gap junctions, or sites of direct electrical connections between neurons, have a significant presence in the cortex, both during development and in adulthood. Their primary function during either of these periods, however, is still poorly understood. In the adult cortex, gap junctions between local, inhibitory neurons have been shown to promote synchronous firing, a network characteristic thought to be important for learning, attention, and memory. During development, gap junctions between excitatory, pyramidal cells, have been conjectured to play a role in synaptic plasticity and the formation of cortical circuits. In the visual cortex, where neurons exhibit tuned responses to properties of visual input such as orientation and direction, recent experiments show that excitatory cells are coupled by gap junctions during the first postnatal week and are replaced by chemical synapses during the second week. In this work, we explore the possible contribution of gap-junction coupling during development to the formation of chemical synapses between the visual cortex from the thalamus and between cortical cells within the visual cortex. Specifically, using a mathematical model of the visual cortex during development, we identify the response properties of gap-junction-coupled cells and their influence on the formation of the cortical map of orientation preference.

Despite the fact that there is a growing awareness to the callosal connections between hemispheres the two hemispheres of the brain are commonly treated as independent structures when peripheral or cortical manipulations are applied to one of them. The contralateral hemisphere is often used as a within-animal control of plastic changes induced onto the other side of the brain. This ensures uniform conditions for producing experimental and control data, but it may overlook possible interhemispheric interactions. In this paper we provide, for the first time, direct proof that cortical, experience-dependent plasticity is not a unilateral, independent process. We mapped metabolic brain activity in rats with 2-[14C] deoxyglucose (2DG) following experience-dependent plasticity induction after a month of unilateral (left), partial whiskers deprivation (only row B was left). This resulted in ∼45% widening of the cortical sensory representation of the spared whiskers in the right, contralateral barrel field (BF). We show that the width of 2DG visualized representation is less than 20% when only contralateral stimulation of the spared row of whiskers is applied in immobilized animals. This means that cortical map remodeling, which is induced by experience-dependent plasticity mechanisms, depends partially on the contralateral hemisphere. The response, which is observed by 2DG brain mapping in the partially deprived BF after standard synchronous bilateral whiskers stimulation, is therefore the outcome of at least two separately activated plasticity mechanisms. A focus on the integrated nature of cortical plasticity, which is the outcome of the emergent interactions between deprived and non-deprived areas in both hemispheres may have important implications for learning and rehabilitation. There is also a clear implication that there is nothing like “control hemisphere” since any plastic changes in one hemisphere have to have influence on functioning of the opposite one.

Hearing loss is the biggest risk factor for tinnitus, and hearing-loss-related pathological changes in the auditory pathway have been hypothesized as the mechanism underlying tinnitus. However, due to the comorbidity of tinnitus and hearing loss, it has been difficult to differentiate between neural correlates of tinnitus and consequences of hearing loss. In this study, we dissociated tinnitus and hearing loss in FVB mice, which exhibit robust resistance to tinnitus following monaural noise-induced hearing loss. Furthermore, knock-down of glutamate decarboxylase 65 (GAD65) expression in auditory cortex (AI) by RNA interference gave rise to tinnitus in normal-hearing FVB mice. We found that tinnitus was significantly correlated with downregulation of GAD65 in the AI. By contrast, cortical map distortions, which have been hypothesized as a mechanism underlying tinnitus, were correlated with hearing loss but not tinnitus. Our findings suggest new strategies for the rehabilitation of tinnitus and other phantom sensation, such as phantom pain.SIGNIFICANCE STATEMENTHearing loss is the biggest risk factor for tinnitus in humans. Most animal models of tinnitus also exhibit comorbid hearing loss, making it difficult to dissociate the mechanisms underlying tinnitus from mere consequences of hearing loss. Here we show that, although both C57BL/6 and FVB mice exhibited similar noise-induced hearing threshold increase, only C57BL/6, but not FVB, mice developed tinnitus following noise exposure. Although both strains showed frequency map reorganization following noise-induced hearing loss, only C57BL/6 mice had reduced glutamate decarboxylase 65 (GAD65) expression in the auditory cortex (AI). Knocking down GAD65 expression in the AI resulted in tinnitus in normal-hearing FVB mice. Our results suggest that reduced inhibitory neuronal function, but not sensory map reorganization, underlies noise-induced tinnitus.

