Impaired Potentiation of Theta Oscillations During a Visual Cortical Plasticity Paradigm in Individuals With Schizophrenia.

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP in vitro and in vivo in animal models, repeated high frequency presentation of a visual stimulus in humans in vivo has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.

Impaired visual cortical plasticity in schizophrenia.

BACKGROUND: Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. METHODS: Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. RESULTS: High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. CONCLUSIONS: Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N-methyl-D-aspartate receptor function.

Distinct mechanisms for the impact of distraction and interruption on working memory in aging.

Interference is known to negatively impact the ability to maintain information in working memory (WM), an effect that is exacerbated with aging. Here, we explore how distinct sources of interference, i.e., distraction (stimuli to-be-ignored) and interruption (stimuli requiring attention), differentially influence WM in younger and older adults. EEG was recorded while participants engaged in three versions of a delayed-recognition task: no interference, a distracting stimulus, and an interrupting stimulus presented during WM maintenance. Behaviorally, both types of interference negatively impacted WM accuracy in older adults significantly more than younger adults (with a larger deficit for interruptions). N170 latency measures revealed that the degree of processing both distractors and interruptors predicted WM accuracy in both populations. However, while WM impairments could be explained by excessive attention to distractors by older adults (a suppression deficit), impairment induced by interruption were not clearly mediated by age-related increases in attention to interruptors. These results suggest that distinct underlying mechanisms mediate the impact of different types of external interference on WM in normal aging.

Translating long-term potentiation from animals to humans: a novel method for noninvasive assessment of cortical plasticity.

Long-term potentiation (LTP) is a synaptic mechanism underlying learning and memory that has been studied extensively in laboratory animals. The study of LTP recently has been extended into humans with repetitive sensory stimulation to induce cortical LTP. In this review article, we will discuss past results from our group demonstrating that repetitive sensory stimulation (visual or auditory) induces LTP within the sensory cortex (visual/auditory, respectively) and can be measured noninvasively with electroencephalography or functional magnetic resonance imaging. We will discuss a number of studies that indicate that this form of LTP shares several characteristics with the synaptic LTP described in animals: it is frequency dependent, long-lasting (> 1 hour), input-specific, depotentiates with low-frequency stimulation, and is blocked by N-methyl-D-aspartate receptor blockers in rats. In this review, we also present new data with regard to the behavioral significance of human sensory LTP. These advances will permit enquiry into the functional significance of LTP that has been hindered by the absence of a human model. The ability to elicit LTP with a natural sensory stimulus noninvasively will provide a model system allowing the detailed examination of synaptic plasticity in normal subjects and might have future clinical applications in the diagnosis and assessment of neuropsychiatric and neurocognitive disorders.

From vision to decision: the role of visual attention in elite sports performance.

Elite sports performance fundamentally relies on a complex set of brain functions engaged once visual signals are relayed from the eye. In this review, we overview a series of these neural mechanisms-focusing specifically on the critical role of attention in sculpting the visual processing that takes place leading up to a decision. These brain functions are introduced within the theoretical concept of the 'Perception-Action Cycle.' Vision does not stop at the eye but requires a coordinated set of brain mechanisms called on to convert visual input into rapid decisions about action.

Deficit in switching between functional brain networks underlies the impact of multitasking on working memory in older adults.

Multitasking negatively influences the retention of information over brief periods of time. This impact of interference on working memory is exacerbated with normal aging. We used functional MRI to investigate the neural basis by which an interruption is more disruptive to working memory performance in older individuals. Younger and older adults engaged in delayed recognition tasks both with and without interruption by a secondary task. Behavioral analysis revealed that working memory performance was more impaired by interruptions in older compared with younger adults. Functional connectivity analyses showed that when interrupted, older adults disengaged from a memory maintenance network and reallocated attentional resources toward the interrupting stimulus in a manner consistent with younger adults. However, unlike younger individuals, older adults failed to both disengage from the interruption and reestablish functional connections associated with the disrupted memory network. These results suggest that multitasking leads to more significant working memory disruption in older adults because of an interruption recovery failure, manifest as a deficient ability to dynamically switch between functional brain networks.

