Effects of rTMS on working memory abilities and time-varying spectrum coherence of LFPS and spikes in rats

Effects of theta burst stimulation on the coherence of local field potential during working memory task in rats

High-frequency rTMS has been widely used to improve working memory (WM) impairment; however, the underlying neurophysiological mechanisms are unclear. We evaluated the effect of high-frequency rTMS on behaviors relevant to WM as well as coupling between theta and gamma oscillations in the prefrontal cortex (PFC) of rats. Accordingly, Wistar rats received high-frequency rTMS daily for 14days (5Hz, 10Hz, and 15Hz stimulation; 600 pulses; n = 6 per group), whereas the control group received sham stimulation. Electrophysiological signals were recorded simultaneously to obtain the local field potential (LFP) from the PFC, while the rats performed T-maze tasks for the evaluation of WM. Phase-amplitude coupling (PAC) was utilized to determine the effect of high-frequency rTMS on the theta-gamma coupling of LFPs. We observed that rats in the rTMS groups needed a smaller number of training days to complete the WM task as compared to the control group. High-frequency rTMS reinforced the coupling connection strength in the PFC of rats. Notably, the effect of rTMS at 15Hz was the most effective among the three frequencies, i.e., 5Hz, 10Hz, and 15Hz. The results suggested that rTMS can improve WM impairment in rats by modulating the coupling of theta and gamma rhythms. Hence, the current study provides a scientific basis for the optimization of TMS models, which would be relevant for clinical application.

Working memory (WM) refers to the short-term maintenance of information with higher cognitive functions. Recent researches show that local field potentials (LFPs) and spikes as different modes of neural signals encode WM respectively. There is a growing interest in how these two signals encode WM in coordination. The aim of this study is to investigate spike-LFP coupling coding WM via joint entropy analysis. The experimental data were multi-channels Spikes and LFPs obtained at prefrontal cortex with implanted microelectrode array in SD rats during WM tasks in Y-maze. The short-time Fourier transform (STFT) was applied to find the principle frequency range in the LFPs during WM. The joint entropy indexes (JEIs) between spikes and the principle components of LFPs were calculated for each pair of spike and LFP during WM. The results show that theta was the principle band in LFP for WM. The JEIs between Spikes and theta components of LFPs encode WM effectively. These findings could lead to improved understanding the mechanism of WM from the view of Spike-LFP joint encoding.

Increase of spike–LFP coordination in rat prefrontal cortex during working memory

Working memory (WM) is a kind of advanced cognitive function, which requires the participation and cooperation of multiple brain regions. Hippocampus and prefrontal cortex are the main responsible brain regions for WM. Exploring information coordination between hippocampus and prefrontal cortex during WM is a frontier problem in cognitive neuroscience. In this paper, an advanced information theory analysis based on bimodal neural electrical signals (local field potentials, LFPs and spikes) was employed to characterize the transcerebral information coordination across the two brain regions. Firstly, LFPs and spikes were recorded simultaneously from rat hippocampus and prefrontal cortex during the WM task by using multi-channel in vivo recording technique. Then, from the perspective of information theory, directional hippocampus-prefrontal cortex networks were constructed by using transfer entropy algorithm based on spectral coherence between LFPs and spikes. Finally, transcerebral coordination of bimodal information at the brain-network level was investigated during acquisition and performance of the WM task. The results show that the transfer entropy in directional hippocampus-prefrontal cortex networks is related to the acquisition and performance of WM. During the acquisition of WM, the information flow, local information transmission ability and information transmission efficiency of the directional hippocampus-prefrontal networks increase over learning days. During the performance of WM, the transfer entropy from the hippocampus to prefrontal cortex plays a leading role for bimodal information coordination across brain regions and hippocampus has a driving effect on prefrontal cortex. Furthermore, bimodal information coordination in the hippocampus → prefrontal cortex network could predict WM during the successful performance of WM.