The primary visual cortex contains a detailed map of retinal stimulus position (retinotopic map) and eye input (ocular dominance map) that results from the precise arrangement of thalamic afferents during cortical development. For reasons that remain unclear, the patterns of ocular dominance are very diverse across species and can take the shape of highly organized stripes, convoluted beads, or no pattern at all. Here, we use a new image-processing algorithm to measure ocular dominance patterns more accurately than in the past. We use these measurements to demonstrate that ocular dominance maps follow a common organizing principle that makes the cortical axis with the slowest retinotopic gradient orthogonal to the ocular dominance stripes. We demonstrate this relation in multiple regions of the primary visual cortex from individual animals, and different species. Moreover, consistent with the increase in the retinotopic gradient with visual eccentricity, we demonstrate a strong correlation between eccentricity and ocular dominance stripe width. We also show that an eye/polarity grid emerges within the visual cortical map when the representation of light and dark stimuli segregates along an axis orthogonal to the ocular dominance stripes, as recently demonstrated in cats. Based on these results, we propose a developmental model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity, and then maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation. In this model, the different ocular dominance patterns simply emerge from differences in local retinotopic cortical topography.SIGNIFICANCE STATEMENTThalamocortical afferents segregate in primary visual cortex by eye input and light-dark polarity. This afferent segregation forms cortical patterns that vary greatly across species for reasons that remain unknown. Here we show that the formation of ocular dominance patterns follows a common organizing principle across species that aligns the cortical axis of ocular dominance segregation with the axis of slowest retinotopic gradient. Based on our results, we propose a model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity along orthogonal axes with the slowest and fastest retinotopic gradients, respectively. This organization maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation in carnivores and primates.

In mice, terminal differentiation of subpopulations of interneurons occurs in late postnatal stages, paralleling the emergence of the adult cortical architecture. Here, we investigated the effects of altered initial cortical architecture on later interneuron development. We identified that a class of somatostatin (SOM)-expressing GABAergic interneurons undergoes terminal differentiation between 2nd and 3rd postnatal week in the mouse somatosensory barrel cortex and upregulates Reelin expression during neurite outgrowth. Our previous work demonstrated that transient expression (E15-P10) of serotonin uptake transporter (SERT) in thalamocortical projection neurons regulates barrel elaboration during cortical map establishment. We show here that in thalamic neuron SERT knockout mice, these SOM-expressing interneurons develop at the right time, reach correct positions and express correct neurochemical markers, but only 70% of the neurons remain in the adult barrel cortex. Moreover, those neurons that remain display altered dendritic patterning. Our data indicate that a precise architecture at the cortical destination is not essential for specifying late-developing interneuron identities, their cortical deposition, and spatial organization, but dictates their number and dendritic structure ultimately integrated into the cortex. Our study illuminates how disruption of temporal-specific SERT function and related key regulators during cortical map establishment can alter interneuron development trajectory that persists to adult central nervous system.

Interhemispheric inhibition (IHI) between motor cortexes is thought to suppress unwanted mirror movements during voluntary behaviors and can be assessed using paired-pulse transcranial magnetic stimulation (TMS). The magnitude of IHI may be related to the size of the cortical representation for a given muscle as a mechanism for facilitating unimanual control. To date, the relationship between IHI and cortical muscle representations remains unknown. Fifteen healthy, right-handed individuals participated in the present study. IHI was examined in the right first dorsal interosseous (FDI) muscle by delivering conditioning TMS to ipsilateral (right) primary motor cortex (M1) followed by a test TMS pulse to contralateral (left) M1. The size of the FDI representation in M1 was determined by delivering suprathreshold TMS over a 5 × 5-cm grid centered on the FDI motor hotspot of the left M1. Both IHI and cortical territory were obtained during three conditions: rest, contralateral (right) FDI contraction, and ipsilateral (left) FDI contraction. Results indicate a significant association between IHI and the size of the FDI representation only in the context of contraction and not when the FDI muscle was relaxed. Specifically, reduced IHI corresponded to larger cortical FDI representations during both contralateral and ipsilateral contraction. These data demonstrate that, for a muscle of the hand, the magnitude of IHI and the cortical territory are associated within the context of muscle contraction. NEW & NOTEWORTHY This study provides evidence from noninvasive brain stimulation that communication between the motor cortexes of the two hemispheres plays a role in shaping the motor cortical map that outputs to a hand muscle during active contraction of that muscle. This relationship exists only when the hand muscle is contracted. The findings presented further our understanding of motor control during unilateral movement and may inform future research targeting clinical populations that exhibit impaired unilateral control.

