Criminal Brains: Intelligence and Criminal Behaviours

I believe that one of the questions asked at least once in everyone’s lifetime is: “why people do what they do? Why in the same conditions/situations do people make completely different decisions?”. One aspect of human behaviour, in particular, is very intriguing from my point of view: why people choose or find themselves engaging in criminal behaviours, and other individuals in similar circumstances don’t? This article doesn’t obviously claim to be a philosophical treatise, although someone of you may find it fascinating – I don’t have the competences for doing so. However, as neuroscience student what I can do is try to identify some of the factors that may contribute to render some brains more propense to develop the criminal outcome decision compared to others.

Correlation between IQ and criminal behaviours

One of the factors that seems to critically influence the tendency to engage in criminal activities is intelligence. A study conducted by Jovanovic D. et al in 2012 on 120 inmates (60 murderers and 60 non-murderer), showed a negative correlation between IQ and criminal activity; that is, the average IQ of the total inmate population resulted to be lower than the general population. Specifically the average intelligence of the inmates investigated was 95.7, placing the cognitive abilities of these individuals in the lower average of normal abilities. Interestingly, the overall intelligence of the homicide group of inmates (97.4) showed to be greater compared to the non homicide group (94.04), suggesting that the individuals convicted for murders seemed to be “smarter” than individuals convicted for other crimes such as robbery, theft and fraud – but still in the lower average compared to general population. It is important to note that the overall score of IQ was given by the combination of two aspects of intelligence: verbal and manipulative-non verbal tasks. The fascinating fact is that while the non-verbal tasks remain mainly unchanged between all inmates and the general population, the component of the test responsible for decreasing the overall IQ score of all inmates was verbal abilities. Another study from Gibson et al conducted in 2001 showed that the interaction between family adversity and below average verbal IQ at the age of seven is a predictive indicator of early onset of offending behaviours. Once again, it appears that the defecting aspect of intelligence in individuals with higher risk of engaging earlier in criminal behaviours is the verbal part. An even more interesting finding from this study is that the children with higher family adversity factors (i.e. more serious situations), had also lower verbal IQs; in constrast, children with lower adversity factor had higher verbal IQs,. These results can be interpreted in many way, but the most intuitive one would be that specific adverse life events can have an important impact on the development of natural abilities.

Can Intelligence development be promoted to ultimately prevent crime?

I am convinced that the results above describe may raise a number of questions…The first of them being: “what is this trait of personality, i.e. intelligence, that seems to be influenced by the environment and life events?”. Well, it is very difficult to define intelligence, and today, a univocal definition of it that is accepted by everyone still does not exist. However, a broad picture of what intelligence is can be given by describing it as ‘the entirety of abilities that allow individuals to understand and develop complex concepts, engage in diverse types of abstract reasoning and consequently adapt efficiently to the external environment’ (Neisser et al 1996). The finding of Gibson’s et al study seems to suggest that these abilities can be enhanced or reduced by external factors, to the point where the result of this interaction can be considered as a predictive indicator of early offending. Other studies also show that socioeconomical status may have an important impact on neurocognitive abilities during development, in particular on language skills (Hackman et al 2010). It is important to underline the fact that in all the studies here described one particular aspect of intelligence, verbal reasoning, seems to be mostly affected by external adverse events and is found to be responsible for lowering the IQ scoring in criminal adults. This finding opens a wide range of considerations, for example that it is plausible that some adverse events in life may interfere more with the development of some aspects of intelligence, for example verbal skills but not with – or at a lesser extent to – others, such as manipulative/non-verbal abilities. Furthermore, it is possible to infere from this that the study of intelligence in correlation to criminal behaviours can also be used as a tool not only to understand the “reasons” of criminal outcomes, but also for reaching a clearer insight of how intelligence works and is developed.

