“Sleep Fingerprints” Can Identify Signatures of Psychiatric Disease

Post by Anastasia Sares

The takeaway

Researchers have developed a way to concisely quantify the activity of tens of thousands of waveforms occurring in a person’s brain during sleep, uncovering stable profiles of different people. This will help us understand individual differences in sleep, from the normal to the pathological: as a first step, it has revealed new insights into the brains of people with schizophrenia.

What's the science?

Our brains don’t turn off when we go to sleep. They remain hard at work, forming memories, dreaming, and recuperating from the day. We know this, in part, because we can observe them through a technique called polysomnography, where we record the electrical activity of the sleeping brain. The signal we get from polysomnography is composed of a symphony of overlapping brain frequencies, as well as short bursts of oscillatory activity called transient oscillations. Among transient oscillations, sleep scientists are especially interested in sleep spindles, which are involved in memory consolidation and are altered in disorders such as Alzheimer’s, autism, and schizophrenia. However, the current methods for defining sleep spindles are based on methods from the early 1900s and are therefore biased toward the waveforms people could see easily by eye in paper tape traces of brain activity. 

This month in the journal Sleep, Stokes and colleagues developed a new approach, which, rather than just looking at traditional spindles, identifies tens of thousands of spindle-like waveforms at all times and frequencies during sleep. They summarized these waveforms in a sleep “fingerprint” that can be used to identify signatures of neurological health and disease.

How did they do it?

The authors analyzed data from both healthy, neurotypical people and people with schizophrenia who had had recordings taken of their brain waves in the lab while they slept. They transformed the signal from each person into a time-frequency plot, with high frequencies (fast oscillations) near the top and low frequencies (slow oscillations) near the bottom, and time going from left to right. They then applied an image processing technique called the watershed algorithm to identify regions with spindle-like brain waveforms. Finally, they created visual summaries showing how these tens of thousands of waveforms continuously evolve across the night. This is more effective than dividing activity into the traditional “sleep stages” because it retains more information.

What did they find?

The team generated these visualizations for each participant, showing how brain activity changed as a person went deeper and deeper into sleep, and also how brain activity related to the slowest sleep oscillations, like tiny waves superimposed on a rising and falling tide. Surprisingly, they found a variety of activity patterns in healthy, neurotypical participants, yet each individual had the same pattern from night to night. Therefore, these representations acted like a fingerprint: different across individuals but consistent over time. They then demonstrated the clinical usefulness of this method by comparing the control and schizophrenia cohorts, which revealed two new classes of spindle-like events that traditional methods had been unable to capture.

What's the impact?

The sleep fingerprints developed by this team offer a highly informative way to summarize a large amount of data: electrical signals gathered over the course of an entire night. What’s more, these fingerprints are different between people but stable within the same person—meaning we may be able to use them to inform clinical approaches for psychiatric conditions, sleep disorders, and more. The researchers have released an open-source toolbox to allow other scientists to use this powerful technique.

Access the original scientific publication here.

Using Magnetic Fields to Treat Alzheimer’s Disease

Post by Christopher Chen

The takeaway

Repetitive transcranial magnetic stimulation (rTMS) can be used as a noninvasive therapy to alleviate some symptoms of Alzheimer’s disease (AD). Applying rTMS to a brain region called the precuneus of patients with AD may slow the disease’s progression and even enhance brain activity in the precuneus itself.

What's the science?

In Alzheimer’s disease (AD), a specific network in the brain called the default mode network (a group of brain regions that are functionally connected) undergoes pathological changes that underlie AD symptoms. The precuneus is a brain region found in the posterior cortex and is one of the primary brain regions included in the default mode network. Research shows that the precuneus is one of the earliest regions within the brain to display amyloid plaques and neurofibrillary tangles, well-known markers of AD. Unsurprisingly, research also links these pathologies to compromised precuneus function, resulting in overall dysfunction in the default mode network. Thus, restoring precuneus activity and connectivity to the default mode network may provide therapeutic benefits to patients with AD. rTMS, which provides indirect magnetic stimulation to specific parts of the brain, has been shown to restore cognitive function in patients with mild forms of AD when applied over a short (two-week) period. Recently in Brain, Koch and colleagues explored whether long-term application of rTMS to the precuneus carries therapeutic value to patients with AD.

How did they do it?

The study consisted of fifty patients with mild to moderate forms of AD. All patients had been prescribed an independent pharmacological treatment for AD. Before the study, the patients were given a battery of assessments designed to measure cognitive function by a team of clinicians and researchers. Following these assessments, patients were divided into the experimental group which would receive rTMS to the precuneus, and the control group which would receive a procedure that resembled rTMS but was not (sham control).

In the first two weeks of the experiment, all patients received extensive experimental or sham rTMS treatment five times a week. The final twenty-two weeks was the maintenance period where patients received experimental or sham treatment once a week. This maintenance period also included a mid-study assessment of cognitive function at twelve weeks. Following the six-month period, patients underwent a final round of assessments to measure cognitive function. Single-pulse TMS combined with EEG was also used to assess precuneus activity and oscillatory activity.

What did they find?