Key points Partial sensory deprivation (deafferentation) by removing whiskers from the rat snout resulted in a reduced responsiveness of related cortical representations.Repetitive transcranial magnetic stimulation (three blocks of intermittent theta‐burst) applied for 5 days in combination with sensory exploration restored the normal responsiveness level of the deafferented barrel cortex.However, intracortical inhibition (lateral and recurrent) appeared to be reduced after repetitive transcranial magnetic stimulation, probably as the cause of improved responsiveness.Repetitive transcranial magnetic stimulation also reduced the asymmetry of the lateral spread of sensory activity. Abstract Repetitive transcranial magnetic stimulation (rTMS) modulates human cortical excitability. It has the potential to support recovery to normal cortical function when the excitation–inhibition balance is altered (e.g. after a stroke or loss of sensory input). We tested cortical map plasticity on the basis of sensory responses (local field potentials, LFPs) and expression of neuronal activity marker proteins within the barrel cortex of rats receiving either active or sham rTMS after selective unilateral deafferentation by whiskers plucking. Rats received daily rTMS [intermittent theta‐burst (iTBS), active or sham] for 5 days before exploring an enriched environment. Our previous studies indicated a disinhibitory effect of iTBS on cortical activity. Therefore, we also expected disinhibitory effects if deafferentation causes depression of sensory responses. Deafferentation resulted in an acute general reduction of sensory responsiveness and enhanced expression of inhibitory activity markers (GAD67, parvalbumin) in the deafferented hemisphere. Active but not sham‐iTBS‐rTMS normalized these measures. The stronger caudal‐to‐frontal horizontal spread of activity across barrels was reduced after deafferentation but not restored after active iTBS, despite generally increased responses. Fitting the LFP data with a computational model of different strengths and types of excitatory and inhibitory connections further revealed an iTBS‐induced reduction of lateral and recurrent inhibition as the most probable scenario. Whether the disinhibitory effect of iTBS for the restoration of normal cortical function in the acute phase of depression after deafferentiation is also beneficial in humans remains to be demonstrated. As recently discussed, disinhibition appears to be required to open a window for neuronal plasticity., Key points Partial sensory deprivation (deafferentation) by removing whiskers from the rat snout resulted in a reduced responsiveness of related cortical representations.Repetitive transcranial magnetic stimulation (three blocks of intermittent theta‐burst) applied for 5 days in combination with sensory exploration restored the normal responsiveness level of the deafferented barrel cortex.However, intracortical inhibition (lateral and recurrent) appeared to be reduced after repetitive transcranial magnetic stimulation, probably as the cause of improved responsiveness.Repetitive transcranial magnetic stimulation also reduced the asymmetry of the lateral spread of sensory activity.

Significance Despite significant research, the biological mechanisms underlying schizophrenia are still unclear. We shed light on structural brain differences in psychosis using an approach called morphometric similarity mapping, which quantifies the structural similarity between brain regions. Morphometric similarity was globally reduced in psychosis patients in three independent datasets, implying that patients’ brain regions were more differentiated from each other and less interconnected. Similarity was especially decreased in frontal and temporal regions. This anatomical pattern was correlated with expression of genes enriched for nervous system development and synaptic signaling and genes previously associated with schizophrenia and antipsychotic treatments. Therefore, we begin to see how combining genomics and imaging can give a more integrative understanding of schizophrenia, which might inform future treatments., Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case–control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case–control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case–control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T2* and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

The topographic organization of sensory cortices is a prominent feature, but its functional role remains unclear. Particularly, how activity is integrated within a cortical area depending on its topography is unknown. Here, we trained mice expressing channelrhodopsin in cortical excitatory neurons to track a bar photostimulation that rotated smoothly over the primary somatosensory cortex (S1). When photostimulation was aimed at vS1, the area which contains a contiguous representation of the whisker array at the periphery, mice could learn to discriminate angular positions of the bar to obtain a reward. In contrast, they could not learn the task when the photostimulation was aimed at the representation of the trunk and legs in S1, where neighboring zones represent distant peripheral body parts, introducing discontinuities. Mice demonstrated anticipation of reward availability, specifically when cortical topography enabled to predict future sensory activation. These results are particularly helpful for designing efficient cortical sensory neuroprostheses.TeaserOptogenetic stimulation sweeping the cortical surface: A way to provide precise sensory information and guide behaviour.

This is the story of a search for a cortical map of auditory space. The search began with a study that was reported in the first issue of The Journal of Neuroscience (Middlebrooks and Pettigrew, 1981). That paper described some unexpected features of spatial sensitivity in the auditory cortex while failing to demonstrate the expected map. In the ensuing 40 years, we have encountered the following: panoramic spatial coding by single neurons; a rich variety of response patterns that are unmasked in the absence of general anesthesia; sharpening of spatial sensitivity when an animal is engaged in a listening task; and reorganization of spatial sensitivity in the presence of competing sounds. We have not encountered a map, but not through lack of trying. On the basis of years of negative results by our group and others, and positive results that are inconsistent with static point-to-point topography, we are confident in concluding that there just ain't no map. Instead, we have come to appreciate the highly dynamic spatial properties of cortical neurons, which serve the needs of listeners in a changing sonic environment.