FIGURE 1. The Atkinson and Shiffrin Model of memory is diagramed in the gray panel. Sensory information is perceived and suppressed via selective attention processes, then briefly held in the limited-capacity modality-specific sensory register. Information enhanced by selective attention enters into short term memory (STM). The process of rehearsal (maintenance) can sustain information in STM. Information in STM is automatically encoded (stored, consolidated) into long term memory (LTM). Although flawed, this model continues to provide a simple and easy approach to understanding memory. Assumptions that proved to be inconsistent with research included that any information in STM will transfer to LTM and that STM is required

α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Long-range synchrony between medial prefrontal cortex, thalamus and hippocampus underlies working memory behavior in mice. Pia-Kelsey O’Neill Presently, there are no antipsychotic drugs capable of treating the cognitive dysfunctions of schizophrenia. In order to inform the development of better therapies, it is essential to understand the mechanism behind dysfunctional cognition, which requires an understanding of functional cognition. Spatial working memory, a measure of cognitive function, can be assessed in the mouse using a task of delayed alternation: the T-maze. In this thesis, I focus on spatial working memory behavior in the mouse and three brain regions that are implicated in this behavior: the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the medial dorsal thalamus (MD). Lesion and electrophysiological studies in each structure have demonstrated their importance during working memory behavior. Disconnection studies also show that the coordination between the mPFC and either the HPC or MD is important for the behavior, but little is known about the mechanism by which they coordinate. The MD and the ventral region of the hippocampus (vHPC) have robust projections into the mPFC. They are therefore in a good position to influence mPFC activity. Previous reports show that the mPFC and the dorsal region of the hippocampus (dHPC) synchronize activity in the theta range (4-12 Hz) with working memory demand. However, the dHPC does not directly connect with the mPFC so it is unclear how this coordination occurs. We hypothesized that the vHPC may also be involved in spatial working memory behavior and that it may mediate the dHPC-mPFC theta synchrony observed. To test these hypotheses, we recorded neural activity simultaneously from the mPFC, dHPC and vHPC in mice performing the T-maze task. Local field potential oscillations (LFPs), thought to be a measure of synchronized synaptic activity, were obtained from each area. We observed an increase in theta synchrony between the mPFC and both the dHPC and vHPC. Removing the influence of vHPC both analytically and experimentally, we found a decrease in synchrony of the dHPC-mPFC. Aside from the disconnection studies, little is known about the MD-mPFC pathway in rodents. However, due to evidence from schizophrenia patients of altered correlation specifically between the MD and PFC, we hypothesized that an electrophysiological correlate of working memory exists in the MD-mPFC pathway as well and that a decrease in MD activity may lead to prefrontal dysfunction. To test these hypotheses, we recorded LFPs from the mPFC and both single unit activity and LFPs from the MD in mice performing the T-maze task. We observed an increase in phase locking of MD cells to mPFC LFPs in beta (13-30Hz) range during the choice phase of the task. We then utilized a pharmacogenetic technique to decrease firing rate in a small portion of MD cells, which resulted in a deficit in both task acquisition and performance. The increase in MD-mPFC beta phase locking we had observed was not present in MDinactivated animals. Interestingly, beta coherence between the two structures across learning was highly correlated with choice accuracy on the task. This suggests that MD-PFC coordination is predictive of working memory performance. These findings illustrate how long-range synchrony of the mPFC with HPC in the theta frequency range and with the MD in the beta frequency range may be important markers for normal working memory behavior and if disrupted in humans, could contribute to the cognitive symptoms of schizophrenia.

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters. Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance. The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters. Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.

BackgroundResearch on hemodynamic responses in the prefrontal cortex during working memory tasks has mainly been performed in cognitive neuroscience research. However, the specific stimuli contributing to working memory deficits in major depressive disorder (MDD) are currently lacking. This study aims to compare working memory performance and prefrontal cortex activation in individuals with MDD and healthy controls during working memory tasks involving textual, visual, and emotional stimuli.MethodFunctional near‐infrared spectroscopy was utilized to record hemodynamic responses from 71 adults (30 with MDD and 41 controls) during the 2‐back tasks with four stimulus types: numbers, letters, polygons, and facial expressions. Working memory performance was measured by accuracy and reaction time during the tasks, and hemodynamic responses were collected by oxyhemoglobin (HbO) activation of the prefrontal cortex during the tasks.ResultMDD demonstrated lower working memory performance than controls during polygon and facial expression‐based 2‐back tasks, while there was no significant difference under number and letter conditions. MDD under the polygon stimulus exhibited abnormal HbO activation in the bilateral ventrolateral prefrontal cortex compared to controls, while under the facial expression stimulus, it showed exclusive abnormal HbO activation in the left medial prefrontal cortex, bilateral orbito prefrontal cortex, and bilateral ventrolateral prefrontal cortex.ConclusionThese findings indicate the importance of stimuli that require cognitive processing not only for logical aspects, such as polygons, but also for emotional aspects, like facial expressions, in evaluating hemodynamic responses of prefrontal cortex and working memory abilities in individuals with MDD.