Researchers compared scores from all clinical and behavioral assessments as well as functional readouts from brain imaging assessments in the experimental and sham groups. While both groups showed a generalized decrease in performance on the cognitive tests over time, patients in the experimental group showed smaller decreases on every cognitive assessment both at the mid-study (twelve-week) point and end-study (twenty-four week) point. The brain imaging assessments – which measured precuneus signaling activity using a noninvasive electroencephalogram (EEG) – revealed significant differences in precuneus activity between experimental and sham groups. In fact, the experimental group showed an increase in precuneus activity following the study’s conclusion.

What's the impact?

While short-term rTMS has been used to alleviate AD symptomology, this study is the first to examine its effects over the long term. Additionally, rTMS treatment in AD patients has been largely focused on the prefrontal cortex, not the precuneus, a region of the brain known to exhibit some of the earliest signs of AD pathology. Based on the beneficial changes precuneus-specific rTMS treatment had on patients with AD, this study shows that the precuneus may be a compelling therapeutic target for AD treatments.  

Access the original scientific publication here.

Microbiota-Induced Immune Activation Promotes Sensory Neuron Regeneration

Post by Leanna Kalinowski

The takeaway

Our skin microbiota, such as the bacteria Staphylococcus aureus, produce an accumulation of immune cells that accelerate sensory neuron regeneration following skin injury.

What's the science?

Barrier tissues, such as our skin, play an important role in both nervous and immune system functions. Our skin contains sensory nerve fibers that are involved in touch, pain, and temperature perception, along with being home to many bacteria, fungi, and viruses that compose the skin microbiota. Following infection or injury, it is important for rapid immune system activation to protect and restore all tissue components, including the sensory nerves. However, the exact role that the microbiota plays in activating the immune system for sensory nerve regeneration is unknown. This week in Cell, Enamorado and colleagues explored the role of microbiota-induced immune activation in sensory neuron regeneration following skin injury.

How did they do it?

The researchers first studied the relationship between the microbiota, immune system, and sensory neuron regeneration during homeostasis (i.e., when there was no skin injury). First, mice received either a topical application or intradermal injection of Staphylococcus aureus (S. aureus) bacteria, which is a microbiota that is commonly found on human skin. When S. aureus is applied topically, it produces an accumulation of T helper 17 cells (Th17) that help produce interleukin 17 (IL-17) and boost future immune system response. On the other hand, when S. aureus is injected intradermally, it causes a pathogenic effect that produces T helper 1 cells (Th1) that actively fight against infection. Following the administration of S. aureus, Th17, and Th1 cells were then collected and sequenced using RNA-seq. Next, to visualize where T cells were located relative to sensory neurons, the researchers topically applied S. aureus to mice engineered for sensory neuron visualization and imaged them using two-photon microscopy.

To test whether S. aureus-induced T cells could contribute to sensory nerve regeneration, the researchers deployed a model of skin injury that causes axonal damage. Mice that previously received topical administration of S. aureus had a small piece of ear skin removed with a small punch biopsy, after which the injury site was imaged under a microscope to visualize Th17 cells.

Finally, the researchers attempted to uncover the immune mechanism that underlies the relationship between the microbiota (i.e., S. aureus) and neuronal regeneration. First, they again deployed the above model of skin injury, this time in mice engineered to block the IL-17a response, after which the injury site was imaged under a microscope to visualize Th17 cells. Then, they isolated sensory neurons in vitro (i.e., in a petri dish), treated them with IL-17A, and sequenced them using RNA-seq.

What did they find?

From the first set of experiments, the researchers found several relevant genes that were upregulated in Th17 cells (i.e., from topical S. aureus) compared to Th1 (i.e., from injected S. aureus) cells. Most notably, several of these genes are responsible for tissue repair (e.g., Tgfb1, Vegfa, Pdgfb, Furin, Mmp10, and Areg), while others are responsible for neuronal interaction and regeneration (e.g., Neu3, Lif, Marveld1, Ramp1, Ramp3, Ccr4, and Tnfsf8). Further, the researchers also found a significant accumulation of Th17 cells that were located close to sensory neurons within the skin. Together, this shows that S. aureus leads to an accumulation of Th17 cells, located in close proximity to sensory neurons, with upregulated genes that are responsible for neuronal regeneration.

From the second experiment, the researchers found that mice who received topical S. aureus had an increased number of Th17 cells accumulating near the injury site compared to controls. This was associated with an increased area and volume of nerve fibers surrounding the injury site, suggesting that the immune response to topical S. aureus enhances neuronal regeneration.

From the final set of experiments, the researchers first found that topical S. aureus does not accelerate neuron regeneration in mice with a blocked IL-17a response. Further, they found that genes implicated in neuronal maintenance, response, and function were unregulated in isolated sensory neurons treated with IL-17A. Together, this suggests a crucial role for IL-17A in promoting sensory neuron regeneration.

What's the impact?

Results from this study show that immunity from the microbiota that live on our skin (e.g., S. aureus) can rapidly jump-start a response to tissue damage by promoting the repair of sensory neurons - an effect that is mediated by IL-17A. Further exploring these relationships may help pave the way for future therapeutic approaches to facilitating sensory neuronal recovery after a skin injury, such as psoriasis.

Access the original scientific publication here.