At this point it is important to notice that, although the external environment plays a crucial role in the development of these abilities, it is widely known that the heritability of intelligence (i.e. the amount of trait variation that is due to the individual genetic code) can be up to 50% (Deary et al 2009). Unfortunately, the genes responsible for heritability of normal range intelligence haven’t been found yet, but what if one day we could map these genes? Could this variable, in conjunction with other indicators such as detrimental life events, family adversity and socioeconomical status, help us to one day predict even more precisely which individuals have higher risk of engaging in criminal activities? And prevent those events by supporting those individuals?

In conclusion, I believe that in light of these considerations, it is reasonable to state that a more supporting society in respect to disadvantaged situations could eventually promote intelligence development in children and could ultimately represent a less criminal society. And even if this wasn’t the case…why not give it a try?

Author: Cristina Cabassi

Edited by Molly Campbell

References:

  • Deary J. I., Johnson W., Houlihan L.M., 2009, Genetic foundations of human intelligence, Hum Genet, 126:215–232

 

  • Gibson L.C., Piquero R.A., Tibbets S.G., 2001 The Contribution of Family Adversity and Verbal IQ to Criminal Behavior,I nternational Journal of Offender Therapy and Comparative Criminology, 45(5), 574-592

 

  • Hackman A.D., Martha J. F., Miachael J.M., 2010, Socioeconomic status and the brain: mechanistic insights from human and animal research, Nat Rev Neurosci; 11(9): 651–659.

 

  • Jovanovic D., Novakovic M., Salamadić A., Petrovic , Maric s., 2012, Analysis of the relation between intelligence and criminal behavior, Journal of Health Sciences, Vol 2, N. 3,

 

  • Neisser et al, 1996, Intelligence: Known and Unknowns, American Psychologist, Vol. 5, N. 2, 77-101

 

 

 

 

 

 

 

 

 

 

 

 

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Lights, Genetics, Action – what are the uses of optogenetics in the field of neuroscience?

Optogenetics is a useful tool employed in many areas of biomedical research including and not limited to neuroscience. But does it have the potential to be a clinical weapon? Since the emergence of this technique, the field of optics in science has evolved. As technology changes science has to keep up and with audacious and revolutionary tools such as optogenetics, it is clear that this is happening. But how useful is it really?

What is optogenetics?

It is a new and revolutionary technique used in bioscience for clinical and laboratory function. Breaking down the word gives more meaning; opto meaning the use of light and genetics is reference to the genome. The basic principle of optogenetics is the use of specific wavelengths of light to control and alter a neurone’s firing potential, be it inhibitory or excitatory. The tools involved in the technique (opsins) are actually proteins that are naturally found in microbes, which when activated by light transport the appropriate ions (Boyden, 2011).

This may in theory seems uncomplicated at first glance, however when you delve into the complicated physics and chemistry of the idea, it is not so simple. These opsins, as mentioned, are naturally found in microbes – not humans. This is where genetics and bioengineering are consulted. In order for there to be any clinical use of opsins in humans, then there has to be an efficient way to alter a person’s DNA in order for them to express these opsin proteins. This is a major challenge currently inhibiting the use of opsins in patients.

However, opsins can be used in the lab setting as research. Transgenic mice can be genetically engineered to express the opsins in different parts of the body. This allows scientists to research the consequences of switching certain channels on and off, thereby allowing them to learn more about a disease, condition or anatomy.

There are actually three types of channels used in the technique (Fig.1). Firstly, are the Bacteriorhodopsins which were discovered by Oesterhelt and Stoeckenius (1971; 1973) in the 1970s and were found in the Halobacterium salinarum bacterium. As shown in the diagram, when activated by green light, protons are pumped out of the cell. The next opsin was discovered in the 1980’s and when exposed to yellow/orange light, inhibits the neurone by causing an influx of negative chloride anions (Boyden, 2011). The final and most commonly used opsin is channelrhodopsin. This opsin, when activated by blue light is excitatory, and allows the influx of various cations into the cell, causing depolarisation. This was discovered in Chlamydomonas reinhardtii (a type of algae) (Sineshchekov et al, 2002), and was found to initiate and control phototaxis (Boyden, 2011).