Significance Here we describe a mechanism for cortical map plasticity. Classically, representational map changes are thought to be driven by changes within cortico-cortical circuits, e.g., Hebbian plasticity of synaptic circuits that lost vs. maintained an excitatory drive from the first-order thalamus, possibly steered by neuromodulatory forces from deep brain regions. Our work provides evidence for an additional gating mechanism, provided by plateau potentials, which are driven by higher-order thalamic feedback. Higher-order thalamic neurons are characterized by broad receptive fields, and the plateau potentials that they evoke strongly facilitate long-term potentiation and elicit spikes. We show that these features combined constitute a powerful driving force for the fusion or expansion of sensory representations within cortical maps., The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.

The retino-cortical visual pathway is retinotopically organized: Neighborhood relationships on the retina are preserved in the mapping to the cortex. Size relationships in that mapping are also highly regular: The size of a patch in the visual field that maps onto a cortical patch of fixed size, follows, along any radius and in a wide range, simply a linear function with retinal eccentricity. This is referred to as M-scaling . As a consequence, and under simplifying assumptions, the mapping of retinal to cortical location follows a logarithmic function along a radius, as was already shown by Fischer (1973) and Schwartz (1977, 1980). The M -scaling function has been determined for many visual tasks. It is standardly characterized by its foveal threshold value, together with the eccentricity where that value doubles, called E 2 . The cortical location function, on the other hand, is commonly specified by parameters that are separately determined from the empirical findings. Here, the psychophysical and neuroscience traditions are brought together by specifying the cortical equations in terms of the parameters customary in psychophysics. The equations go beyond those published in the past in being more explicit and ready for application, and they allow easy switching between M -scaling and cortical mapping. A new parameter, d 2 , is proposed to describe the cortical map, as a cortical counterpart to E 2 and typical values for it are given. The resulting cortical-location function is then applied to data from a number of fMRI studies. One pitfall is discussed and spelt out as a set of equations, namely the common myth that a pure logarithmic function will give an adequate map: The popular omission of a constant term renders the equations ill-defined in and around the retinotopic center. The correct equations are finally extended to describe the cortical map of Bouma’s law on visual crowding. The result contradicts recent suggestions that critical crowding distance corresponds to constant cortical distance.

Recent experiments in the developing mammalian visual cortex have revealed that gap junctions couple excitatory cells and potentially influence the formation of chemical synapses. Though gap junctions between inhibitory cells are ubiquitous in the adult cortex, and their presence has been shown to promote synchronous network firing, their function among excitatory, pyramidal cells remains poorly understood. During development, pyramidal cells that were derived from the same progenitor cell, called sister cells, are preferentially connected by a gap junction during the first postnatal week, while chemical synapses are still being formed. Additionally, these sister cells tend to share an orientation preference and a chemical synapse in the adult cortex, a property that is diminished when gap junctions are blocked. In this work, we construct an idealized model of the mouse visual cortex during the first two postnatal weeks of development to analyze the response properties of gap-junction-coupled cells and their effect on synaptic plasticity. Further, as an application of this model, we investigate the interplay of gap-junction coupling and synaptic plasticity on the order, or organization, of the resulting cortical map of orientation preference.Author summaryGap junctions, or sites of direct electrical connections between neurons, have a significant presence in the cortex, both during development and in adulthood. Their primary function during either of these periods, however, is still poorly understood. In the adult cortex, gap junctions between local, inhibitory neurons have been shown to promote synchronous firing, a network characteristic thought to be important for learning, attention, and memory. During development, gap junctions between excitatory, pyramidal cells, have been conjectured to play a role in synaptic plasticity and the formation of cortical circuits. In the visual cortex, where neurons exhibit tuned responses to properties of visual input such as orientation and direction, recent experiments show that excitatory cells are coupled by gap junctions during the first postnatal week and are replaced by chemical synapses during the second week. In this work, we explore the possible contribution of gap-junction coupling during development to the formation of chemical synapses both into the visual cortex from the thalamus and within the visual cortex between cortical cells. Specifically, within a mathematical model of the visual cortex during development, we identify the response properties of gap-junction-coupled cells and their influence on the formation of the cortical map of orientation preference.