The influence of perceptual training on working memory in older adults.

Normal aging is associated with a degradation of perceptual abilities and a decline in higher-level cognitive functions, notably working memory. To remediate age-related deficits, cognitive training programs are increasingly being developed. However, it is not yet definitively established if, and by what mechanisms, training ameliorates effects of cognitive aging. Furthermore, a major factor impeding the success of training programs is a frequent failure of training to transfer benefits to untrained abilities. Here, we offer the first evidence of direct transfer-of-benefits from perceptual discrimination training to working memory performance in older adults. Moreover, using electroencephalography to evaluate participants before and after training, we reveal neural evidence of functional plasticity in older adult brains, such that training-induced modifications in early visual processing during stimulus encoding predict working memory accuracy improvements. These findings demonstrate the strength of the perceptual discrimination training approach by offering clear psychophysical evidence of transfer-of-benefit and a neural mechanism underlying cognitive improvement.

Predictive knowledge of stimulus relevance does not influence top-down suppression of irrelevant information in older adults.

Our ability to focus attention on task-relevant stimuli and ignore irrelevant distractions is reflected by differential enhancement and suppression of neural activity in sensory cortices. Previous research has shown that older adults exhibit a deficit in suppressing task-irrelevant information, the magnitude of which is associated with a decline in working memory performance. However, it remains unclear if a failure to suppress is a reflection of an inability of older adults to rapidly assess the relevance of information upon stimulus presentation when they are not aware of the relevance beforehand. To address this, we recorded the electroencephalogram (EEG) in healthy older participants (aged 60-80 years) while they performed two different versions of a selective face/scene working memory task, both with and without prior knowledge as to when relevant and irrelevant stimuli would appear. Each trial contained two faces and two scenes presented sequentially followed by a 9 sec delay and a probe stimulus. Participants were given the following instructions: remember faces (ignore scenes), remember scenes (ignore faces), remember the xth and yth stimuli (where x and y could be 1st, 2nd, 3rd or 4th), or passively view all stimuli. Working memory performance remained consistent regardless of task instructions. Enhanced neural activity was observed at posterior electrodes to attended stimuli, while neural responses that reflected the suppression of irrelevant stimuli was absent for both tasks. The lack of significant suppression at early stages of visual processing was revealed by P1 amplitude and N1 latency modulation indices. These results reveal that prior knowledge of stimulus relevance does not modify early neural processing during stimulus encoding and does not improve working memory performance in older adults. These results suggest that the inability to suppress irrelevant information early in the visual processing stream by older adults is related to mechanisms specific to top-down suppression.

Mechanisms of working memory disruption by external interference.

The negative impact of external interference on working memory (WM) performance is well documented; yet, the mechanisms underlying this disruption are not sufficiently understood. In this study, electroencephalogram and functional magnetic resonance imaging (fMRI) data were recorded in separate experiments that each introduced different types of visual interference during a period of WM maintenance: distraction (irrelevant stimuli) and interruption (stimuli that required attention). The data converged to reveal that regardless of the type of interference, the magnitude of processing interfering stimuli in the visual cortex (as rapidly as 100 ms) predicted subsequent WM recognition accuracy for stored items. fMRI connectivity analyses suggested that in the presence of distraction, encoded items were maintained throughout the delay period via connectivity between the middle frontal gyrus and visual association cortex, whereas memoranda were not maintained when subjects were interrupted but rather reactivated in the postinterruption period. These results elucidate the mechanisms of external interference on WM performance and highlight similarities and differences of distraction and multitasking.

Long-term potentiation (LTP) of human sensory-evoked potentials.

Long-term potentiation (LTP) is the principal candidate synaptic mechanism underlying learning and memory, and has been studied extensively at the cellular and molecular level in laboratory animals. Inquiry into the functional significance of LTP has been hindered by the absence of a human model as, until recently, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. In this brief review, we describe the results of paradigms recently developed in our laboratory for inducing LTP-like changes in visual-, and auditory-evoked potentials. We describe how rapid, repetitive presentation of sensory stimuli leads to a persistent enhancement of components of sensory-evoked potential in normal humans. Experiments to date, investigating the locus, stimulus specificity, and NMDA receptor dependence of these LTP-like changes suggest that they have the essential characteristics of LTP seen in experimental animals. The ability to elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the assessment of cognitive disorders. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

Early top-down control of visual processing predicts working memory performance.

