Vikram Rao

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging

Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non–rapid eye movement (NREM) sleep and impaired long-term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age-related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep–dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life.

NMDA and AMPA receptors: old channels, new tricks

Learning and memory depend on persistent changes in synaptic strength that require neuronal gene expression. An unresolved question concerns the mechanisms by which activity at synapses is transduced into a nuclear transcriptional response. In the prevailing view, N-methyl-D-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors have distinct roles in controlling synaptic strength: AMPA receptors effect short-term changes in synaptic strength, whereas NMDA receptors regulate genes that are required for the long-term maintenance of these changes. Here, we review recent data on the roles of these two types of receptor in activity-dependent gene expression. We discuss evidence that signals from NMDA receptors and AMPA receptors are integrated to specify transcriptional responses for particular plasticity related genes.

REM Sleep Depotentiates Amygdala Activity to Previous Emotional Experiences

Clinical evidence suggests a potentially causal interaction between sleep and affective brain function; nearly all mood disorders display co-occurring sleep abnormalities, commonly involving rapid-eye movement (REM) sleep. Building on this clinical evidence, recent neurobiological frameworks have hypothesized a benefit of REM sleep in palliatively decreasing next-day brain reactivity to recent waking emotional experiences. Specifically, the marked suppression of central adrenergic neurotransmitters during REM (commonly implicated in arousal and stress), coupled with activation in amygdala-hippocampal networks that encode salient events, is proposed to (re)process and depotentiate previous affective experiences, decreasing their emotional intensity. In contrast, the failure of such adrenergic reduction during REM sleep has been described in anxiety disorders, indexed by persistent high-frequency electroencephalographic (EEG) activity (>30 Hz); a candidate factor contributing to hyperarousal and exaggerated amygdala reactivity. Despite these neurobiological frameworks, and their predictions, the proposed benefit of REM sleep physiology in depotentiating neural and behavioral responsivity to prior emotional events remains unknown. Here, we demonstrate that REM sleep physiology is associated with an overnight dissipation of amygdala activity in response to previous emotional experiences, altering functional connectivity and reducing next-day subjective emotionality.

AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc

Learning and memory depend critically on long-term synaptic plasticity, which requires neuronal gene expression. In the prevailing view, AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but they do not directly regulate neuronal gene expression. By studying regulation of Arc, a gene required for long-term plasticity, we uncovered a new role for AMPA receptors in neuronal gene expression. Spontaneous synaptic activity or activity induced by brain-derived neurotrophic factor (BDNF) elicited Arc expression in cultures of rat cortical neurons and in organotypic brain slices. Notably, inhibiting AMPA receptors strongly potentiated activity-dependent Arc expression. We found that AMPA receptors negatively regulate Arc transcription, but not translation or stability, through a mechanism involving a pertussis toxin–sensitive G protein. These results provide insights into the activity-dependent mechanisms of Arc expression and suggest that, in addition to effecting short-term plasticity, AMPA receptors regulate genes involved in long-term plasticity.

β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.

Splice Variants of the NR1 Subunit Differentially Induce NMDA Receptor-Dependent Gene Expression

Subunits of the NMDA receptor (NMDAR) associate with many postsynaptic proteins that substantially broaden its signaling capacity. Although much work has been focused on the signaling of NR2 subunits, little is known about the role of the NR1 subunit. We set out to elucidate the role of the C terminus of the NR1 subunit in NMDAR signaling. By introducing a C-terminal deletion mutant of the NR1 subunit into cultured neurons from NR1−/− mice, we found that the C terminus was essential for NMDAR inactivation, downstream signaling, and gene expression, but not for global increases in intracellular Ca2+. Therefore, whereas NMDARs can increase Ca2+ throughout the neuron, NMDAR-dependent signaling, both local and long range, requires coupling through the NR1 C terminus. Two major NR1 splice variants differ by the presence or absence of a C-terminal domain, C1, which is determined by alternative splicing of exon 21. Analysis of these two variants showed that removal of this domain significantly reduced the efficacy of NMDAR-induced gene expression without affecting receptor inactivation. Thus, the NR1 C terminus couples to multiple downstream signaling pathways that can be modulated selectively by RNA splicing.