BACKGROUND: Machine learning (ML) can distinguish cases with psychotic disorder from healthy controls based on magnetic resonance imaging (MRI) data, but it is not yet clear which MRI metrics are the most informative for case-control ML, or how ML algorithms relate to the underlying biology.METHODS: We analyzed multimodal MRI data from 2 independent case-control studies of psychotic disorders (cases, n = 65, 28; controls, n = 59, 80) and compared ML accuracy across 5 selected MRI metrics from 3 modalities. Cortical thickness, mean diffusivity, and fractional anisotropy were estimated at each of 308 cortical regions, as well as functional and structural connectivity between each pair of regions. Functional connectivity data were also used to classify nonpsychotic siblings of cases (n = 64) and to distinguish cases from controls in a third independent study (cases, n = 67; controls, n = 81).RESULTS: In both principal studies, the most informative metric was functional MRI connectivity: The areas under the receiver operating characteristic curve were 88% and 76%, respectively. The cortical map of diagnostic connectivity features (ML weights) was replicable between studies (r = .27, p < .001); correlated with replicable case-control differences in functional MRI degree centrality and with a prior cortical map of adolescent development of functional connectivity; predicted intermediate probabilities of psychosis in siblings; and was replicated in the third case-control study.CONCLUSIONS: ML most accurately distinguished cases from controls by a replicable pattern of functional MRI connectivity features, highlighting abnormal hubness of cortical nodes in an anatomical pattern consistent with the concept of psychosis as a disorder of network development.

Highlights • Cortical signatures selective to AD could provide an early MRI biomarker. • Autosomal dominant Alzheimer disease (ADAD) may model an ideal AD signature. • ADAD and late-onset maps overlap in parietal cortex but contain unique features. • Signatures predicted increasing amyloid within their own, but not across cohorts. • These results indicate atrophy in AD can take multiple spatial patterns., Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.

Crowding has become a hot topic in vision research, and some fundamentals are now widely agreed upon. For the classical crowding task, one would likely agree with the following statements. (1) Bouma’s law can be stated, succinctly and unequivocally, as saying that critical distance for crowding is about half the target’s eccentricity. (2) Crowding is predominantly a peripheral phenomenon. (3) Peripheral vision extends to at most 90° eccentricity. (4) Resolution threshold (the minimal angle of resolution) increases strongly and linearly with eccentricity. Crowding increases at an even steeper rate. (5) Crowding is asymmetric as Bouma has shown. For that inner-outer asymmetry, the peripheral flanker has more effect. (6) Critical crowding distance corresponds to a constant cortical distance in primary visual areas like V1. (7) Except for Bouma’s seminal article in 1970, crowding research mostly became prominent starting in the 2000s. I propose the answer is “not really” or “not quite” to these assertions. So should we care? I think we should, before we write the textbook chapters for the next generation. Open-Access-Publikationsfonds 2020 peerReviewed

Echolocating bats use echoes of their sonar emissions to determine the position and distance of objects or prey. Target distance is represented as a map of echo delay in the auditory cortex (AC) of bats. During a bat’s flight through a natural complex environment, echo streams are reflected from multiple objects along its flight path. Separating such complex streams of echoes or other sounds is a challenge for the auditory system of bats as well as other animals. We investigated the representation of multiple echo streams in the AC of anesthetized bats ( Phyllostomus discolor) and tested the hypothesis that neurons can lock on echoes from specific objects in a complex echo-acoustic pattern while the representation of surrounding objects is suppressed. We combined naturalistic pulse/echo sequences simulating a bat’s flight through a virtual acoustic space with extracellular recordings. Neurons could selectively lock on echoes from one object in complex echo streams originating from two different objects along a virtual flight path. The objects were processed sequentially in the order in which they were approached. Object selection depended on sequential changes of echo delay and amplitude, but not on absolute values. Furthermore, the detailed representation of the object echo delays in the cortical target range map was not fixed but could be dynamically adapted depending on the temporal pattern of sonar emission during target approach within a simulated flight sequence. NEW & NOTEWORTHY Complex signal analysis is a challenging task in sensory processing for all animals, particularly for bats because they use echolocation for navigation in darkness. Recent studies proposed that the bat’s perceptional system might organize complex echo-acoustic information into auditory streams, allowing it to track specific auditory objects during flight. We show that in the auditory cortex of bats, neurons can selectively respond to echo streams from specific objects.

Neocortical activity is permeated with endogenously generated fluctuations, but how these dynamics affect goal-directed behavior remains a mystery. We found that ensemble neural activity in primate visual cortex spontaneously fluctuated between phases of vigorous (On) and faint (Off) spiking synchronously across cortical layers. These On-Off dynamics, reflecting global changes in cortical state, were also modulated at a local scale during selective attention. Moreover, the momentary phase of local ensemble activity predicted behavioral performance. Our results show that cortical state is controlled locally within a cortical map according to cognitive demands and reveal the impact of these local changes in cortical state on goal-directed behavior.