Selective attention confers a behavioral benefit on both perceptual and working memory (WM) performance, often attributed to top-down modulation of sensory neural processing. However, the direct relationship between early activity modulation in sensory cortices during selective encoding and subsequent WM performance has not been established. To explore the influence of selective attention on WM recognition, we used electroencephalography to study the temporal dynamics of top-down modulation in a selective, delayed-recognition paradigm. Participants were presented with overlapped, "double-exposed" images of faces and natural scenes, and were instructed to either remember the face or the scene while simultaneously ignoring the other stimulus. Here, we present evidence that the degree to which participants modulate the early P100 (97-129 msec) event-related potential during selective stimulus encoding significantly correlates with their subsequent WM recognition. These results contribute to our evolving understanding of the mechanistic overlap between attention and memory.

Practice-related improvement in working memory is modulated by changes in processing external interference.

Working memory (WM) performance is impaired by the presence of external interference. Accordingly, more efficient processing of intervening stimuli with practice may lead to enhanced WM performance. To explore the role of practice on the impact that interference has on WM performance, we studied young adults with electroencephalographic (EEG) recordings as they performed three motion-direction, delayed-recognition tasks. One task was presented without interference, whereas two tasks introduced different types of interference during the interval of memory maintenance: distractors and interruptors. Distractors were to be ignored, whereas interruptors demanded attention based on task instructions for a perceptual discrimination. We show that WM performance was disrupted by both types of interference, but interference-induced disruption abated across a single experimental session through rapid learning. WM accuracy and response time improved in a manner that was correlated with changes in early neural measures of interference processing in visual cortex (i.e., P1 suppression and N1 enhancement). These results suggest practice-related changes in processing interference exert a positive influence on WM performance, highlighting the importance of filtering irrelevant information and the dynamic interactions that exist between neural processes of perception, attention, and WM during learning.

Induction of orientation-specific LTP-like changes in human visual evoked potentials by rapid sensory stimulation.

Recent research suggests that rapid visual stimulation can induce long-term potentiation-like effects non-invasively in humans. However, to date, this research has provided only limited evidence for input-specificity, a fundamental property of cellular long-term potentiation. In the present study we extend the evidence for input-specificity by investigating the effect of stimulus orientation. We use sine wave gratings of two different orientations to show that rapid visual stimulation can induce orientation-specific potentiation, as indexed by changes in the amplitude of a late phase of the N1 complex of the visual-evoked potential. This result suggests that discrete populations of orientation-tuned neurons can be selectively potentiated by rapid visual stimulation. Furthermore, our results support earlier studies that have suggested that the locus of potentiation induced by rapid visual stimulation is visual cortex.

Induction of LTP-like changes in human auditory cortex by rapid auditory stimulation: an FMRI study.

PURPOSE: Previously we have shown that rapid sensory stimulation, in this case, auditory tone pips, can induce long-lasting plastic changes akin to Long Term Potentiation (LTP) within adult human sensory cortex. In a previous study, auditory LTP was reflected as an increase in the amplitude of the N1 component of the auditory event-related potential as measured by EEG. The goal of the present study was to investigate potential effects of LTP-like changes on the hemodynamic response of the human auditory cortex. METHODS: Silent sparse-sampled fMRI recordings were obtained while subjects passively listened to tone-pips both before and after a short block of rapidly presented auditory tone-pips (auditory tetanus) was delivered. RESULTS: The BOLD response within the primary auditory cortex was significantly enhanced after the auditory tetanus. CONCLUSION: This is the first study demonstrating LTP-like changes of the hemodynamic response in the auditory system, and thus supports the growing literature demonstrating LTP can be induced in adult human cortex. These results have implications in the fields of perceptual learning and rehabilitation.

Graded cue information in dichotic pitch: effects on event-related potentials.