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Fig.1: diagrams showing the three opsin channels used in current research and how they work when the appropriate light is used to stimulate. The colour of the channels represent the light waves used to specifically stimulate the channel. Diagram from (Boyden, 2011).

How does optogenetics work?

First of all you need to use bioengineering in order for the opsin to be expressed in the genome. As Fig.2 shows, the gene for the opsin in question is coupled to a promoter region, allowing for the protein to be expressed via DNA transcription and translation.

Once the genetic construct has been made, it is then introduced into a viral vector. The virus takes up the genetically modified construct and is merged into its genome. The virus is then injected locally to the target neurones only, in the rodent. Here the virus takes on its normal biological function and hijacks the DNA machinery in the rodent, causing it to transcribe the opsin gene. A fibre-optic electrode is then implanted into the rodent and once turned on, it stimulates the opsin channel.

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Fig.2: a summary of how optogenetics works, from the bioengineering to the stimulation of the opsin channel. http://optogenetics.weebly.com/why–how.html

To allow for variability as well as co-occurrence of different opsin channels, each channel is only stimulated at a certain wavelength of light or colour of light (Fig.3). As shown, channel rhodopsin (ChR2) is stimulated by blue light, in the range of roughly 470nm, whereas channel halorhodopsin (NphR) is stimulated by yellow light in the range of roughly 590nm.

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Fig.3: a graph showing the activation wavelengths of various opsin channels. ChemistryViews, 2013.

Once stimulated, the opsin channel opens, leading to an influx/efflux of positive or negative ions depending on the channel’s function. Taking channelrhodopsin as an example; the optrode is turned on, allowing light to shine on the channel and causing it to open. When the neurone is at rest at roughly -70mV, there is a larger concentration of cations on the outside of the cell with respect to the inside, creating a biophysical gradient as well as a concentration gradient. These two factors favour an influx into the neurone, leading to cellular depolarisation and the generation of an action potential. The optrode, when turned on, causes the neurone to fire. This, alongside a whole population of neurones, concurrently depolarise leading to signal generation (summarised in Fig.4).

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Fig.4: diagram summarising the molecular events that occur once the opsin channel (channelrhodopsin used as example) has been stimulated by light. The black arrows indicate biochemical and electrophysical gradient and the direction in which the cations flow. The red arrow is used as a reference point on the action potential trace. +/ symbols represent cations and anions respectively.

Uses of optogenetics in the clinical field

A specific reaction occurs depending on the population of neurones, the location and which pathway you want to control. This is particularly useful for researchers as they can study specific neural circuitry and pathways that may be involved in disorders.

Using optogenetics in the treatment of stroke

The selective stimulation of pyramidal neurones in layer V of the primary motor cortex (M1) was shown to induce the repair processes following a stroke in a study conducted by Cheng et al in 2013. Optogenetics was used in the study in order to test whether specific stimulation of a pathway could help stroke-inflicted mice. Not only were the results promising, but you could say groundbreaking. They found that vs non-optogentically-stimulated mice, the stimulated mice performed significantly better in a range of biochemical as well as behavioural tests.

Fig.5 only provides a snapshot to what they found; Fig.5a shows a significant increase in change in CBF (cerebral blood flow) between stimulated and non-stimulated mice. The reason why CBF was measured is because it is a hallmark for repair. When the brain is damaged, an innate reaction called the neurovascular response kicks in and tries to help alleviate the damage. The % change in CBF was used as a function for repair, because a change indicates that this recovery response is occurring.

There are other hallmarks of repair and recovery, which is shown in Fig.5b. There was a significant increase in neutrophic mRNA expression in either the contralesional primary motor cortex (CM1) or the contralesional somatosensory cortex (CS1). The neurotrophins tested all play a part in repair; Brain Derived Neurotrophin Factor (BDNF) is responsible for inducing axonal and dendritic sprouting; Nerve Growth Factor (NGF) controls the growth of nerves and Neurotrophin3 (NTF3) is involved in survival and differentiation of cells.