Impaired Prefrontal Sleep Spindle Regulation of Hippocampal-Dependent Learning in Older Adults

A hallmark feature of cognitive aging is a decline in the ability to form new memories. Parallel to these cognitive impairments are marked disruptions in sleep physiology. Despite recent evidence in young adults establishing a role for sleep spindles in restoring hippocampal-dependent memory formation, the possibility that disrupted sleep physiology contributes to age-related decline in hippocampal-dependent learning remains unknown. Here, we demonstrate that reduced prefrontal sleep spindles by over 40% in older adults statistically mediates the effects of old age on next day episodic learning, such that the degree of impaired episodic learning is explained by the extent of impoverished prefrontal sleep spindles. In addition, prefrontal spindles significantly predicted the magnitude of impaired next day hippocampal activation, thereby determining the influence of spindles on post-sleep learning capacity. These data support the hypothesis that disrupted sleep physiology contributes to age-related cognitive decline in later life, the consequence of which has significant treatment intervention potential.

Neuroimaging measures of error-processing: Extracting reliable signals from event-related potentials and functional magnetic resonance imaging

Error-related brain activity has become an increasingly important focus of cognitive neuroscience research utilizing both event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Given the significant time and resources required to collect these data, it is important for researchers to plan their experiments such that stable estimates of error-related processes can be achieved efficiently. Reliability of error-related brain measures will vary as a function of the number of error trials and the number of participants included in the averages. Unfortunately, systematic investigations of the number of events and participants required to achieve stability in error-related processing are sparse, and none have addressed variability in sample size. Our goal here is to provide data compiled from a large sample of healthy participants (n=180) performing a Go/NoGo task, resampled iteratively to demonstrate the relative stability of measures of error-related brain activity given a range of sample sizes and event numbers included in the averages. We examine ERP measures of error-related negativity (ERN/Ne) and error positivity (Pe), as well as event-related fMRI measures locked to False Alarms. We find that achieving stable estimates of ERP measures required four to six error trials and approximately 30 participants; fMRI measures required six to eight trials and approximately 40 participants. Fewer trials and participants were required for measures where additional data reduction techniques (i.e., principal component analysis and independent component analysis) were implemented. Ranges of reliability statistics for various sample sizes and numbers of trials are provided. We intend this to be a useful resource for those planning or evaluating ERP or fMRI investigations with tasks designed to measure error-processing.

Multi-day rhythms modulate seizure risk in epilepsy

Epilepsy is defined by the seemingly random occurrence of spontaneous seizures. The ability to anticipate seizures would enable preventative treatment strategies. A central but unresolved question concerns the relationship of seizure timing to fluctuating rates of interictal epileptiform discharges (here termed interictal epileptiform activity, IEA), a marker of brain irritability observed between seizures by electroencephalography (EEG). Here, in 37 subjects with an implanted brain stimulation device that detects IEA and seizures over years, we find that IEA oscillates with circadian and subject-specific multidien (multi-day) periods. Multidien periodicities, most commonly 20–30 days in duration, are robust and relatively stable for up to 10 years in men and women. We show that seizures occur preferentially during the rising phase of multidien IEA rhythms. Combining phase information from circadian and multidien IEA rhythms provides a novel biomarker for determining relative seizure risk with a large effect size in most subjects.The ability to identify periods of heightened seizure risk could enable new treatments for patients with epilepsy. Here, the authors describe long term EEG recordings from 37 patients which allow them to identify multi-day fluctuations in interictal activity.

Clinical Approach to Posttraumatic Epilepsy

Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity. The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this silent period, much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis. Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endophenotypes associated with PTE. Appropriate treatment of patients who have or are at risk for seizures varies as a function of time after TBI, and the clinicians armamentarium includes an ever-expanding diversity of pharmacological and surgical options. Most recently, neuromodulation with implantable devices has emerged as a promising therapeutic strategy for some patients with refractory PTE. Here, we review the epidemiology, diagnostic considerations, and treatment options for PTE and develop a roadmap for providers encountering this challenging clinical entity.