To determine whether electroencephalogram components elicited by dichotic pitch stimuli are all-or-none threshold-like responses or graded responses that depend on the saliency of the stimuli, we recorded electroencephalograms while participants listened to dichotic pitch stimuli constructed with different signal-to-background ratios. The object-related negativity and P400 components were largest when the dichotic pitch was most salient (high signal-to-background ratio), and decreased in amplitude with decreasing signal-to-background ratio. These results are similar to those reported for mistuned harmonics, thereby providing additional evidence that the object-related negativity and P400 components observed for these disparate stimulus types reflect similar processing. They also support the notion that the object-related negativity and P400 amplitudes are dependent on the level of relevant cue-based stimulus information.

Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex.

Previously we have demonstrated that rapidly presented sensory stimulation (visual or auditory) can induce long-lasting increases in sensory evoked potentials recorded from the human cortex. Long-term potentiation was suggested as the underlying mechanism of these increases. In the present experiment, we applied the same visual paradigm to anesthetized rats to investigate the properties and mechanisms of this effect. Our results indicated that visual evoked responses were significantly enhanced for at least 1 h and, when followed, up to 5 h after the presentation of a 'photic tetanus.' Furthermore, the potentiation was N-methyl-D-aspartate receptor-dependent and cortically generated. This type of sensory long-term potentiation may underlie perceptual learning, and serves as a model system for investigating sensory-evoked plasticity.

Long-term enhanced desynchronization of the alpha rhythm following tetanic stimulation of human visual cortex.

It had been shown previously that a photic tetanus induces LTP-like changes in the visual cortex, as indexed by an enhancement of the N1b component of the visual evoked potential, recorded non-invasively by electroencephalography. This potentiation was shown to last over 1 h. In the present study, the effect of a photic tetanus on oscillatory activity is investigated. EEGs were collected from eight healthy subjects in three conditions while visual checkerboards were displayed. Following baseline presentations in two conditions a lateralized visual tetanus was given, either to the left or right visual field, and in a third condition no tetanus was given. This was followed by a return to baseline presentations, both immediately after the tetanus/control block, and 1 h later. Enhanced event-related desynchronization (ERD) of the alpha rhythm lasting 1 h was seen following the photic tetanus over occipital electrodes. Because ERD of the alpha rhythm is thought to represent active cortex, these results suggest that the visual tetanus induces long-lasting cortical changes, with stronger neuronal assemblies and increased neuronal output.

Effects of long-term potentiation in the human visual cortex: a functional magnetic resonance imaging study.

Applying functional magnetic resonance imaging techniques, hemodynamic responses elicited by slowly flashing checkerboards (0.25 Hz) were measured both before and after a block of rapidly presented checkerboards (9 Hz -- a 'photic tetanus') was delivered. It has been shown previously, using electroencephalography, that this photic tetanus potentiates components of the visual-evoked potential. In the present study, hemodynamic responses in the extrastriate visual cortex were significantly increased to checkerboards presented at a low frequency after the administration of the photic tetanus. These results support the idea that long-term potentiation can be demonstrated non-invasively within the human visual cortex and provide evidence that the plastic changes are localized within the secondary visual cortex.

Long-term potentiation of human visual evoked responses.

Long-term potentiation (LTP) is a candidate synaptic mechanism underlying learning and memory that has been studied extensively at the cellular and molecular level in laboratory animals. To date, LTP has only been directly demonstrated in humans in isolated cortical tissue obtained from patients undergoing surgery, where it displays properties identical to those seen in non-human preparations. Inquiry into the functional significance of LTP has been hindered by the absence of a human model. Here we give the first demonstration that the rapid repetitive presentation of a visual checkerboard (a photic 'tetanus') leads to a persistent enhancement of one of the early components of the visual evoked potential in normal humans. The potentiated response is largest in the hemisphere contralateral to the tetanized visual hemifield and is limited to one component of the visual evoked response (the N1b). The selective potentiation of only the N1b component makes overall brain excitability changes unlikely and suggests that the effect is due instead to an LTP process. While LTP is known to exist in the human brain, the ability to elicit LTP from non-surgical patients will provide a human model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the assessment of cognitive disorders.