Prefrontal transcranial direct current stimulation (tDCS) enhances behavioral and EEG markers of proactive control.

This study examined the effects of stimulation targeting dorsolateral prefrontal cortex (DLPFC) on behavioral and neural oscillatory markers of proactive cognitive control in healthy adults. We hypothesized that active stimulation targeting the DLPFC would enhance proactive control compared to sham, leading to changes in the pattern of error rates and gamma-band power on the Dot Pattern Expectancy (DPX) task. We recorded EEG while participants completed the DPX, after receiving either 20 minutes of active DLPFC stimulation at 2 mA or sham stimulation in a counterbalanced within-participants design. The results showed significant tDCS-induced changes in the pattern of error rates on the DPX task indicative of enhanced proactive control, as well as predicted increases in gamma power associated with the engagement of proactive control. These results provide support for the role of DLPFC-mediated gamma activity in proactive cognitive control, and further, indicate that proactive control can be enhanced with non-invasive neurostimulation.

Entrainment enhances theta oscillations and improves episodic memory.

Neural oscillations in the theta band have been linked to episodic memory, but it is unclear whether activity patterns that give rise to theta play a causal role in episodic retrieval. Here, we used rhythmic auditory and visual stimulation to entrain neural oscillations to assess whether theta activity contributes to successful memory retrieval. In two separate experiments, human subjects studied words and were subsequently tested on memory for the words ('item recognition') and the context in which each had been previously studied ('source memory'). Between study and test, subjects in the entrainment groups were exposed to audiovisual stimuli designed to enhance activity at 5.5 Hz, whereas subjects in the control groups were exposed to white noise (Expt. 1) or 14 Hz entrainment (Expt. 2). Theta entrainment selectively increased source memory performance in both studies. Electroencephalography (EEG) data in Expt. 2 revealed that theta entrainment resulted in band-specific enhancement of theta power during the entrainment period and during post-entrainment memory retrieval. These results demonstrate a direct link between theta activity and episodic memory retrieval. Targeted manipulation of theta activity could be a promising new approach to enhance theta activity and memory performance in healthy individuals and in patients with memory disorders.

Neural oscillations during conditional associative learning.

Associative learning requires mapping between complex stimuli and behavioural responses. When multiple stimuli are involved, conditional associative learning is a gradual process with learning based on trial and error. It is established that a distributed network of regions track associative learning, however the role of neural oscillations in human learning remains less clear. Here we used scalp EEG to test how neural oscillations change during learning of arbitrary visuo-motor associations. Participants learned to associative 48 different abstract shapes to one of four button responses through trial and error over repetitions of the shapes. To quantify how well the associations were learned for each trial, we used a state-space computational model of learning that provided a probability of each trial being correct given past performance for that stimulus, that we take as a measure of the strength of the association. We used linear modelling to relate single-trial neural oscillations to single-trial measures of association strength. We found frontal midline theta oscillations during the delay period tracked learning, where theta activity was strongest during the early stages of learning and declined as the associations were formed. Further, posterior alpha and low-beta oscillations in the cue period showed strong desynchronised activity early in learning, while stronger alpha activity during the delay period was seen as associations became well learned. Moreover, the magnitude of these effects during early learning, before the associations were learned, related to improvements in memory seen on the next presentation of the stimulus. The current study provides clear evidence that frontal theta and posterior alpha/beta oscillations play a key role during associative memory formation.

Brain activity related to working memory for temporal order and object information.

Maintaining items in an appropriate sequence is important for many daily activities; however, remarkably little is known about the neural basis of human temporal working memory. Prior work suggests that the prefrontal cortex (PFC) and medial temporal lobe (MTL), including the hippocampus, play a role in representing information about temporal order. The involvement of these areas in successful temporal working memory, however, is less clear. Additionally, it is unknown whether regions in the PFC and MTL support temporal working memory across different timescales, or at coarse or fine levels of temporal detail. To address these questions, participants were scanned while completing 3 working memory task conditions (Group, Position and Item) that were matched in terms of difficulty and the number of items to be actively maintained. Group and Position trials probed temporal working memory processes, requiring the maintenance of hierarchically organized coarse and fine temporal information, respectively. To isolate activation related to temporal working memory, Group and Position trials were contrasted against Item trials, which required detailed working memory maintenance of visual objects. Results revealed that working memory encoding and maintenance of temporal information relative to visual information was associated with increased activation in dorsolateral PFC (DLPFC), and perirhinal cortex (PRC). In contrast, maintenance of visual details relative to temporal information was characterized by greater activation of parahippocampal cortex (PHC), medial and anterior PFC, and retrosplenial cortex. In the hippocampus, a dissociation along the longitudinal axis was observed such that the anterior hippocampus was more active for working memory encoding and maintenance of visual detail information relative to temporal information, whereas the posterior hippocampus displayed the opposite effect. Posterior parietal cortex was the only region to show sensitivity to temporal working memory across timescales, and was particularly involved in the encoding and maintenance of fine temporal information relative to maintenance of temporal information at more coarse timescales. Collectively, these results highlight the involvement of PFC and MTL in temporal working memory processes, and suggest a dissociation in the type of working memory information represented along the longitudinal axis of the hippocampus.

