Which Brain Circuits Determine Maternal Behavior?

MedicalResearch.com Interview with:
“Mother and Child” by Mary Cassatt (American, Pittsburgh, Pennsylvania 1844–1926 Le Mesnil-Théribus, Oise) via The Metropolitan Museum of Art is licensed under CC0 1.0Yi-Ya Fang

NYU School of Medicine
Dayu Lin, PhD
Neuroscience Institute, New York University Langone School of Medicine,  Department of Psychiatry,
Center for Neural Science
New York, NY

Response: Maternal behaviors are essential for survival of offspring across mammalian species. In rodents, mothers show several characteristic pup caring behaviors including grooming pups, crouching over pups and approaching and retrieving pups. Decades of research has been trying to understand how the neural circuit is wired to generate these elaborate maternal behaviors. Medial preoptic area (MPOA), which is located at anterior part of hypothalamus, has been indicated to be important for maternal behaviors. Many studies consistently found deficits in maternal behaviors after damaging the MPOA. To dissect the maternal circuits in the brain, we looked into the properties of the Esr1+ cells.

In this study, we identify estrogen receptor α (Esr1) expressing cells in MPOA as key mediators of pup approach and retrieval. We focused on Esr1 (Esr1) expressing cells in the MPOA since estrogen has been shown to facilitate maternal behaviors, presumably through its action of estrogen sensing cells. We found that reversible inactivation of MPOA Esr1+ cells impairs maternal behaviors whereas optogenetic activation of MPOA Esr1+ cells induces immediate pup retrieval. Additionally, we found that MPOA Esr1+ cells are preferentially activated during maternal behaviors, and the cell responses changed across reproductive states. Tracing studies revealed that MPOA Esr1+ cells project strongly to ventral tegmental area (VTA), a region that has been indicated in motivation and reward. Specifically, MPOA Esr1+ cells provide strong inhibitory inputs preferentially to the GABAergic cells in the VTA, which in turn could disinhibit the dopaminergic cells.  VTA dopaminergic cells are highly activated during maternal behaviors.

Altogether, our study provides new insight into the neural circuit that generates maternal behaviors.

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Duchenne Muscular Dystrophy: As Survival Increases, New Focus on Quality of Life

MedicalResearch.com Interview with:
David Birnkrant, MD
Professor of Pediatrics, Case Western Reserve University School of Medicine
Director of Pediatric Pulmonology & Student Education, MetroHealth Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study updates guidance on all aspects of the multi-disciplinary care of patients with Duchenne muscular dystrophy (DMD). The project was funded by the CDC’s National Center on Birth Defects and Developmental Disabilities and the results were recently published as three articles in The Lancet Neurology. The project was guided by a 25-member steering committee. Eleven expert committees worked over a period of three years to develop guidelines based on the RAND/UCLA appropriateness method, in which assessments and interventions were evaluated for appropriateness and necessity. The recommendations update those originally published in 2010.

Duchenne muscular dystrophy is transmitted by X-linked recessive inheritance and thus affects primarily boys and men. Patients affected by DMD do not produce functional dystrophin protein, resulting in progressive weakness of skeletal, respiratory, and heart muscles, causing a shortened life span. Teens and young men may require surgery for curvature of the spine, a ventilator device to assist breathing, and a feeding tube to help ensure adequate nutrition. The approach of the various subspecialties involved in DMD management has evolved, with more anticipatory assessment and therapy, identifying and addressing predictable medical complications as early as possible for optimal patient outcomes. With this kind of multi-disciplinary care, people with DMD now live into their 30s and beyond.

Along with the emergence of new genetic and molecular therapies, the recognition that people with DMD are living longer was one of the main motivations behind the need for these updated care considerations. Patients with DMD, their families and their advocacy organizations are driving a new emphasis on optimizing quality of life, not just prolongation of survival. Thus, there was a need to address issues related to transitions of care from childhood to adulthood, coordination of care across subspecialties, and other topics related to education, vocation, independence, personal relationships, emotional health, and intimacy. The updated care considerations thus include eleven topic areas, eight of which were part of the 2010 guidelines.

These are: (1) diagnosis, (2) neuromuscular management, (3) rehabilitation management, (4) gastrointestinal and nutritional management, (5) respiratory management, (6) cardiac management, (7) orthopedic and surgical management, and (8) psychosocial management. Three topics are new: (9) primary care and emergency management, (10) endocrine management (including growth, puberty, adrenal insufficiency, and bone health), and (11) transitions of care across the lifespan.

