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.

Human Sensory LTP Predicts Memory Performance and Is Modulated by the BDNF Val66Met Polymorphism.

Background: Long-term potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to brain-derived neurotrophic factor (BDNF) Val66Met; a single-nucleotide polymorphism (SNP) implicated in memory function. Methods: Participants were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory. Results: The magnitude of LTP 40 min after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance. Conclusions: The current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.

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.

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.

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.

The hippocampal indexing theory and episodic memory: updating the index.

A little over 20 years ago, (Teyler and DiScenna,1986; Behav Neurosci 100:147-152) proposed the hippocampal memory index theory. It offered an account of episodic memory based on the intrinsic organization of the hippocampus, its synaptic physiology and its anatomical relationship to other regions of the brain. The essence of their idea was that the hippocampus was functionally designed and anatomically situated to capture information about neocortical activity generated by the individual features of behavioral episode. Moreover, because the hippocampus projects back to these neocortical regions the information it stored could serve as an index to the pattern of neocortical activity produced by the episode. Consequently, a partial cue that activated the index could activate the neocortical patterns and thus retrieve the memory of the episode. In this article we revisit and update indexing theory. Our conclusion is that it has aged very well. Its core ideas can be seen in many contemporary theories and there is a wealth of data that support this conceptual framework.

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.

BDNF protects against stress-induced impairments in spatial learning and memory and LTP.

The present study investigated whether infusion of brain-derived neurotrophic factor (BDNF) could ameliorate stress-induced impairments in spatial learning and memory as well as hippocampal long-term potentiation (LTP) of rats. Chronic immobilization stress (2 h/day x 7 days) significantly impaired spatial performance in the Morris water maze, elevated plasma corticosterone, and attenuated LTP in hippocampal slices from these animals as compared with normal control subjects. BDNF was infused into the left hippocampus (0.5 mul/h) for 14 days, beginning 7 days before the stress exposure. The BDNF group was protected from the deleterious effects of stress and performed at a level indistinguishable from normal control animals despite the presence of elevated corticosterone. BDNF alone and sham infusions had no effect on performance or LTP. These results demonstrate that spatial learning and memory, and LTP, a candidate neural substrate of learning and memory, are compromised during chronic stress, and may be protected by BDNF administration.