BackgroundMachine learning (ML) can distinguish cases with psychotic disorder from healthy controls based on magnetic resonance imaging (MRI) data, with reported accuracy in the range 60-100%. It is not yet clear which MRI metrics are the most informative for case-control ML.MethodsWe analysed multi-modal MRI data from two independent case-control studies of patients with psychotic disorders (cases, N = 65, 28; controls, N = 59, 80) and compared ML accuracy across 5 MRI metrics. Cortical thickness, mean diffusivity and fractional anisotropy were estimated at each of 308 cortical regions, as well as functional and structural connectivity between each pair of regions. Functional connectivity data were also used to classify non-psychotic siblings of cases (N=64) and to distinguish cases from controls in a third independent study (cases, N=67; controls, N = 81).ResultsIn both principal studies, the most diagnostic metric was fMRI connectivity: the areas under the receiver operating characteristic curve were 92% and 77%, respectively. The cortical map of diagnostic connectivity features was replicable between studies (r = 0.31, P < 0.001); correlated with replicable case-control differences in fMRI degree centrality, and with prior cortical maps of aerobic glycolysis and adolescent development of functional connectivity; predicted intermediate probabilities of psychosis in siblings; and replicated in the third case-control study.ConclusionsML most accurately distinguished cases from controls by a replicable pattern of fMRI connectivity features, highlighting abnormal hubness of cortical nodes in an anatomical pattern consistent with the concept of psychosis as a disorder of network development.

The knowledge of the size of our own body parts is essential for accurately moving in space and efficiently interact with objects. A distorted perceptual representation of the body size often represents a core diagnostic criterion for some psychopathological conditions. The metric representation of the body was shown to depend on somatosensory afferences: local deafferentation indeed causes a perceptual distortion of the size of the anesthetized body part. A specular effect can be induced by altering the cortical map of body parts in the primary somatosensory cortex. Indeed, the present study demonstrates, in healthy adult participants, that repetitive Transcranial Magnetic Stimulation to the somatosensory cortical map of the hand in both hemispheres causes a perceptual distortion (i.e., an overestimation) of the size of the participants' own hand (Experiments 1-3), which does not involve other body parts (i.e., the foot, Experiment 2). Instead, the stimulation of the inferior parietal lobule of both hemispheres does not affect the perception of the own body size (Experiment 4). These results highlight the role of the primary somatosensory cortex in the building up and updating of the metric of body parts: somatosensory cortical activity not only shapes our somatosensation, it also affects how we perceive the dimension of our body.

We developed a cortical language map from performance data on a language test battery in patients with brain lesions. The research problem was how to select the subtest that was most related to the function of each cortical area from the battery. When studied by voxel-based lesion-symptom mapping (VLSM), patients were divided into two groups: those with and without a lesion at each particular region. We considered the task that optimally discriminated between the two groups to be the task most related to the function of a given region. One hundred and fifty left-lesioned patients were examined using the Japanese Standard Language Test of Aphasia (SLTA), which is composed of 26 subtests. Using logistic discriminant analysis, we selected the subtest that optimally discriminated the lesioned and non-lesioned groups for each cortical region. Patients with left middle frontal gyrus (area 46) lesions were optimally discriminated from patients without lesions in that area by the speech sound–kana letter choice matching subtest. Patients with lesions in the inferior postcentral gyrus were optimally distinguished by the disturbance of word repetition. Patients with lesions in the anterior cingulate gyrus were characterized by impaired performance on the category fluency subtest. Voxel-based discriminant analysis can thus select the subtest that can be regarded as most related to the function of each cortical area., Highlights • From a cognitive test battery, we selected the subtest most related to the function of each cortical area. • We conducted voxel-based lesion-symptom mapping using t-test and logistic regression. • The t-statistic and G-statistic can be used as indicators of differences in task performance. • This method is useful for clarifying the primary function of each region of cortex.

Schizophrenia has been conceived as a disorder of brain connectivity but it is unclear how this network phenotype is related to the emerging genetics. We used morphometric similarity analysis of magnetic resonance imaging (MRI) data as a marker of inter-areal cortical connectivity in three prior case-control studies of psychosis: in total, N=185 cases and N=227 controls. Psychosis was associated with globally reduced morphometric similarity (MS) in all 3 studies. There was also a replicable pattern of case-control differences in regional MS which was significantly reduced in patients in frontal and temporal cortical areas, but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in MS was spatially correlated with cortical expression of a weighted combination of genes enriched for neu-robiologically relevant ontology terms and pathways. In addition, genes that were normally over-expressed in cortical areas with reduced MS were significantly up-regulated in a prior post mortem study of schizophrenia. We propose that this combination of neuroimaging and transcriptional data provides new insight into how previously implicated genes and proteins, as well as a number of unreported proteins in their vicinity on the protein interaction network, may interact to drive structural brain network changes in schizophrenia.