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Early Clinical Trials of AMO-02 Show Promise in Congenital and Childhood Myotonic Dystrophy Type 1

MedicalResearch.com Interview with:

Joseph Horrigan MD, Pediatric neuropsychiatrist

Dr. Horrigan

Dr. Joseph Horrigan MD
Pediatric neuropsychiatrist

Chief medical officer

 


MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by myotonic dystrophy? What are the manifestations of this disease?

Response: This was the first pharmaceutical intervention study conducted in adolescents and adults with congenital and juvenile onset DM1. Myotonic dystrophy type 1 (DM1) is a disorder that impacts multiple body systems following a trinucleotide expansion repeat of the DMPK gene on chromosome 19. Children with Congenital DM1 present at birth with respiratory insufficiency, talipes equinovarus (clubfoot), feeding difficulties and hypotonia. There is a risk mortality rate in the first year of life. As children grow, they are at risk for intellectual impairment, autistic features, gastrointestinal symptoms, motor delay and a variety of muscle-based symptoms.

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Do We Have Free Will? Neuroscientists Aren’t Sure

MedicalResearch.com Interview with:

Veljko Dubljević, Ph.D., D.Phil. Assistant Professor of Philosophy, Department of Philosophy and Religious Studies, and  Science Technology and Society Program, North Carolina State University Raleigh, NC 27607 

Dr. Veljko Dubljević

Veljko Dubljević, Ph.D., D.Phil.
Assistant Professor of Philosophy,
Department of Philosophy and Religious Studies, and
Science Technology and Society Program,
North Carolina State University
Raleigh, NC 27607 

MedicalResearch.com: What is the background for this study?

Response: There is considerable controversy about the interpretation of data of the neuroscientific studies done by Benjamin Libet. On the one hand, Libet claimed that his work disproves certain metaphysical conceptions of free will (Libertarianism), whereas it does not disprove others (e.g., Compatibilism). In a nutshell, the reason for these claims is that Libet found preparatory brain activity (Readiness Potentials or RPs) some 500ms before the conscious decision to act was felt by study participants. That seemed to exclude the possibility that mental causation was taking place. At the same time, the onset of movement left a time-window for a ‘veto-decision’. This led Libet to conclude that there is no ‘free will’, but that there is a ‘free won’t’.

On the other hand, there were many criticisms of the study – methodological or substantive. Most notably, Patrick Haggard argued that it is not RPs that are correlates of a decision to act, but Lateralized Readiness Potentials (LRPs). Haggard agreed with many critics of Libet in that RPs could be connected to a range of other phenomena, and that preparatory brain activity that is most important for a decision to act already has to be ‘lateralized’. Namely, the decision to move the left or right arm is critical in this regard, and will lead to RP being focused in one or the other hemisphere, thus making LRPs the point of interest for any conscious decision to act. All in all, Haggard claimed to have replicated Libet’s major findings, with the caveat that timing of LRPs excludes the time-frame for a ‘veto-decision’. This Haggard claimed makes the evidence more in line with the metaphysical doctrine of ‘hard determinism’, which excludes agency and responsibility.

Many other neuroscientists followed Libet’s (and Haggard’s) lead and these experiment became part of ‘lore’ in neuroscience education – many other labs performed similar experiments and claimed to basically replicate the findings.

Our study was the first to review all available evidence.

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Lack of Awareness of Cognitive Issues Presages Alzheimer’s Disease

MedicalResearch.com Interview with:
Joseph Therriault

Integrative Program in Neuroscience 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Neurologists have known for a long time that Anosognosia, or unawareness of illness, appears in individuals with Alzheimer’s disease. For example, these patients will have diminished awareness of their memory loss, and will also engage in dangerous behaviors, such as leaving the house to go for a walk, without knowing they are at high risk of getting lost.

However, it was not known if decreased awareness of cognitive problems existed in the pre-dementia phase of Alzheimer’s disease. In our study, we compared the ratings of cognitive decline from the patient and their close relative, who also filled out the same questionnaire. When a patient reported having no cognitive problems but the family member reported significant difficulties, the patient was considered to have poor awareness of illness.

We found that patients who are less aware had increased disease pathology, and were nearly three times as likely to progress to dementia within two years, even when taking into account other factors like genetic risk, age, gender and education. The increased progression to dementia was mirrored by increased brain metabolic dysfunction in regions vulnerable to Alzheimer’s disease.

