Identification of a Novel Neural Circuit for Depressive Symptoms in Chronic Pain

Post by Lincoln Tracy

What's the science?

People with chronic pain (pain that lasts longer than three months) commonly also present with depressive symptoms. The combination of pain and depression can make it complicated for these patients to receive treatment, as depressive symptoms may result in longer-lasting and more intense pain. There are suggestions that the dysfunction of the brain’s serotonin system is related to both pain and depression. However, we lack a good understanding of how chronic pain may affect the functioning of the serotonin system and how this, in turn, might impact depressive symptoms. Previous evidence suggests that the central nucleus of the amygdala (CeA) is a likely convergence point between chronic pain and depression. This week in Nature Neuroscience, Zhou and colleagues aimed to identify the neural circuit underlying the comorbid depressive symptoms in chronic pain by investigating the functional organization of the CeA and the involvement of serotonin using viral tracing, electrophysiological, optogenetic, and chemogenetic methods.

How did they do it?

First, the researchers identified the types of neurons that project into the CeA and their function. Second, they used the spared nerve injury chronic pain model in mice to assess the potential role of the CeA-projecting neurons in comorbid depressive symptoms. The spared nerve injury model involves severing two of the three branches of the sciatic nerve; the nerve running from the back to the lower legs. Whole-cell recordings and in-vivo microdialysis high-performance liquid chromatography were used to record neuronal activity and determine the serotonin concentration, respectively. Third, they tested the functional causality of the DRN-CeA circuit in the development of depressive-like behaviors in mice. Fourth, they investigated which other areas of the brain the CeA neurons project to. Finally, they used resting state functional magnetic resonance imaging to assess whether the neural circuits underlying the depressive symptoms in the mouse model of chronic pain also play a role in the depressive symptoms seen in humans with chronic pain.

What did they find?

First, they found that serotonergic neurons from the dorsal raphe nucleus (DRN) project to somatostatin interneurons in the CeA. The neurons from the DRN inhibit the somatostatin interneurons in the amygdala. Second, they found that inhibiting the somatostatin neurons in the CeA reduced depressive behaviors in mice afflicted by the spared nerve injury. Third, they showed that the DRN-CeA circuit is required for the development of depressive-like behavior specifically in mice with chronic pain, but not in non-pain-related mouse models of depression. Fourth, they identified that the somatostatin neurons of the CeA mainly send glutamatergic projections to neurons within the lateral habenula, a region of the brain that has previously been implicated in the pathophysiology of depression. The authors also identified that the DRN-CeA-lateral habenula circuit connections form part of a disinhibitory circuit that may underlie the depressive symptoms seen in chronic pain. Finally, they found that humans with both chronic pain and depression display decreased brain connectivity between the DRN and the centromedial amygdala, the equivalent of the CeA in mice. The functional connectivity between these two brain regions showed a negative correlation with the Hamilton Depression Rating Scale score (a widely used measure of depression), meaning the lower functional connectivity, the greater the depression experienced.

What's the impact?

This study found that a neural pathway involving serotoninergic neurons in the DRN, somatostatin neurons in the CeA, and the lateral habenula may be the cause of some of the aspects of the commonly occurring depression symptoms that occur in chronic pain. Activating this neural circuit relieved painful symptoms in mice. Pharmacological treatments for comorbid depressive symptoms in chronic pain are limited. Therefore, the findings from this study allow for the possibility of non-pharmacological treatment approaches (such as deep brain or transcranial magnetic stimulation) to target the converging pain and depression pathways.

Zhou et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nature Neuroscience (2019). Access the original scientific publication here. 

Ripples in the Hippocampus are Linked to Visual Memory Recall

Post by Anastasia Sares 

What's the science?

The hippocampus is the ‘seat’ of memory. From experiments with animals, scientists have been able to determine many aspects of its function, including the roles of its different cell layers and the growth of new cells over time. One interesting element of memory formation is called the sharp-wave ripple complex; a burst of synchronized neuronal activity that happens during memory consolidation and also during memory retrieval. However, animals can’t communicate their cognitive experience in detail, so we can’t be sure whether these retrieval-related ripples are accompanied by conscious memories. This week in Science, Norman and colleagues were able to connect these sharp-wave ripple complexes to reported memories in humans. 

How did they do it?

The authors used intracranial electroencephalography, a rare opportunity to measure human brain activity in patients with electrodes directly implanted into the brain tissue. These patients have the electrodes implanted for unrelated medical reasons, often to monitor brain activity before surgery. The participants in this experiment had electrodes in both the hippocampus and the visual cortex, so the sharp-wave ripples could be measured along with visual activity.

