Tag Archives: Brain

More on Brain Health in Young Children and Effect on Life Course

Brain health in early childhood is a recurring theme of your News Blog. Peter Chilton referred me to an interesting article in Nature Human Behaviour published at the end of last year.[1] This study was based on a prospective study of children in the South Island of New Zealand. The investigators wanted to determine the prognosis for the 20% of the population with the worst brain health indicators at age three. These indicators include single parent family; low socioeconomic group; poor self-control; and low IQ. Outcome variables covered a range of important economically burdensome outcomes, such as obesity, cigarette smoking, and crime. These variables were harvested from various databases where health and crime statistics are recorded. A 20% ‘segment’ of this young population could be defined which predicted 80% of crime, and similar high rates on other outcomes. This 20:80 ratio, called the Pareto ratio, is often encountered in social science – for example, wealth distributes itself roughly in this proportion across many societies (about 20% of people control 80% of wealth). The authors say that their study shows plenty of ‘headroom’ for preventive interventions. That is to say, society could achieve massive gains if health and social outcomes among the highest risk segment could be improved to average levels. We have discussed interventions, such as early childhood education, before.[2-4] Many studies show statistically significant and economically worthwhile results for such interventions, but the gains come nowhere near the theoretical headroom defined here. Likely this is because brain health at age three is only partly the result of remediable factors.

— Richard Lilford, CLAHRC WM Director

References:

  1. Caspi A, Houts RM, Belsky DW, Harrington H, Hogan S, Ramrakha S, Poulton R, Moffitt TE. Childhood forecasting of a small segment of the population with large economic burden. Nature Hum Behav. 2016; 1: 0005.
  2. Lilford RJ. Pregnancy before age 16 – dropping quite rapidly from a peak in 1997. NIHR CLAHRC West Midlands News Blog. February 10, 2017.
  3. Lilford RJ. If you want to reduce partner violence or teenage pregnancy, then teach algebra and history? NIHR CLAHRC West Midlands News Blog. December 9, 2016.
  4. Lilford RJ. Evidence-based education (or how wrong the CLAHRC WM Director was). NIHR CLAHRC West Midlands News Blog. July 15, 2016.

Legalisation of Marijuana

Having borne down heavily on tobacco, it seems like everyone is now campaigning to make marijuana legal – are they mad?

A libertarian would say that there is no case to ban tobacco (or effectively ban it by draconian taxes on consumption). All tobacco can do is kill you, and as long as you know this you may use it. Marijuana is a different case altogether. It appears that it does not just kill you, it maims you – and not just your body, but you – your personality, your memory, your intelligence, i.e. your essence. And it is particularly attractive to teenagers – those with the most precious and vulnerable brains. Use is increasing in the US and has increased in association with decriminalisation, even if cause and effect is hard to prove.[1] Meanwhile a recent longitudinal cohort study found that persistent cannabis dependence was linked to downward socioeconomic mobility, financial difficulties, workplace problems, and relationship conflict.[2] It gets worse, the concentration of psycogenic compounds is increasing in the plant due to selective breeding. The attitude and fashion among liberal metropolitans “tobacco is vulgar, but marijuana is cool.” Have we gone mad? If we could confine the need to people over 18, and campaign against it, then over time we could reduce use. But a chemical that actually alters the structure of the adolescent brain and is more ubiquitous than boxing? We urgently need more information on the effects legalising cannabis has on usage. Also, more research on its effects on the brain using functional MRI. I wonder if Mendelian randomisation could shed light on causality?

— Richard Lilford, CLAHRC WM Director

References:

  1. Azofeifa A, Mattson ME, Grant A. Monitoring Marijuana Use In the United States: Challenges in an Evolving Environment. JAMA. 2016; 316:1765-6.
  2. Cerdá M, Moffitt TE, Meier MH, et al. Persistent Cannabis Dependence and Alcohol Dependence Represent Risks for Midlife Economic and Social Problems: A Longitudinal Cohort Study. Clin Psychol Sci. 2016; 4(6): 1028-46.