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How does SURPRISE! Make You Stop What You Are Doing?

MedicalResearch.com Interview with:

Jan R. Wessel, Ph.D. Asst. Professor Department of Psychological and Brain Sciences Department of Neurology Iowa Neuroscience Institute University of Iowa

Dr. Wessel

Jan R. Wessel, Ph.D.
Asst. Professor
Department of Psychological and Brain Sciences
Department of Neurology
Iowa Neuroscience Institute
University of Iowa 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: We found that the occurence of unexpected events, such as sudden, surprising sounds lead to an automatic engagement of a well-known brain network for action-stopping, thereby leading to a suppression of ongoing motor activity. Specifically, we found that when participants had to stop an action, their ability to do so was significantly improved when the cue to stop was accompanied by a sudden, unexpected sound. This improvement was accompanied by an amplification of the brain activity that is related to action-stopping, and was also accompanied by an increase of suppression of excitability of the motor cortex.  Continue reading

Similar Incidence of Autoimmune and Infectious Brain Inflammatory Disease Encephalitis

MedicalResearch.com Interview with:

Eoin Flanagan, M.B., B.Ch. Mayo Clinic Rochester, Minnesota

Dr. Flanagan

Eoin Flanagan, M.B., B.Ch.
Mayo Clinic
Rochester, Minnesota 

MedicalResearch.com: What is the background for this study?

 

Response: Traditionally it has been thought that infections (e.g., viruses)  account for the majority of encephalitis cases. Recent discoveries of neural autoantibody markers of encephalitis (e.g., NMDA receptor autoantibodies) have led to an appreciation that encephalitis cases can be caused by the body’s own immune system attacking the brain, what we term autoimmune encephalitis. Continue reading

Lampreys Can Regenerate Severed Spinal Cord – Maybe Humans Can Too

MedicalResearch.com Interview with:
Ona Bloom PhD
“Duluth Boat Show - Sea Lamprey Booth” by USFWSmidwest is licensed under CC BY 2.0Associate Professor, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases,
The Feinstein Institute for Medical Research
Associate Professor, Department of Molecular Medicine,
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Scientists have known for years that an ancient species of fish called the lamprey has a remarkable ability to rebuild their spinal cord after it’s been severed. After the lamprey spinal cord is cut, they recover from paralysis to fully swimming again in about twelve weeks, without taking any medicines or other treatments. We are studying the lamprey because we want to know the recipe of molecular ingredients that supports successful recovery after spinal cord injury.

The genome of this animal was reported about 5 years ago, in a publication led by my colleagues Dr. Jeramiah Smith at the University of Kentucky and Dr. Weiming Li at Michigan State University.  It turns out that many aspects of the lamprey genome are similar to ours, particularly in the central nervous system. Therefore, we think it is a reasonable expectation that what we learn from lamprey could give us some relevant clues about what might be different about the responses in mammals and other animals that are not good at regenerating their spinal cord.

In this study, we found that the expression of many genes in the spinal cord and brain of lampreys change during their recovery from spinal cord injury. Some of the genes that get activated are similar to what happens when our peripheral nervous system is injured, which is better at regenerating than the central nervous system. We also identified that a pathway called the Wnt pathway plays an important role in the regeneration and recovery process. This is a large, complex network of genes that are important in many biological processes, from embryological development in fruit flies to cancer in humans. Continue reading

Genetics Underlies Differences in Parkinson’s Disease Progression

MedicalResearch.com Interview with:

Rachel Saunders-Pullman, MD, MPH Associate Professor of Neurology Icahn School of Medicine at Mount Sinai Chief, Movement Disorders, Mount Sinai Beth Israel Co-Director Clinical/Translational Research and Research Mentoring Movement Disorders, Department of Neurology, Mount Sinai Beth Israel New York, NY 10003

Dr. Saunders-Pullman

Rachel Saunders-Pullman, MD, MPH
Associate Professor of Neurology
Icahn School of Medicine at Mount Sinai
Chief, Movement Disorders, Mount Sinai Beth Israel
Co-Director Clinical/Translational Research and Research Mentoring
Movement Disorders, Department of Neurology,
Mount Sinai Beth Israel
New York, NY 10003

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: There is a diversity in causes of Parkinson’s Disease (PD), and this may lead to heterogeneity in drug response. While LRRK2 PD due to G2019S mutations may fully mimic idiopathic PD (IPD), cross-sectional study suggests that the course may be slightly milder than IPD. Further, the pathology is heterogeneous with a minority not demonstrating Lewy bodies, and this may also correspond to less severe non-motor features.

