Over-activity in a single brain region called the subgenual anterior cingulate cortex (sgACC) underlies several key symptoms of mood and anxiety disorders, but an antidepressant only successfully treats some of the symptoms. A new study suggests that sgACC is a crucial region in depression and anxiety, and targeted treatment based on a patient’s symptoms could lead to better outcomes.
Depression is a debilitating disorder affecting hundreds of millions of people worldwide, but people experience it differently. Some mainly have symptoms of elevated negative emotion like guilt and anxiety; some have a loss of ability to experience pleasure (called anhedonia); and others a mix of the two.
Research at the University of Cambridge has found that increased activity in sgACC – a key part of the emotional brain– could underlie increased negative emotion, reduced pleasure and a higher risk of heart disease in depressed and anxious people. More revealing still is the discovery that these symptoms differ in their sensitivity to treatment with an antidepressant, despite being caused by the same change in brain activity.
Using marmosets, a type of non-human primate, the team of researchers infused tiny concentrations of an excitatory drug into sgACC to over-activate it. Marmosets are used because their brains share important similarities with those of humans and it is possible to manipulate brain regions to understand causal effects.
The researchers found that sgACC over-activity increases heart rate, elevates cortisol levels and exaggerates animals’ responsiveness to threat, mirroring the stress-related symptoms of depression and anxiety.
“We found that over-activity in sgACC promotes the body’s ‘fight-or-flight’ rather than ‘rest-and-digest’ response, by activating the cardiovascular system and elevating threat responses,” said Dr Laith Alexander, one of the study’s first authors from the University of Cambridge’s Department of Physiology, Development and Neuroscience.
“This builds on our earlier work showing that over-activity also reduces anticipation and motivation for rewards, mirroring the loss of ability to experience pleasure seen in depression.”
To explore threat and anxiety processing, the researchers trained marmosets to associate a tone with the presence of a rubber snake, an imminent threat which marmosets find innately stressful. Once marmosets learnt this, the researchers ‘extinguished’ the association by presenting the tone without the snake. They wanted to measure how quickly the marmosets could dampen down and ‘regulate’ their fear response.
“By over-activating sgACC, marmosets stayed fearful for longer as measured by both their behaviour and blood pressure, showing that in stressful situations their emotion regulation was disrupted,” said Alexander.
Similarly, when the marmosets were confronted with a more uncertain threat in the form of an unfamiliar human, they appeared more anxious following over-activation of sgACC.
“The marmosets were much more wary of an unfamiliar person following over-activation of this key brain region – keeping their distance and displaying vigilance behaviours,” said Dr Christian Wood, one of the lead authors of the study and senior postdoctoral scientist in Cambridge’s Department of Physiology, Development and Neuroscience.
The researchers used brain imaging to explore other brain regions affected by sgACC over-activity during threat. Over-activation of sgACC increased activity within the amygdala and hypothalamus, two key parts of the brain’s stress network. By contrast, it reduced activity in parts of the lateral prefrontal cortex – a region important in regulating emotional responses and shown to be underactive in depression.
“The brain regions we identified as being affected during threat processing differed from those we’ve previously shown are affected during reward processing,” said Professor Angela Roberts in the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study.
“This is key, because the distinct brain networks might explain the differential sensitivity of threat-related and reward-related symptoms to treatment.”
The researchers have previously shown that ketamine – which has rapidly acting antidepressant properties – can ameliorate anhedonia-like symptoms. But they found that it could not improve the elevated anxiety-like responses the marmosets displayed towards the human intruder following sgACC over-activation.
“We have definitive evidence for the differential sensitivity of different symptom clusters to treatment – on the one hand, anhedonia-like behaviour was reversed by ketamine; on the other, anxiety-like behaviours were not,” Professor Roberts explained.
“Our research shows that the sgACC may sit at the head and the heart of the matter when it comes to symptoms and treatment of depression and anxiety.”
This research was funded by Wellcome.
Abnormal proteins unleash latent toxicity in neurodegenerative diseases
Most neurological diseases have one thing in common: an accumulation of abnormal proteins around neurons. Researchers agree that these improperly fabricated proteins become progressively more toxic by interacting with healthy proteins, disrupting their functions. This picture, however, may be incomplete, according to a study.