 

Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain

This News Blog has frequently discussed synaptic pruning [1] [2] – a process that occurs in the foetus at mid-gestation, children at around the age of two, and in late adolescence. Abnormalities in neural synaptic pruning are associated with diseases, such as schizophrenia and autism.[3] It turns out that there is another period of synaptic pruning – during pregnancy. Functional MRI shows that many areas of grey matter shrink in pregnancy. Greater pruning is associated with higher scores on standard questionnaires measuring a mother’s attachment to her baby.[4] More brain does not necessarily mean better brain.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening Up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. van Spronsen M, Hoogenraad CC. Synapse Pathology in Psychiatric and Neurologic Disease. Curr Neurol Neurosci Rep. 2010; 10(3): 207-14.
  4. Hoekzema E, Barba-Müller E, Pozzobon C, et al. Pregnancy leads to long-lasting changes in human brain structure. Nature Neurosci. 2016.

A Fascinating Account of the Opening Up of an Area of Scientific Enquiry

News Blog readers may have seen previous posts on synaptic pruning.[1] Synaptic pruning involves the elimination of synapses with weak connections between brain neurons. Pruning is especially exuberant after periods of rapid neuronal multiplication (in mid-gestation, around the age of two years, and in late adolescence). Over-exuberant synaptic pruning is associated with schizophrenia. It may also play a crucial role in degenerative brain diseases, such as Alzheimer’s, and in people with memory loss after West Nile fever. The biochemical trigger arises from products of the complement cascade. Astrocytes induce neuronal cells to make the protein C1q, which triggers the complement cascade in neurons. Complement factors, such as C3 attach to weak synapses, and micro-glia (the macrophages of the brain) then ingest the tagged synapses. This process can be visualised by staining living brain cells – bits of synapse end up in the micro-glia. A genetic predisposition to over-express certain complement components increases the risk of schizophrenia markedly, as reported in a previous post.[2] As brains age C1q levels increase four-fold, and this likely predisposes to degenerative diseases, such as Alzheimer’s. Drugs to dampen down this cascade are entering clinical trials. For a lively account if the human story behind one of the leading scientists involved in unravelling this story, see an article by Emily Underwood.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands. 11 March 2016.
  2. Lilford RJ. Molecular Diagnostic Testing, Including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder. NIHR CLAHRC West Midlands. 23 October 2015.
  3. Underwood E. This woman may know a secret to saving the brain’s synapses. Aug 18 2016.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.

Addiction as a Brain Disease

News Blog readers know that the CLAHRC WM Director is a completely unapologetic advocate of Enlightenment values. Sciences does not just provide information about nature. It also changes our world view of nature. Since we humans are part of nature, it has the potential to change how we think about ourselves. A natural, but untutored, view of addiction is that it is a moral failure – a lack of personal responsibility leading to voluntary indulgence in hedonistic pursuits. However, addiction is a neuro-physiological condition with an organic basis – just like other psychological phenomena.[1] The clue was always there – the condition affects some people but not others, and applies to behaviours such as video-gaming, not just toxic substances. Activation of specific neurobiological circuits is associated with:

  1. Intoxication
  2. Withdrawal
  3. Craving.

Intoxication leads to a learned response so that, over time, dopamine cells start firing, not in association with the reward, but in anticipation of it – the classical mechanism in learning. The CLAHRC WM Director does not think of alcohol until dinner-time. The dinner is activating his dopaminergic neurons and creating craving. Fortunately, they stop firing when he has a glass of wine so he can stop drinking (most days). But a person predisposed to addiction would not experience satiation. Worse, dopaminergic responses to the stimulus attenuate over time so that more of the agent is required to produce the same gain. Worse still, dopaminergic responses to other (non-addictive) positive stimuli – say from getting a paper published in a high-ranking journal – are also attenuated. So the addicted person enters a downward spiral. Compensatory down-regulation of dopamine signalling elsewhere in the brain leads to dysphoria (depression) and a drop in motivation. An afflicted person’s life thus descends into further chaos.
Why are some people more susceptible than others? Here are risks:

  1. Genetic predisposition; a number of specific genetic polymorphisms predisposing to addiction have been found.
  2. Early exposure – the adolescent years especially, as this is a time of high neuroplasticity.
  3. Poor familial and social support.
  4. Restricted alternatives – sport should be encouraged.