To better understand the course of PD associated with the G2019S LRRK2 mutation (the most common LRRK2 mutation), we evaluated motor and cognitive progression in individuals enrolled in the LRRK2 Ashkenazi Jewish Consortium. Subjects were recruited from a Center in Tel Aviv, Israel, Sourasky Medical Center, and from two centers in New York, Columbia University and Mount Sinai Beth Israel. 144 participants were LRRK2 mutation carriers and 401 were not. We utilized all study visits, and constructed linear mixed-effects models to estimate the association between harboring the LRRK2 mutation and rate of change of both motor features- as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS), and cognition, as measured by the Montreal Cognitive Assessment Scale (MoCA). Models adjusted for sex, site, age, disease duration and (for the motor models) cognitive score.

We found a small but significant difference in rate of progression, with LRRK2 PD progressing at 0.69 points/year, and IPD at 1.06 points/year. While the cognitive decline was also less in the LRRK2 PD (-0.10 vs. -0.19 in the IPD, this difference was not statistically different (p=0.08).

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Multiple Sclerosis: Rituximab Had Better Short and Medium Term Outcomes

MedicalResearch.com Interview with:
Fredrik Piehl MD PhD, prof. of Neurology

Neuroimmunology Unit. Dept Clinical Neuroscience
Neurology Dept.
Karolinska University Hospital (Solna)
Stockholm

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years we have seen a drastic increase in treatment options for relapsing-remitting multiple sclerosis (RRMS). However, it is difficult to deduce long term performance of different drugs based only on data from randomized controlled trials, since such trials are performed in selected patients without major co-morbidities and perhaps also enriched for those with a milder disease course. In addition, most trials only last for two years and lack relevant comparators. This lack of knowledge makes it difficult to predict if a drug will work or not for a given patient, in turn leading to frequent treatment switches but also different treatment practices across countries, regions or even between centers. This is also the case in Sweden, but with the additional aspect that some regions have opted to treat most newly diagnosed RRMS patients with rituximab (Rituxan/Mabthera), a drug not formally approved for RRMS, but with extensive safety data from other indications.

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Babies’ Brain Responses Predict Dyslexic Reading Skills in School

MedicalResearch.com Interview with:

Kaisa Lohvansuu, PhD
Postdoctoral Researcher
Jyväskylä Centre for Interdisciplinary Brain Research
Department of Psychology
University of Jyväskylä 

MedicalResearch.com: What is the background for this study?
Response: Developmental dyslexia, a specific reading disability, has a strong genetic basis: The risk of having developmental dyslexia at school age is eight times higher than usual if either of the parents has reading difficulty. It has been known that dyslexia and also family risk for dyslexia are strongly associated with a speech perception deficit, but the underlying mechanism of how the impaired speech processing leads to reading difficulties has been unclear.

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SVC As Marker of Respiratory Decline in Amyotrophic Lateral Sclerosis

MedicalResearch.com Interview with:

Jinsy Andrews, MD, MS Director of Neuromuscular Clinical Trials Columbia University The Neurological Institute New York, NY 10032 

Dr. Andrews

Jinsy Andrews, MD, MS
Director of Neuromuscular Clinical Trials
Columbia University
The Neurological Institute
New York, NY 10032 

MedicalResearch.com: What is the background for this study?

Response: The importance of respiratory function in Amyotrophic Lateral Sclerosis (ALS) has long been recognized. Despite ALS being a clinical diagnosis with variable presentation and variable rates of disease progression, all patients experience respiratory symptoms and inevitably die typically from respiratory failure. At present there is no validated biomarker of disease progression or clinical staging system. Direct measure of respiratory function in ALS is important and can be measured using vital capacity. Although the forced maneuver (FVC) has been widely used in patients with ALS, it can underestimate the actual lung capacity by causing fatigue or inducing bronchospasm in patients with ALS. More recently, the slow maneuver (SVC) has been used since it can be obtained from patients with advancing disease which can potentially minimize missing data and may reduce any underestimation of actual lung capacity due to a forceful effort. However, the prognostic value of the decline in SVC is unclear in patients with ALS.