Cortical representations expand during skilled motor learning. We studied a unique model of motor learning with cellular phone texting, where the thumbs are used exclusively to interact with the device and the prominence of use can be seen where 3200 text messages are exchanged a month in the 18–24 age demographic. The purpose of the present study was to examine the motor cortex representation and input–output (IO) recruitment curves of the abductor pollicis brevis (APB) muscle of the thumb and the ADM muscle with transcranial magnetic stimulation (TMS), relative to individuals’ texting abilities and short-term texting practice. Eighteen individuals performed a functional texting task (FTT) where we scored their texting speed and accuracy. TMS was then used to examine the cortical volumes and areas of activity in the two muscles and IO curves were constructed to measure excitability. Subjects also performed a 10-min practice texting task, after which we repeated the cortical measures. There were no associations between the cortical measures and the FTT scores before practice. However, after practice the APB cortical map expanded and excitability increased, whereas the ADM map constricted. The increase in the active cortical areas in APB correlated with the improvement in the FTT score. Based on the homogenous group of subjects that were already good at texting, we conclude that the cortical representations and excitability for the thumb muscle were already enlarged and more receptive to changes with short-term practice, as noted by the increase in FTT performance after 10-min of practice.

Cortical reorganization subsequent to post-stroke motor rehabilitative training (RT) has been extensively examined in animal models and humans. However, similar studies focused on the effects of motor training after traumatic brain injury (TBI) are lacking. We previously reported that after a moderate/severe TBI in adult male rats, functional improvements in forelimb use were accomplished only with a combination of skilled forelimb reach training and aerobic exercise, with or without nonimpaired forelimb constraint. Thus, the current study was designed to examine the relationship between functional motor cortical map reorganization after experimental TBI and the behavioral improvements resulting from this combinatorial rehabilitative regime. Adult male rats were trained to proficiency on a skilled reaching task, received a unilateral controlled cortical impact (CCI) over the forelimb area of the caudal motor cortex (CMC). Three days post-CCI, animals began RT (n = 13) or no rehabilitative training (NoRT) control procedures (n = 13). The RT group participated in daily skilled reach training, voluntary aerobic exercise, and nonimpaired forelimb constraint. This RT regimen significantly improved impaired forelimb reaching success and normalized reaching strategies, consistent with previous findings. RT also enlarged the area of motor cortical wrist representation, derived by intracortical microstimulation, compared to NoRT. These findings indicate that sufficient RT can greatly improve motor function and improve the functional integrity of remaining motor cortex after a moderate/severe CCI. When compared with findings from stroke models, these findings also suggest that more intense RT may be needed to improve motor function and remodel the injured cortex after TBI.

While past neuroimaging methods have contributed greatly to our understanding of brain function after traumatic brain injury (TBI), resting state functional MRI (rsfMRI) connectivity methods have more recently provided a far more unbiased approach with which to monitor brain circuitry compared to task-based approaches. However, current knowledge on the physiologic underpinnings of the correlated blood oxygen level dependent signal, and how changes in functional connectivity relate to reorganizational processes that occur following injury is limited. The degree and extent of this relationship remain to be determined in order that rsfMRI methods can be fully adapted for determining the optimal timing and type of rehabilitative interventions that can be used post-TBI to achieve the best outcome. Very few rsfMRI studies exist after experimental TBI and therefore we chose to acquire rsfMRI data before and at 7, 14 and 28 days after experimental TBI using a well-known, clinically-relevant, unilateral controlled cortical impact injury (CCI) adult rat model of TBI. This model was chosen since it has widespread axonal injury, a well-defined time-course of reorganization including spine, dendrite, axonal and cortical map changes, as well as spontaneous recovery of sensorimotor function by 28 d post-injury from which to interpret alterations in functional connectivity. Data were co-registered to a parcellated rat template to generate adjacency matrices for network analysis by graph theory. Making no assumptions about direction of change, we used two-tailed statistical analysis over multiple brain regions in a data-driven approach to access global and regional changes in network topology in order to assess brain connectivity in an unbiased way. Our main hypothesis was that deficits in functional connectivity would become apparent in regions known to be structurally altered or deficient in axonal connectivity in this model. The data show the loss of functional connectivity predicted by the structural deficits, not only within the primary sensorimotor injury site and pericontused regions, but the normally connected homotopic cortex, as well as subcortical regions, all of which persisted chronically. Especially novel in this study is the unanticipated finding of widespread increases in connection strength that dwarf both the degree and extent of the functional disconnections, and which persist chronically in some sensorimotor and subcortically connected regions. Exploratory global network analysis showed changes in network parameters indicative of possible acutely increased random connectivity and temporary reductions in modularity that were matched by local increases in connectedness and increased efficiency among more weakly connected regions. The global network parameters: shortest path-length, clustering coefficient and modularity that were most affected by trauma also scaled with the severity of injury, so that the corresponding regional measures were correlated to the injury severity most notably at 7 and 14 days and especially within, but not limited to, the contralateral cortex. These changes in functional network parameters are discussed in relation to the known time-course of physiologic and anatomic data that underlie structural and functional reorganization in this experiment model of TBI.