Low-frequency local field potentials reveal integration of spatial and non-spatial information in prefrontal cortex.

On Altered Patterns of Brain Activation in At-Risk Adolescents and Young Adults

Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety

The goal of the present study was to see whether one neuron is involved exclusively in one type of memory or in different types of memory. Single-unit activity was recorded from rat hippocampal CA1, CA3, dentate gyrus, and auditory cortex (AC) during performances of auditory working memory (WM) and reference memory (RM) tasks. Both the memory tasks employed identical apparatus and stimuli and differed only in the type of memory required for correct performance. Around 10% and 43% of the units from the four brain regions showed sensory correlates (differences in activity due to the type of sensory stimulus) only in the WM or RM task, respectively. Only the AC had units showing different kinds of sensory correlates between the WM and RM tasks. About 30% of the units from the four regions had sensory-retention correlates (sustained differential activity during the delay) only in the RM task, whereas the AC had units with sensory-retention correlates only in the WM task or in both the WM and RM tasks. Approximately 35% of the units from the hippocampal regions showed motor correlates (increments of activity immediately prior to responses) only in the WM task. Another 30% of the hippocampal units showed such correlates both in the WM and RM tasks. About 22% of the hippocampal CA1 and CA3 units showed comparison-motor correlates (increases of activity prior to correct responses) only in the WM task. These results indicate that some neurons are involved solely in WM or RM, whereas other neurons are involved in both WM and RM. The results also suggest that more neurons are involved in sensory and retention processing for RM than for WM, and that the AC alone has flexible neurons involved in the processes for both types of memory. More hippocampal neurons are involved in the motor and comparison processes for WM than for RM.

The primate dorsolateral prefrontal cortex (dlPFC) subserves top-down regulation of attention and working memory abilities. Depletion studies show that the neuromodulator acetylcholine (ACh) is essential to dlPFC working memory functions, but the receptor and cellular bases for cholinergic actions are just beginning to be understood. The current study found that nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhance the task-related firing of delay and fixation cells in the dlPFC of monkeys performing a working memory task. Iontophoresis of α4β2-nAChR agonists increased the neuronal firing and enhanced the spatial tuning of delay cells, neurons that represent visual space in the absence of sensory stimulation. These enhancing effects were reversed by coapplication of a α4β2-nAChR antagonist, consistent with actions at α4β2-nAChR. Delay cell firing was reduced when distractors were presented during the delay epoch, whereas stimulation of α4β2-nAChR protected delay cells from these deleterious effects. Iontophoresis of α4β2-nAChR agonists also enhanced the firing of fixation cells, neurons that increase firing when the monkey initiates a trial, and maintain firing until the trial is completed. These neurons are thought to contribute to sustained attention and top-down motor control and have never before been the subject of pharmacological inquiry. These findings begin to build a picture of the cellular actions underlying the beneficial effects of ACh on attention and working memory. The data may also help to explain why genetic insults to α4 subunits are associated with working memory and attentional deficits and why α4β2-nAChR agonists may have therapeutic potential.SIGNIFICANCE STATEMENT The acetylcholine (ACh) arousal system in the brain is needed for robust attention and working memory functions, but the receptor and cellular bases for its beneficial effects are poorly understood in the newly evolved primate brain. The current study found that ACh stimulation of nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhanced the firing of neurons in the primate prefrontal cortex that subserve top-down attentional control and working memory. α4β2-nAChR stimulation also protected neuronal responding from the detrimental effects of distracters presented during the delay epoch, when information is held in working memory. These results illuminate how ACh strengthens higher cognition and help to explain why genetic insults to the α4 subunit weaken cognitive and attentional abilities.