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Parasitic Infection With Toxoplasmosis May Be Linked To Parkinson’s & Alzheimer’s Disease

MedicalResearch.com Interview with:

Under a magnification of 900X, this hematoxylin and eosin-stained (H&E) photomicrograph of a brain tissue specimen revealed a case of neurotoxoplasmosis in a patient who had also been diagnosed with multiple myeloma. Note the Toxoplasma gondii tissue cyst, within which bradyzoites could be seen developing. CDC Image

Rima McLeod, M.D., F.A.C.P, F.I.D.S.A
Professor of Ophthalmology and Visual Sciences,Pediatrics (Infectious Diseases), and The College,
Director, Toxoplasmosis Center,
Senior Fellow,Institute of Genomics, Genetics and Systems Biology, Member, Commitees on Immunology, and Molecular Medicine and Pathogenesis,
Member Global Health Center, Affiliate CHeSS;
Attending Physician, Chicago Medicine,
The University of Chicago

MedicalResearch.com: What is the background for this study?

* One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii.
* Approximately fifteen million of these have congenital toxoplasmosis.
* The parasite interconverts between slow-growing, encysted bradyzoites and rapid-growing tachyzoites.
* In mice, T. gondii creates a chronic intra-neuronal infection and an inflammatory process.
* Mice with acute and chronic infection have alterations in neurotransmitters, memory, seizures, and neurobehavior.
* Some epidemiologic-serologic studies show associations between seropositivity for T. gondii and human neurologic diseases, for example, Parkinson’s and Alzheimer’s diseases.
* Although neurobehavioral disease is associated with seropositivity, causality is unproven.
* Serologic studies of humans with diverse genetics are not optimal to detect strong associations or directionality.
* Epidemiologic associations also do not reveal parasite-modulated gene networks in human brain that could provide insights into how to cure and prevent resultant diseases.
* We need integrative approaches to examine relationships between brain parasitism and other brain diseases, to provide a foundation to identify key pathways and molecules for drug and vaccine design
* To address these problems, we considered two central questions: (i) If chronic brain parasitism associates with other neurologic diseases, what are they? And (ii) Which macromolecular networks are modulated by the parasite in human brain that lead to neuropathology which could underpin and facilitate design of treatments?
* We hypothesized that a systems approach integrating multiple levels of host parasite interactions might resolve these questions.
* To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain.  Continue reading

Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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Considering Circadian Rhythms May Aide in Diagnosis of Consciousness Disorders

MedicalResearch.com Interview with:

Copyright Anna-Lisa Bexten Dr. Christine Blume PhD Post-Doctoral Researcher University of Salzburg Centre for Cognitive Neuroscience (CCNS) Laboratory for Sleep, Cognition & Consciousness Research Salzburg

Dr. Christine Blume

Dr. Christine Blume PhD
Post-Doctoral Researcher
University of Salzburg
Centre for Cognitive Neuroscience (CCNS)
Laboratory for Sleep, Cognition & Consciousness Research
Salzburg

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We are governed by rhythmic processes. Many of these processes follow a circadian pattern, that is, they have a period length of approximately 24 hours and are under tight control of a biological master clock located in the suprachiasmatic nucleus of the hypothalamus. Given the circadian variation in global states like alertness, it is not surprising that consciousness also varies rhythmically in healthy individuals, it follows the sleep-wake cycle.

From a clinical perspective, misalignment of circadian rhythms, which occurs when the sleep-wake schedule is at odds with the light-dark cycle as in the case of night shifts, can cause considerable stress, have detrimental effects on the immune system and impair cognitive abilities. Despite the knowledge that entrained circadian rhythms are important for healthy body and brain functioning, very little is known about circadian rhythms in patients diagnosed with a disorder of consciousness (DOC) following severe brain injuries. We argue that studying circadian rhythms in DOC patients may be especially interesting and important for two reasons.

First, the presence or absence of circadian rhythms as well as anomalies in them could be informative about the state of the patient as well as their potential for recovery.

Second, this could provide information about time points that best capture remaining cognitive functions thereby minimising the risk of misdiagnoses.

Beyond this, examining circadian processes may also provide targets for therapeutic interventions such as light stimulation, which has proven successful in individuals with e.g. circadian sleep disorders. Interestingly, analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3h).

We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised (CRS-R) were closely linked to the integrity of circadian variations in body temperature.

Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in two out of eight patients.

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