In a recent study published in the Journal of Cell Biology, scientists from Daegu Gyeongbuk Institute of Science and Technology, Korea, have discovered the mechanism of action by which abnormal proteins actually unleash the inherent, but normally latent, toxicity of a natural protein in neurons, causing defects in dendrites (branched parts of a neuron that connect to the next neuron). Therefore, their results provide some clarity as to what actually goes on in diseased neurons. Though the researchers focused on Machado-Joseph disease (MJD), the implications of their results are relevant to other diseases as well.
First, they screened existing data to find candidate genes that were abnormally expressed in MJD patients and mice models. Then, based on the results and using MJD flies as animal models, they identified a problematic transcription factor–a protein that controls and regulates the transcription from DNA of other proteins–called NF-κB. Though this transcription factor is essential for the proper functioning and development of dendrites, the researchers found that something went awry with it when abnormal MJD proteins were around.
Through multiple subsequent experiments, they elucidated a long chain of inhibitory/promoting interactions between native proteins that, at a certain point, clashes with the accumulated abnormal proteins and cascades into a “deregulation” of NF-κB. In turn, this improper regulation unlocks the latent toxicity of NF-κB.
Professor Sung Bae Lee, who led the study, remarks: “Our results open-up a new avenue toward finding cures for neurodegenerative diseases by creating inhibition-based drugs that target improperly regulated latent toxic factors.” Such new potential treatments would directly target the early stages of neuron damage, stopping neurological disorders right on their tracks.
This study lights a beacon of hope for many countries that are struggling to deal with the problems of an aging society. “Korea will become a super-aged society in the near future and establishing an appropriate social system to care for and treat people with neurodegenerative diseases is turning into an urgent social issue,” comments Professor Lee. This might be the first step in a completely new road toward treating these chronic age-related diseases.
Individualised brain stimulation therapy improves language performance in stroke survivors
Canadian scientists are pioneering the use of individualised brain stimulation therapy to treat aphasia in recovering stroke patients.
Aphasia is a debilitating language disorder that impacts all forms of verbal communication, including speech, language comprehension, and reading and writing abilities. It affects around one-third of stroke survivors, but can also be present in those with dementia, especially in the form of primary progressive aphasia.
“Aphasia can be very isolating,” says Dr. Jed Meltzer, Baycrest’s Canada Research Chair in Interventional Cognitive Neuroscience and a neurorehabilitation scientist at Baycrest’s Rotman Research Institute (RRI).
“It can negatively affect people’s personal relationships, and it often determines whether or not someone can continue working.”
In a recent study published in the journal Scientific Reports, Dr. Meltzer and his team tested language performance and used magnetoencephalography (MEG) to measure brain waves in 11 stroke survivors with aphasia before and after they underwent brain stimulation therapy.
The scientists found that the participants had abnormal electrical activity in brain regions close to but outside the area destroyed by the stroke. This abnormal activity was mainly a shift to slower brain waves, a pattern they have also observed in individuals with dementia.
“We mapped that abnormal activity and targeted it using non-invasive brain stimulation,” says Dr. Meltzer.
“We found that the stimulation made the activity more normal – that is, faster – and improved language performance in the short term.”
Previous research has demonstrated that brain stimulation can improve language performance in aphasia patients. However, this study is one of the first to link this performance improvement to changes in the brain activity surrounding the tissue destroyed by stroke.
In other words, this study suggests not only that brain stimulation works in aphasia patients, but also that the reason it works may be because it addresses abnormalities in the brain surrounding the destroyed tissue.
Another novel aspect of this work is that the scientists targeted each individual’s abnormal brain activity with the stimulation treatment. In contrast, the standard approach in previous studies has been to use the exact same treatment, targeting the same brain areas, on every patient.
“Our results demonstrate a promising method to personalise brain stimulation by targeting the dysfunctional activity outside of the destroyed brain tissue,” says Dr. Meltzer.
“Aphasia patients are highly variable in terms of where their brain damage is and what part of the brain should be stimulated for therapy. By mapping individuals’ brain waves, we are finding ways to target the right area to improve their language performance.”
While the participants in this study were stroke survivors, individuals with dementia have similar dysfunctional tissue in their brains, and the scientists are also examining the use of brain stimulation in this group.
Dr. Meltzer and his team looked at the immediate effects of single stimulation sessions in this study. As a next step, they have received funding from the Heart and Stroke Foundation to conduct a full-scale clinical trial looking at the longer-term impacts of repeated stimulation for stroke survivors with aphasia.