Participants saw a series of images, then were blindfolded and asked to recall as many of the images as possible (there was another task in between these learning and recall sessions to prevent people from mentally rehearsing what they had just seen). This is known as a “free recall” task. The entire time, the electrodes were recording brain activity and a microphone was recording what the participant said.

What did they find?

The rate of ripples was highest when participants were initially viewing the images and while at rest (presumably, at rest, memories are being consolidated). During the free recall, there was a very specific increase in the rate of ripple events about one second before the participant verbally recalled a memory. On top of this, images that produced a higher number of ripples when viewing them for the first time were more likely to be successfully recalled. The number of ripples elicited during this initial viewing stage predicted the participants' performance in the subsequent free recall stage.

The authors also identified sites in the visual cortex that had a preference for (i.e. responded to) certain types of images during viewing (for example, preferring faces over places). Then, during recall, when the participant reported an image, they observed that the ripples from the hippocampus were coupled with activity in the visual sites that were selective to that image. The authors interpreted this as a “reactivation” of the visual memory. They could even train an algorithm to predict the image based on the neural activity of these two areas alone. The authors argue that this is consistent with a two-stage recollection process, involving a fast subconscious stage (the ripple) and a slower conscious one, in which the brain uses the retrieved content to re-create an experience.

What's the impact?

Because this study was able to use human reports of memories along with precise measurements of neuronal activity, it presents a strong case that these sharp-wave ripple complexes from the hippocampus are indeed involved in conscious memory retrieval. More work is needed to explain exactly how the hippocampus interacts with the rest of the brain during this process, however, these findings represent an important step forward in understanding the role of sharp-wave ripples in visual memory.

Norman et al. Hippocampal sharp-wave ripples linked to visual episodic recollection in humans. Science (2019). Access the original scientific publication here.

High Blood Pressure Is Associated with Late-Life Brain Pathology

Post by Deborah Joye

What's the science?

High blood pressure, also known as hypertension, is a common health issue in adults that tends to get worse with age. Hypertension in midlife (between 40 and 70 years of age) is also associated with increased risk for brain pathology later in life, including cerebrovascular disease (disorders that affect blood supply to the brain) and Alzheimer’s disease. But how might changes in blood pressure result in late-life brain pathology, and at what age are people most sensitive to these changes? This week in The Lancet Neurology, Lane and colleagues study longitudinal blood pressure changes and late-life brain scans, revealing that increases in blood pressure from early adulthood into midlife are associated with increased white matter hyperintensity volume and smaller brain volumes in late-life (around age 70).

How did they do it?

The authors analyzed data from Insight 46, a neuroscience substudy of over 5000 individuals born throughout mainland Britain during one week in 1946. Over the course of the study, blood pressure measurements were collected at ages 36, 43, 53, 60-64, and 69 years. From 2015 through 2018, the authors recruited close to 500 participants of Insight 46 (mean age 70.7 years) to undergo brain-imaging MRI scans and determine possible neurological changes. The primary measures were white matter hyperintensity volume, a marker of vascular disease in the brain; presence of amyloid-beta, a hallmark pathology in Alzheimer’s disease; whole-brain and hippocampal volumes, to determine possible reductions in brain size; and tests of episodic memory, processing speed, and global cognition using the Preclinical Alzheimer Cognitive Composite.

What did they find?

The authors found that increased systolic and diastolic blood pressure were associated with greater white matter hyperintensity volume at all measured ages, with a stronger association after 53 years of age. Higher systolic blood pressure across time points was associated with smaller whole-brain volume, and greater increases in systolic blood pressure between 36 and 43 years old were associated with smaller hippocampal volume. Interestingly, blood pressure at any age was not associated with the presence of amyloid-beta, and there were no consistent associations between blood pressure and scores on cognitive tests.

What's the impact?

This study is the first to examine blood pressure at multiple timepoints and associate blood pressure changes with systematically measured brain pathologies and volumes. The authors show that early adulthood into midlife may present a sensitive period where rapid increases in blood pressure can affect brain pathologies such as white matter hyperintensities in later life. It should be noted that the participants of this study were exclusively white British participants broadly representative of the population of mainland Britain born in 1946; however, this may reduce generalizability to other ageing populations. These findings suggest that blood pressure management may need to begin at or before age 40 to prevent negative impacts on late-life brain health.

Lane et al., Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study, The Lancet Neurology (2019). Access the original scientific publication here.