A randomized, double-blind, placebo-controlled trial of blue wavelength light exposure on sleep and recovery of brain structure, function, and cognition following mild traumatic brain injury.

Sleep and circadian rhythms are among the most powerful but least understood contributors to cognitive performance and brain health. Here we capitalize on the circadian resetting effect of blue-wavelength light to phase shift the sleep patterns of adult patients (aged 18-48 years) recovering from mild traumatic brain injury (mTBI), with the aim of facilitating recovery of brain structure, connectivity, and cognitive performance. During a randomized, double-blind, placebo-controlled trial of 32 adults with a recent mTBI, we compared 6-weeks of daily 30-min pulses of blue light (peak lambda = 469 nm) each morning versus amber placebo light (peak lambda= 578 nm) on neurocognitive and neuroimaging outcomes, including gray matter volume (GMV), resting-state functional connectivity, directed connectivity using Granger causality, and white matter integrity using diffusion tensor imaging (DTI). Relative to placebo, morning blue light led to phase-advanced sleep timing, reduced daytime sleepiness, and improved executive functioning, and was associated with increased volume of the posterior thalamus (i.e., pulvinar), greater thalamo-cortical functional connectivity, and increased axonal integrity of these pathways. These findings provide insight into the contributions of the circadian and sleep systems in brain repair and lay the groundwork for interventions targeting the retinohypothalamic system to facilitate injury recovery.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Effects of Aging on Sleep-Dependent Consolidation of Declarative Memory

Sleep plays a critical role in memory consolidation. However, aging is associated with changes in sleep architecture and memory impairments. The goal of the present study was to identify age-related changes in the memory function of sleep by investigating sleep-dependent changes in neural activation patterns during memory retrieval in young and older adults. Healthy young (21-29 years) and older (62-74 years) adults were trained on a declarative word-pair learning task. Recall was tested 5 hr later while undergoing functional magnetic resonance imaging (fMRI). Participants completed this testing procedure twice, separated by 1 week; once following a mid-day nap and once following continuous wakefulness in a counter-balanced order. Sleep was recorded by polysomnography for the naps and subsequent nocturnal intervals. It was found that napping, as compared to wakefulness, was associated with decreased hippocampal activation and decreased hippocampo-frontal co-activation in young adults. Specifically, slow wave sleep (SWS) in the young adult naps was associated with better memory retention (r = .61, p = .035) and decreased hippocampal activation (r = -.71, p = .01) lending support to the two-stage model of memory consolidation (McClelland, McNaughton & O’Reilly, 1995). On the other hand, sleep-dependent neural reorganization patterns were different in the older adult group. Following a nap, retrieval still required hippocampal activation and hippocampo-frontal co-activation (adjusted R2 = .701, F(1,10) = 22.08, p = .002). Furthermore, in contrast to a SWS-dependent decrease in anterior cingulate cortex (ACC) activation in young adults for successful retrieval (r = -.61, p = .037), ACC activation in older adults was increased when retrieval was tested following a nap compared to wakefulness, and was not significantly associated with measures of SWS. This suggests that successful retrieval following a nap required allocation of error monitoring processes in older adults. In summary, the present study shows that the efficiency with which systems level consolidation takes place in the first sleep opportunity following learning of a declarative memory task changes in healthy aging. Slow wave sleep-dependent reactivation processes may be disrupted, leaving memory traces at a more labile state of storage that requires additional allocation of cognitive control processes

Studying Brain Organization via Spontaneous fMRI Signal

In recent years, some substantial advances in understanding human (and nonhuman) brain organization have emerged from a relatively unusual approach: the observation of spontaneous activity, and correlated patterns in spontaneous activity, in the “resting” brain. Most commonly, spontaneous neural activity is measured indirectly via fMRI signal in subjects who are lying quietly in the scanner, the so-called “resting state.” This Primer introduces the fMRI-based study of spontaneous brain activity, some of the methodological issues active in the field, and some ways in which resting-state fMRI has been used to delineate aspects of area-level and supra-areal brain organization

Functional interactions between the hippocampus, medial entorhinal cortex and medial prefrontal cortex for spatial and nonspatial processing