Finally, Fig.5c shows results from a distance behavioural test. There is a clear significant difference between distance travelled for stimulated and non-stimulated stroke mice, which if the mice can travel further, indicates recovery from the stroke infliction. If these data can be replicated with a better sample, such as increased number of participants or a change in species tested, then this holds a great potential use in stroke patients.

5aA

5b B

5cC

5dD

Fig.5: figures a. and c. taken from Cheng et al’s study, figure b. is a summarised figure of data from the same study. a. = shows the % change in cerebral blood flow (CBF) between stimulated and non-stimulated mice at post-stroke day 15; b. = graph showing the mRNA content of different neurotrophins in stimulated mice in either the contralesional primary motor cortex (CM1) or the contralesional somatosensory cortex (CS1); c. = a behavioural distance test focusing on stimulated and non-stimulated mice.

 

 

Using optogenetics in the treatment of amnesia

A truly fascinating and useful study using optogenetics was conducted by Ryan et al in 2015, in which they used the technique to study engram cells. These cells are believed to play a part in the consolidation of memory and are changed by learning information (storage) and are reactivated once appropriate retrieval conditions are in place (Tonegawa et al, 2015). This theory is used as the basis behind amnesia in this study. The authors wanted to employ optogenetics in order to stimulate these engram cells, in order to retrieve a memory that should be lost due to disruptions in long term potentiation (LTP) protein synthesis by administrating an inhibitor (anisomycin).

As a control, a group of mice were injected with saline, yet were still optogentically altered to respond to pulses of blue light due to ChR2 presence. The mice were habituated with the optoelectrode and after habituation, they were shocked in order to induce contextual fear conditioning (CFC). This is when the mice associate a previously non-harmful situation/environment to a harmful one due to its association with an electrical shock for example. The mice were then habituated again and optogenetic stimulation induced freezing behaviour in both the anisomycin group (ANI) and the saline group (SAL). Mice were then returned to the chamber they had been shocked in, in order to provoke CFC. Freezing behaviour occurred in both groups and the two groups were then injected with either ANI or SAL. 3 days following the injection, the two groups of mice were returned to the CFC chamber, where the SAL group showed significantly more freezing behaviour (P < 0.01) than ANI, suggesting that ANI had disrupted further memory consolidation of the noxious environment. 4 days later, both groups of mice were stimulated in a non-harmful environment and remarkably, both groups showed significant light-induced freezing behaviour (SAL = P < 0.001 and ANI = P < 0.003) (summarised in Fig.6).

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Fig.6: experimental paradigm from Ryan et al’s 2015 study showing the effects of ChR2 activation by optogenetics on contextual fear conditioning freezing behaviour.

This showed the researchers that by specifically stimulating these engram cells with optogenetics can ‘re-form’ a lost memory. This has massive implications in not only amnesia research, but possibly with disorders such as Alzhemier’s disease, where lost memories can maybe be brought back. The implications are immensely promising, however the logistics and practicality of engineering the technique in humans is a big problem.

Using optogenetics in the treatment of Parkinson’s disease

Parkinson’s disease is a disorder that is characterised by movement deficits, particularly the infamous ‘shuffling gate’. The disease is believed to be caused by the destruction of dopaminergic (DA) neurones within the substantia nigra pars compacta (SNc), leading to atypical neuronal activity in the basal ganglia (BG) (Gradinaru et al, 2009). It is specifically the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) where the irregular neuronal activity leads to the abnormalities including difficulties in initiating and executing motor movements (Albin et al, 1989; Alexander and Crutcher, 1990; DeLong, 1990).