The thalamocortical pathway is the main route of communication between the eye and the cerebral cortex. During embryonic development, thalamocortical afferents travel to L4 and are sorted by receptive field position, eye of origin, and contrast polarity (i.e., preference for light or dark stimuli). In primates and carnivores, this sorting involves numerous afferents, most of which sample a limited region of the binocular field. Devoting abundant thalamocortical resources to process a limited visual field has a clear advantage: It allows many stimulus combinations to be sampled at each spatial location. Moreover, the sampling efficiency can be further enhanced by organizing the afferents in a cortical grid for eye input and contrast polarity. We argue that thalamocortical interactions within this eye–polarity grid can be used to represent multiple stimulus combinations found in nature and to build an accurate cortical map for multidimensional stimulus space. Expected final online publication date for the A...

In this mini-review I have proposed that there are two kinds of position sense, one a sense of the position of one part of the body relative to another, the other a sense of the location in space of our body and its limbs. A common method used to measure position sense is to ask subjects to match with one arm the position adopted by the other. Here all of the evidence points to muscle spindles as the major proprioceptors, with cutaneous receptors acting as proprioceptors providing a supporting role. Other senses such as vision do not play a major role. The sense of localisation in space measured by pointing to the arm, rather than matching its position, I propose, is not served by proprioceptors but by exteroceptors, vision, touch and hearing. Here the afferent input is relayed to sensory areas of the brain, to address the postural schema, a cortical map of the body and limbs, specifying its size and shape. It is here that spatial location is computed. This novel interpretation of position sense as two separate entities has the advantage of proposing new, future experiments and if it is supported by the findings, it will represent an important step forward in our understanding of the central processing of spatial information.

What, if anything, is the functional significance of spatial patterning in cortical feature maps? We ask this question of four major theories of cortical map formation: self-organizing maps, wiring optimization, place coding, and reaction-diffusion. We argue that (i) self-organizing maps yield spatial patterning only as a by-product of efficient mechanisms for developing environmentally appropriate distributions of feature preferences, (ii) wiring optimization assumes rather than explains a map-like organization, (iii) place-coding mechanisms can at best explain only a subset of maps in functional terms, and (iv) reaction-diffusion models suggest two factors in the evolution of maps, the first based on efficient development of feature distributions, and the second based on generating feature-specific long-range recurrent cortical circuitry. None of these explanations for the existence of topological maps requires spatial patterning in maps to be useful. Thus despite these useful frameworks for understanding how maps form and how they are wired, the possibility that patterns are merely epiphenomena in the evolution of mammalian neocortex cannot be rejected. The article is intended as a nontechnical introduction to the assumptions and predictions of these four important classes of models, along with other possible functional explanations for maps.

© 2015 The Authors. Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs) dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluδmice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult. Development of VNS delivery paradigms that reduce therapy duration and maximize efficacy would facilitate clinical translation. The goal of the current study was to determine whether primary auditory cortex (A1) plasticity can be generated more quickly by shortening the interval between VNS-tone pairing events or by delivering fewer VNS-tone pairing events. While shortening the inter-stimulus interval between VNS-tone pairing events resulted in significant A1 plasticity, reducing the number of VNS-tone pairing events failed to alter A1 responses. Additionally, shortening the inter-stimulus interval between VNS-tone pairing events failed to normalize neural and behavioral responses following acoustic trauma. Extending the interval between VNS-tone pairing events yielded comparable A1 frequency map plasticity to the standard protocol, but did so without increasing neural excitability. These results indicate that the duration of the VNS-event pairing session is an important parameter that can be adjusted to optimize neural plasticity for different clinical needs.