Memory formation and recall depend on a complex circuit that includes the hippocampus and associated cortical regions. The goal of this thesis was to understand how two of the cortical connections, the medial entorhinal cortex (MEC) and medial prefrontal cortex (mPFC), influence spatial and nonspatial activity in the hippocampus. Cells in the MEC exhibit prominent spatially selective activity and have been hypothesized to drive place representation in the hippocampus. In Experiment 1 the MEC was transiently inactivated using the inhibitory opsin ArchaerhodopsinT (ArchT), and simultaneous recordings from CA1 were made as rats ran on an elliptical track. In response to MEC disruption some cells in the hippocampus shifted the preferred location of activity, some changed firing rate and others were unaffected. The new representation that developed following MEC disruption remained stable despite the fact that inhibition was transient. If the MEC is the source of spatial activity in the hippocampus the activity would be either time-locked to periods of inhibition or unstable throughout the period of inconsistent input. These results show that the MEC guides spatial representation in the hippocampus but does not directly drive spatial firing. The mPFC is generally thought to guide behavior in response to contextual elements. Experiment 2 examined the interaction between the mPFC and the hippocampus as rats performed a contextual discrimination task. Recordings were made in CA1, and the mPFC was disrupted using ArchT during the odor sampling phase of the discrimination. As animals perform this task neurons in the hippocampus respond to a conjunction of odor and location which indicates an association of what and where information in the hippocampus. Optogenetic disruption of the mPFC led to a decrease in nonspatial representation. Individual cells showed lower levels of odor selectivity, but there was no change in the level of spatial representation. This indicates that the mPFC is important for determining how the hippocampus represents nonspatial information but does not alter the spatial representation. The results are discussed within a model of memory formation that includes binding spatial and nonspatial information in the hippocampus

Post-learning hippocampal dynamics promote preferential retention of rewarding events

Reward motivation is known to modulate memory encoding, and this effect depends on interactions between the substantia nigra/ventral tegmental area complex (SN/VTA) and the hippocampus. It is unknown, however, whether these interactions influence offline neural activity in the human brain that is thought to promote memory consolidation. Here we used fMRI to test the effect of reward motivation on post-learning neural dynamics and subsequent memory for objects that were learned in high- and low-reward motivation contexts. We found that post-learning increases in resting-state functional connectivity between the SN/VTA and hippocampus predicted preferential retention of objects that were learned in high-reward contexts. In addition, multivariate pattern classification revealed that hippocampal representations of high-reward contexts were preferentially reactivated during post-learning rest, and the number of hippocampal reactivations was predictive of preferential retention of items learned in high-reward contexts. These findings indicate that reward motivation alters offline post-learning dynamics between the SN/VTA and hippocampus, providing novel evidence for a potential mechanism by which reward could influence memory consolidatio

The role of medial entorhinal cortex activity in hippocampal CA1 spatiotemporally correlated sequence generation and object selectivity for memory function

The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval

The Role of Consolidation in Conceptual Memory

Concepts allow us to bring meaning to the world; they require the integration of information from across multiple episodes and events, and the abstraction of statistical patterns and regularities from both new and existing knowledge. Processes during consolidation have been shown to benefit the extraction of gist, the detection of hidden rules and the integration of memory elements into coherent representations. Consolidation may therefore play an important role in the development of conceptual memory. To explore this, we used a range of consolidation delay manipulations and two paradigms that assessed the development of concept-based representations. In Chapter 2 and 3 we used an abstract cross-modal information-integration categorisation task, which allowed us to investigate the integration of information from across modalities (visual and auditory) and the extraction of an underlying category structure. In these experiments we did not find any immediate consolidation benefits on categorisation performance. However, post-consolidation improvements in category learning were observed, if participants had a sleep-filled delay; suggesting that processes during sleep may enhance the effectiveness of future concept-based learning. In Chapters 4 and 5, we used an associative memory task that allowed us to dissociate the impact of consolidation on generalised concept-based representations from trained item knowledge. In this task we found sleep-associated improvements in memory; however, these were specific to trained-item knowledge, with no sleep-associated benefits in measures of memory generalisation. An investigation into intrinsic brain connectivity in Chapter 5 suggests that general variations in functional connectivity can in part explain individual differences in long-term memory performance; with decoupling between heteromodal and sensory-motor brain regions supporting memory generalisation and the formation of concepts. Our results provide new insights into the role of consolidation in the development of conceptual memory and highlight important directions for future research