The main advantage of using optogenetics is its selectivity of certain neurones. Deep brain stimulation is a technique used in Parkinson’s disease treatment; however its selectivity for neurones is robust and not very accurate, leading to undesirable effects. This is why Gradinaru et al conducted an optogenetics study in 2009 that primarily targeted the STN by stimulating NpHR opsins, which inhibited the excitatory network. The authors studied the effects of optogenetic stimulation of afferent axonal projections that entered the STN.

Depending on the frequency (be it high or low) determined the therapeutic effects of stimulating the STN afferents using optogenetics. Based on rotational behaviour and head position bias tests, high frequency stimulation (HFS) of the afferents showed remarkable effects (Fig.7). The stimulation ameliorated the parkinsonian symptoms immediately, with significantly reduced rotations per minute (decreased rotations is a sign of Parkinson symptom decrease) compared to pre and post optogenetic HFS. LFS also showed the exact opposite effects.

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Fig.7: the effects of High frequency and Low frequency stimulation (HFS and LFS respectively) on rotational behavioural tests. Note that the Pre and Post indicate before and after optogenetic stimulation. *P < 0.05, n = 5; ***P < 0.001, n = 5 based on t-test.

Based on previous research (Li et al, 2007; Degos et al, 2008) the primary motor cortex M1 and the STN connections may underline the malformed circuitry in Parkinson’s disease. This is why the authors then looked at using optogenetics in the M1. They found that by stimulating from the M1 and recording from the STN (Fig.8a) that similar results were found in reference to LFS and HFS on the rats’ behaviour (Fig.8b).

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Fig.8: a = diagram showing the optogenetic stimulation of the M1 with simultaneous recordings taken from the STN; b = rotational beam behavioural tests at different stages of optogenetic stimulation. **P < 0.01, n = 5 based on t-test.

 

This study helped to show that the selective optogenetic stimulation on certain pathways at high frequency stimulation can help ameliorate Parkinson symptoms, more so than deep brain stimulation. Though hard practically, using optogenetics as a substitute for DBS looks to hold more benefits in treating the movement symptoms.

Using optogenetics in the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a lethal neurodegenerative disorder that is the leading cause of dementia and is characterised by memory loss and gradual loss of functional and cognitive processing (Roy et al, 2016). As the disease progresses, neural atrophy gets worse leading to the associated symptoms. Post-mortem brains of patients that suffered AD and those that did not show complete disparity in its structure and general appearance (shown in Fig.9).

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Fig.9: pictures A and B are from patients that did not have Alzheimer’s disease and pictures C and D are from patients that did have the disease. The white arrows are present to compare one picture from another. Note that ventricles in picture D are almost non-existent due to the atrophy. Pictures from Soto-Rojas et al, 2015.

The aforementioned study regarding optogenetic stimulation of engram cells in treating amnesia serves as a basis or as previous research to a study conducted in 2016 by Roy et al. This team built on the ideas and theories found by Ryan et al, as they too used optogenetics to stimulate engram cells (in the hippocampus) in order to retrieve lost memories that occur in the early stages of Alzheimer’s disease (AD).

The team used an AD model which included the over-expression of the delta exon version of presenilin 1 (PSEN1) and also had a mutation in the β-amyloid precursor (APP) leading to increased plaque formations. As well as this model, the team successfully rescued memory recall by optogenetic stimulation in two further models; transgenic mice made from mating c-Fos-tTA mice together (which also had the APP/PSEN1 mutation) and the other model used was a commonly used AD model known as MAPT (Roy et al, 2016). They found that stimulating 7-month-old AD mice could induce memory recall.

It is important to note that a reduction in dendritic spine density has been suggested to play a part in the memory decline of AD patients. Furthermore, the authors detected reduced density of the dentate gyrus (DG) engram spines in 7-month old AD mice against the control (Fig.10).

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Fig.10: the pictures show the difference in spinal density between control mice (left) and the 7-month old AD group (right). There is a clear reduction in the number/density of the dendritic spines in the AD group.