This deeper knowledge of the molecular and neuro-anatomical basis of addiction is leading, not just to new pharmacological and neuro-biological treatments, but a profound change in social attitudes. This is manifest in, for example, more lenient sentencing for non-violent offences perpetrated by people with addictions. Science is a civilising process that does not just inform how to reach an objective, but also colours our choice of objectives.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Volkow ND, Koob GF, McLellan T. Neurobiologic Advances from the Brain Disease Model of Addiction. New Engl J Med. 2016; 374: 363-71.

Walking after Paraplegia

For those with paraplegia following spinal cord injury (SCI), a wheelchair is their primary means of mobility. However, this can often lead to medical co-morbidities that contribute significantly to SCI-related medical care costs. According to surveys these patients highly prioritise restoration of walking as a way to improve their quality of life.

A recent paper by King et al. looked at the feasibility of using a brain-computer interface to give paraplegic patients the chance to walk again.[1] The procedure involved linking an electroencephalogram-based system to a functional electrical stimulation system on leg muscles, which can then be controlled by thought. The study used a physically active 26 year-old male who underwent virtual reality training in order to reactivate the areas of the brain responsible for gait, and reconditioning of leg muscles using electro-stimulation. Over 19 weeks the patient was able to successfully complete 30 over-ground walking tests with no adverse events.

The authors concluded that these results provide proof-of-concept for using direct brain control to restore basic walking. Although the current system is likely to be too cumbersome for full-scale adoption, it may represent a precursor to a future, fully implantable system.

— Peter Chilton, Research Fellow

Reference:

  1. King CE, Wang PT, McCrimmon CM, Chou CCY, Do AH, Nenadic Z. The feasibility of a brain-computer interface functional electrical stimulation system for the restoration of overground walking after paraplegia. J Neuroeng Rehab. 2015; 12: 80.

 

 

Molecular Diagnostic Testing, including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder

CLAHRC WM News Blog features articles of generic, rather than specific, interest. The general interest here lies in the use of molecular techniques to unravel the mechanisms of diseases, especially neurological diseases, that are inaccessible to study in other ways.
A study of 258 consecutively ascertained children with ASD was recently reported in JAMA.[1] The incidence of genetic abnormalities was low (about 6%) in ASD children with no morphological abnormalities, but unsurprisingly reached much higher levels (38%) when complex morphological abnormalities were present. To the CLAHRC WM Director this finding suggests that ASD, when not associated with atypical physical features, is seldom caused by embryonic de novo or inherited genetic disorder. But could it be caused by propagation of a clone of neurons with a new mutation derived during the first wave of brain remodelling in utero?[2] [3]

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Tammimies K, Marshall CR, Walker S, et al. Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children with Autism Spectrum Disorder. JAMA. 2015; 314(9): 895-903.
  2. Lilford R. An hypothesis on the cause of many chronic neurological conditions, such as schizophrenia and Alzheimer’s disease. January 18 2013.
  3. Lilford R. Biological mechanism of generalised brain disease such as Alzheimer’s disease and schizophrenia. March 1 2013.

Why is the Science of Consciousness so Intractable? Because it is Deeply Philosophical

The Economist newspaper has recently featured a series of articles on major scientific topics. These articles are beautifully written and accessible to the intelligent – that is News Blog – reader. They cover topics such as time and space; matter and energy; and the Cambrian explosion in life forms that started about 540m years ago. The September 10th edition grappled with the intriguing, but enigmatic, topic of consciousness.[1] This “science brief” covered “theory of mind” (i.e. ability to imagine what another person is thinking or feeling), and neurophysiology (importance of the claustrum and parietal-temporal area of the brain). But what is consciousness? At this point science and philosophy merge, as adumbrated in this fortnight’s News Blog. The article cites the work of the philosopher Nagel, who asks us to try to imagine being a bat in possession of consciousness. While we are able to imagine what it feels like to hang upside down, the bat would build consciousness on its predominant sense – echolocation. The form of such consciousness must remain ineffable to humans. The article goes on to point out that other scientific phenomena are equally ineffable – no scientist can really imagine wave particle duality or light years. But what makes these problems tractable is mathematics. Space/time is hard to imagine, but the speed of light can be converted to distance and included in Pythagoras’ theorem, c2t2 – x2 – y2 – z2, to identify a point in space time. No such approach can be used to fully understand what another creature – bat or human – is experiencing.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. The Economist. What is Consciousness? The Hard Problem. 2015. [Online]