Brain Stimulation Using Light and Sound Reduces Alzheimer’s Pathology and Improves Cognition

Post by Deborah Joye

What's the science?

Alzheimer’s disease is a progressive form of dementia characterized by build-up of amyloid-beta (Aβ) protein plaques between nerve cells and tau protein ‘tangles’ inside of cells. Treatment options are limited, but promising research shows that neural activity can be manipulated to reduce Alzheimer’s pathology. Specifically, Alzheimer’s patients show a reduction in fast electrical ripples throughout the brain called gamma waves. Gamma waves can be induced non-invasively using a light programmed to flicker at a frequency of 40 Hz (gamma entrainment using sensory stimuli or GENUS). Exposure to the flickering light can produce gamma waves in the primary visual cortex, but it also reduces aggregates of Aβ protein, and activates microglia (the brain’s defense cells) to get rid of Aβ protein. But can GENUS be induced by other sensory systems? And can GENUS improve cognition in a model of Alzheimer’s disease? This week in Cell, Martorell and colleagues demonstrate that GENUS can be induced through both auditory and visual stimuli, reduce pathological Aβ and tau proteins, impact brain regions beyond primary sensory regions, and improve cognitive function in a mouse model of Alzheimer’s disease.

How did they do it?

The authors first checked to ensure that GENUS could be induced using an auditory tone by exposing mice to trains of tones repeating at various frequencies while simultaneously recording neural activity in the auditory cortex, hippocampus, and prefrontal cortex. To test whether auditory GENUS could improve recognition and spatial memory in a mouse model of Alzheimer’s disease, the authors employed several behavioral tasks that test hippocampus-dependent memory function: the novel object location and novel object recognition tests, which probe memory for identity or placement of an object, and the Morris Water Maze, which tests spatial memory for the location of a hidden platform. To investigate how GENUS might alter various Alzheimer’s-related proteins and cell-specific characteristics, the authors used immunohistochemistry to label Aβ and tau proteins, as well as other proteins involved with changes to astrocytes and microglia.

What did they find?

The authors found that exposure to a 40 Hz auditory tone induced GENUS in the auditory cortex, hippocampus, and prefrontal cortex. Critically, mice exposed to auditory GENUS performed better than control mice in three distinct hippocampal-dependent memory tasks, suggesting that GENUS can boost hippocampal function. Auditory GENUS also reduced the amount of Aβ protein and the pathological spreading of tau in the auditory cortex and hippocampus. Similar to effects of visual GENUS, auditory GENUS activated microglia, which increased in size and took up more Aβ. Finally, auditory GENUS increased the number of astrocytes, widened blood vessels, and increased a protein which helps to clear Aβ from the brain. When the two types of GENUS were combined, the authors found that microglia clustered around Aβ plaques, generally a precursor to phagocytosis and pathogen removal. Interestingly, auditory plus visual GENUS also reduced amyloid pathology throughout the neocortex, suggesting that inducing gamma oscillations with multiple sensory modalities can result in widespread reduction in Aβ throughout the brain.

What's the impact?

This study is the first to show that gamma waves can be induced in regions of the brain using trains of auditory tones. This study builds on previous work, demonstrating that GENUS can be induced using both auditory and visual stimuli. The authors show that auditory GENUS can improve hippocampus-dependent cognitive function in a mouse model of Alzheimer’s pathology, suggesting that GENUS could be used as a non-invasive treatment to improve cognition in Alzheimer’s patients. This research demonstrates that both auditory and visual GENUS can be used to decrease AD pathology, and that multi-sensory GENUS results in unique microglial responses to Aβ protein plaques that might increase their removal from the brain. 

Martorell et al., Multi-sensory Gamma Stimulation Ameliorates Alzheimer’s-Associated Pathology and Improves Cognition. Cell (2019). Access the original scientific publication here.

Locomotion Changes How Neurons are Coupled to Distributed Networks

Post by Stephanie Williams

What's the science?

Computations in the brain often occur at the network level. How individual neurons participate in these computations, and how they are coupled to local (neurons nearby) and distal (neurons located further away) dynamics is still under investigation. This week in Nature Neuroscience, Clancy and colleagues investigated how the coupling of neurons to local and distant networks can dynamically change across different behavioral states.

How did they do it?                                 

The authors measured activity patterns in different brain regions of 25 mice while the mice exhibited different behaviors (eg. staying still vs. running on a wheel). The authors used different techniques to measure the activity of neurons, including electrophysiological recordings, two-photon imaging and a technique called wide-field calcium imaging. Calcium imaging relies on recording fluorescent signals emitted from neurons. When neurons spike, calcium flows into cells, activating a calcium-sensitive fluorescent protein and causing it to glow brighter. The authors recorded spiking in several regions, including: (1) visual cortex (specifically, a region called V1) and (2) retrosplenial cortex, a region known to be involved in spatial navigation. To record spiking activity from individual units, the authors inserted silicon probes into visual and retrosplenial brain areas of mice. Then, they simultaneously imaged activity across dorsal cortex using wide-field calcium imaging. They analyzed how the activity in faraway brain regions were related to the single units they were recording. The authors used the relationship between the single units and distal regions to create correlation maps of individual units with different brain areas. A major mystery of cortical activity is how variable cortical neurons are — some neurons seem to do things very differently from their neighbours. The authors investigated whether the activity of neurons that didn't seem to follow the spiking of their neighbours was more likely to be correlated with distant brain areas, which would suggest they might be directly driven by long-range projections. The authors examined how behavioral state (e.g. locomotion) impacted the activity of the neurons they recorded, and how it changed the way that individual neurons were coupled to activity in local and distal regions.