However, this study has been suspended because of the restrictions on in-person research participation due to the COVID-19 pandemic. In the meantime, the scientists have pivoted to optimize other aspects of aphasia treatment.
With additional funding, the researchers could test different types of stimulation with more patients over more sessions, allowing them to make faster progress in developing this treatment for individuals with aphasia.
Living with a spinal cord injury and maintaining good mental health during lockdown
In conjunction with Mental Health Day 2020, Irwin Mitchell organised a webinar offering valuable insights into maintaining good mental health for those affected by Spinal Cord Injury (SCI).
The speakers were a mixture of professionals and people living with a SCI.
Dr Parashar Ramanuj, Consultant Psychiatrist gave an in depth clinical insight as to what a person who has recently sustained an SCI may be dealing with and what ‘coping’ really means
Sophie Lester, a case manager and spinal occupational therapist provided some really helpful guidance on how to maintain good mental health alongside rehabilitation and sustaining a healthy balance.
Ian Younghusband and Anne Luttman-Johnson provided first-hand insight into specific challenges of living with SCI and offered tips, advice and practical strategies to develop coping mechanisms in support of you and/or your loved ones.
The webinar offered some invaluable tips, but after seven months of different degrees of lockdown there were two key points that struck home with me. These were firstly the importance of reaching out to friends, family and charities and secondly keeping to some sort of daily routine and structure which includes hobbies, interests and exercise.
Lockdown was difficult for everyone, but especially for those who were deemed to be high risk. For those living with a SCI, a common cold has the potential to be life threatening. Most people with a SCI live with suppressed immune systems and/or possible respiratory issues, and so the possible impact of coronavirus has the potential to be devastating. Accordingly, people with a SCI were considered to be potentially high risk and were advised to shield.
For anyone who was asked to shield, in order to protect themselves, they were advised to isolate and effectively cut themselves off from their families, support networks and normal daily routines. This would have undoubtedly had an impact upon their mental health and wellbeing.
In response to the growing situation, a number of positive and innovative projects have been launched to support the tens of thousands of SCI people who were isolating.
The Spinal Injuries Association (“SIA”) set up a movement, Together in Isolation. The SIA along with other charities and partners, joined forces to support and provide advice to those living with a SCI.
This included weekly inspirational blogs, an online drop-in café at 3pm every Wednesday with SCI Nurse Specialists and Horatio’s Garden providing gardening tips. Back Up, another national SCI charity also set up an online BackUp Lounge for people to just chat.
NeuroKinex is a not for profit organisation which in usual times, provides hands-on activity based rehabilitation for those living with an SCI. They continued to provide therapies and treatment virtually for a number of their clients, providing continuity of their rehabilitation, treatment and routine.
Online accessible experiences
Accessible exercise and fitness and wellness experiences have also become available online, to assist wheelchair users to continue to access exercise from home.
AirBNB launched their ‘experiences’ back in 2017, but when travel had to stop, these converted to virtual experiences with the option of filtering your results to those designed for accessibility. The experiences which have been featured include seated fitness and wellness experiences including Cardiobox, seated adaptive yoga, wheelchair dance and fitness, Mindfulness and Positive thinking with Paralympic heroes. Back Up moved their national wheelchair skills to virtual videos.
Additionally a number of free accessible exercise videos have been shared on social media. Ella, a GB U25 Wheelchair basketball player created Ella’s Wheelchair Workouts, a page on YouTube and Facebook offering and sharing exercise videos to do at home. She does this in conjunction with GymPossible an accessible gym in the North East who then started to produce adaptive fitness videos online.
The last seven months have been tough for everyone, and I am sure that it has had a huge impact on mental health across the country. But I am encouraged by the innovation and sense of community fostered by the use of online and virtual communication which has been sparked by this pandemic, and hope it has assisted some people to be able to continue with accessing their support networks and connecting with others, while participating in their hobbies and exercising from home.
Having access to positive experiences, friendships and exercise virtually when we can’t be there in person helps maintain good mental health. And although it doesn’t replace face to face in person experiences, I am hopeful that this positive community movement continues when life returns to what will be our new ‘normal’.
For those who are interested, I would really recommend watching the webinar recording which gives practical tips and guidance. This can be seen below:
Written by Jessica Bowles, a solicitor specialising in serious injury with a specific interest in Spinal Cord Injuries and rehabilitation at Irwin Mitchell.
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