Reduction of brain kynurenic acid improves cognitive function.

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

Oscillatory activity during maintenance of spatial and temporal information in working memory.

Working memory (WM) processes help keep information in an active state so it can be used to guide future behavior. Although numerous studies have investigated brain activity associated with spatial WM in humans and monkeys, little research has focused on the neural mechanisms of WM for temporal order information, and how processing of temporal and spatial information might differ. Available evidence indicates that similar frontoparietal regions are recruited during temporal and spatial WM, although there are data suggesting that they are distinct processes. The mechanisms that allow for differential maintenance of these two types of information are unclear. One possibility is that neural oscillations may differentially contribute to temporal and spatial WM. In the present study, we used scalp electroencephalography (EEG) to compare patterns of oscillatory activity during maintenance of spatial and temporal information in WM. Time-frequency analysis of EEG data revealed enhanced left frontal theta (5-8 Hz), enhanced posterior alpha (9-12 Hz), and enhanced left posterior beta (14-28 Hz) power during the delay period of correct temporal order trials compared to correct spatial trials. In contrast, gamma (30-50 Hz) power at right lateral frontal sites was increased during the delay period of spatial WM trials, as compared to temporal WM trials. The present results are consistent with the idea that neural oscillatory patterns provide distinct mechanisms for the maintenance of temporal and spatial information in WM. Specifically, theta oscillations are most critical for the maintenance of temporal information in WM. Possible roles of higher frequency oscillations in temporal and spatial memory are also discussed.

Amelioration of ketamine-induced working memory deficits by dopamine D1 receptor agonists.

RATIONALE: Ketamine has been used in humans to model cardinal symptoms of schizophrenia, including working memory impairments and behavioral disorganization. Translational studies with ketamine in nonhuman primates promise to extend the neurobiological understanding of this model. OBJECTIVES: By establishing the dose-dependent effects of ketamine on spatial working memory and behavior, we sought to test and compare the capacity of antipsychotic and procognitive agents to reverse these symptoms. METHODS: Behavioral observations were taken following administration of placebo/ketamine (0.1-1.7 mg/kg, intramuscularly) and animals were tested on the spatial delayed response task 15 min post-injection. Pretreatments with risperidone as well as full and partial D1 receptor agonists were tested for their ability to reverse ketamine-induced impairments. RESULTS: Ketamine (median 1.0 mg/kg) produced a profound cognitive impairment and behavioral sequelae reminiscent of positive and negative symptoms. Risperidone within the therapeutic dose range failed to antagonize behavioral or cognitive consequences of acute ketamine but A77636 (0.1 and 1 microg/kg) and SKF38393 (0.1 microg/kg-100 microg/kg) ameliorated the spatial working memory deficit. This effect of A77636 was blocked by the D1 receptor antagonist, SCH39166 (1 and 10 microg/kg). CONCLUSIONS: These findings establish a valuable ketamine platform relevant to the treatment of cognitive dysfunction in schizophrenia. The reversal of ketamine-induced working memory deficits by a D1 receptor agonist, but not a commonly prescribed atypical antipsychotic, provides behavioral evidence for significant D1/N-methyl-D: -aspartate receptor interactions in prefrontal dysfunction and concurs with suggestions that D1 agonists may be useful in the treatment of cognitive impairments in schizophrenia.

Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction.

Working memory impairments are a core aspect of schizophrenia, yet current medicines do not address such cognitive dysfunction. We have developed a model of these working memory deficits by acutely disrupting glutamatergic synaptic transmission by administration of the N-methyl-d-aspartate (NMDA) antagonist ketamine in the nonhuman primate. The current studies evaluated the effect of positive allosteric modulators ("potentiators") of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the working memory and behavioral effects of ketamine. AMPA receptors mediate fast excitatory synaptic transmission throughout the brain and play a critical role in the activity-dependent regulation of NMDA receptors. We find that positive modulation of AMPA receptors with LY451646 (0.1-1.0mg/kg, SC) and structurally distinct PF-4778574 (0.01mg/kg, SC) robustly ameliorates ketamine-induced working memory impairments without altering behavioral effects of acute ketamine we consider related to positive- and negative-like symptoms. These results support AMPA receptor potentiators as a potential adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS).

Glycine transporter inhibition reverses ketamine-induced working memory deficits.

Glycine transporter inhibitors have recently been reported to improve symptoms in patients with schizophrenia. Here we used acute ketamine in the nonhuman primate to test the effectiveness of the novel glycine transporter inhibitor, PF-3463275, in a model of cognitive dysfunction relevant to schizophrenia. PF-3463275 (0.01-0.17 mg/kg; subcutaneously) or a vehicle was given before the administration of ketamine (median dose of 1.0 mg/kg intramuscularly) or placebo (saline). Ketamine induced hallucinatory-like behaviors that were not reversed by PF-3463275. In contrast, all doses of PF-3463275 alleviated the deficit in spatial working memory induced by ketamine. Theses findings build upon those in patients by providing translational support for targeting glycine transporter in adjunctive treatment for cognitive dysfunction in schizophrenia.