What did they find?

The authors found that many neurons showed activity similar to other neurons in the same area. However, some neurons went against this pattern and were correlated with activity in distal regions. When mice switched from quietly sitting to running on a wheel, the authors found that the coupling patterns of neurons to local and distal regions dynamically changed. They found that the firing of neurons in the visual brain area called V1 became more correlated with local activity, and more similar to one another. In contrast, the neurons in the retrosplenial cortex that were correlated with local activity when the mice were not moving became different from one another, and more correlated with activity in distant areas. This suggests that behavioral state of an animal determines how individual neurons are coupled to activity in distant regions. The authors suggest their findings support the idea that locomotion induces a major network reorganization in which the strongly locally correlated neurons become silenced, and the distally correlated neurons become “unmasked”. These changes may gate how sensory information is processed in the retrosplenial cortex.

What's the impact?

The author’s work expands upon previous findings, which had suggested neurons are primarily coupled locally, and instead shows that many cortical neurons are correlated with activity in diverse distant regions. Their work shows that behavioral state can shift how neurons are coupled both locally and distally, and that this impact of running on different brain regions is distinct, perhaps reflecting how these different areas contribute to processing information relevant to navigation.

Clancy, K et al. Locomotion-dependent remapping of distributed cortical networks. Nature Neuroscience (2019). Access the original scientific publication here.

Impaired Decision Making Associated with Delusion Severity in Individuals with Schizophrenia

Post by Elisa Guma

What's the science?

Delusions, a core symptom of schizophrenia, are defined as a belief that is firmly maintained despite being met with contradictory evidence. They can be very distressing and interfere with the social functioning of individuals. The cognitive mechanisms underlying the formation and maintenance of delusions is not well understood. This week in Brain, Baker and colleagues aimed to understand how individuals with severe delusions update beliefs based on new information using computational analyses of an inference-based decision-making task.

How did they do it?

Healthy controls and individuals with schizophrenia (half of whom were unmedicated) with varying severity of delusions completed a novel variant of a task commonly referred to as the ‘beads task’ to assess the relationship between delusion severity and evidence-based decision-making. During each trial of the novel ‘bead-task’, participants had to decide whether to draw beads from a hidden jar, at a small cost, or, if they felt confident enough, to guess the color most represented in that hidden jar, at a larger penalty in the case that their guess was wrong.

The authors made great efforts to remove certain confounds from this test. Firstly, participants were given very detailed instructions, practice trials, a comprehension quiz, and post-task debriefing; participants who did not understand the task were excluded from analyses. To remove effects of general cognitive deficits and stress of time pressures, choice screens displayed the sequence of beads participants had drawn from the start of the trial to that point, and trial times were self-paced. To model their beads task data, the authors used a computational model (partially observable Markov decision process) in order to balance three components: (Bayesian) belief updating, value comparison, and choice. In short, the model estimates the expected value of guessing the beard color of the hidden jar (considering the cost of a potential incorrect guess), the expected cost of future guesses after drawing a bead (considering the cost of drawing a bead), and of potential incorrect guesses in the future. They tested whether individuals with higher delusion severity were more conservative or liberal with their guesses, and further investigated the effects of medication, other symptomatology, socio-economic status, and other aspects of working memory (based on two other tests).

What did they find?

The authors found that individuals with schizophrenia that had higher delusion severity were more conservative in their ‘draws-to-decision’ (i.e. the number of beads drawn before making a guess on the colour of the beads). In line with previous findings, individuals with schizophrenia, with low-delusion severity were found to be more liberal than both controls and high-delusion patients. Further, they found that the relationship between delusion severity and draws-to-decision was unaffected when accounting for hallucination severity, medication status, working-memory, income, and socio-economic status. Based on their modelling, the authors propose that the increased draws-to-decision in delusional patients was associated with an inability to update beliefs based on new, incoming information. Patients who acquired a biased either at baseline or sequentially throughout the task had abnormal belief updating, as modelled by Bayesian methods, which altered their value-based decision-making abilities. This is fitting in light of the fact that delusions are, by definition, rigid beliefs (i.e. resistant to updating).

What's the impact?

This study found that a failure to update beliefs in the face of new evidence by relying too heavily on prior beliefs, underlies delusions in schizophrenia. Conversely, individuals with schizophrenia and low delusion severity may seek less information in their decision-making process. The specific association between delusion and impaired decision making may aid in our understanding of the mechanisms underlying delusions, and schizophrenia more broadly. Future work could investigate whether this relationship holds true in high-risk phases.

Baker et al. A distinct inferential mechanisms for delusions in schizophrenia. Brain (2019). Access the original scientific publication here.