The authors also induced long-term potentiation (LTP) by using optogenetics in order to help consolidate a memory and restoring spine density. Fig.11 shows how after optogenetic-induced LTP, the AD mice group that also had 100 Hz showed an increased freezing response relative to normal AD group. This suggests that optogenetics induced the LTP, which helped the mice recall contextual memory.

This study is relatively recent, yet holds many potential useful future projects, as this way of tackling AD is unique and different from the standard way of administering Acetylcholinesterase inhibitors, which are relatively useless.

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Fig.11: outline of natural memory recall test in which rodents were contextually trained to noxious stimulus and

Future for optogenetics: a conclusion

Optogenetics is a brilliant and innovative tool that has clearly shown promise based on the studies mentioned. The exciting prospect of this tool is that it will only get better and more expansive, as over the next few decades it will surely be used in frontline medicine, as well as in research. The brilliance of using optogenetics in order to try and regain a lost memory is second to none, and is surely a step forward in combating Alzheimer’s disease; a problem that is on the rise in the western world due to increased health procedures.

Though it is very useful in the lab doing research on circuitry, it is harder to employ in in vivo subjects, as the practicality of bioengineering is no easy task. This surely is the biggest obstacle facing optogenetics. Once a way has been found e.g. a possible mixture of implantation by surgery or even using lentiviral vectors, then optogenetics will surely be one of the greatest tools in modern medicine.

 

Author: Ryan Gourlay

References

Albin, R.L., Young, A.B. and Penney, J.B. (1989). The functional anatomy of basal ganglia disorders. Trends Neurosci, 12, 366-375.

Alexander, G.E. and Crutcher, M.D. (1990). Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci, 13, 266-271.

Boyden, E. S. (2011). A history of optogenetics: the development of tools for controlling brain circuits with light. F1000 Biology Reports3, 11.

Cheng, M.Y., Eric, H., Wanga, E.H., Wooson, W.J., Wanga, S., Suna, G., Leed, A.G., Araca, A., Fennoc, L.E., Deisseroth, K. and Stainberg, G.K. (2014). Optogenetic neuronal stimulation promotes functional recovery after stroke. Proceedings of the National Academy of Sciences, 111, 12913-12918.

Degos, B., Deniau, J.M., Le Cam, J., Mailly, P. and Maurice, N. (2008). Evidence for a direct subthalamo-cortical loop circuit in the rat. Eur. J. Neurosci, 27, 2599-2610.

DeLong, M.R. (1990). Primate models of movement disorders of basal ganglia origin. Trends Neurosci, 13, 281-285.

Gradinaru, V, Mogri, M, Thompson, K. R, Henderson, J. M. and Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science, 324, 354–359.

Li, S., Arbuthnott, G.W., Jutras, M.J. Goldberg, J.A. and Jaeger, D. (2007). Resonant Antidromic Cortical Circuit Activation as a Consequence of High-Frequency Subthalamic Deep-Brain Stimulation. J. Neurophysiol, 98, 3525-3537.

Oesterhel, D., Stoeckenius, W. (1971). Rhodopsin-like protein from the purple membrane of Halobacterium halobium. Nat New Biol, 233, 149–52.

Oesterhelt, D., Stoeckenius, W. (1973). Functions of a new photoreceptor membrane. Proc Natl Acad Sci U S A, 70, 2853–7.

Roy, D.S., Arons A., Mitchell, T.I., Pignatelli, M., Ryan, T.J. and Tonegawa, S. (2016). Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature, 531, 508-512.

Ryan, T.J., Roy, D.S., Pignatelli, M., Arons, A. and Tonegawa, S. (2015). Engram cells retain memory under retrograde amnesia. Science, 348, 1007-1013.

Sineshchekov, O.A., Jung, K.H., Spudich, J.L. (2002). Two rhodopsins mediate phototaxis to low- and high-intensity light in Chlamydomonas reinhardtii. Proc Natl Acad Sci U S A, 99, 8689–94.

Soto-Rojas, L.O. et al. (2015). Neuroinflammation and Alteration of the Blood-Brain Barrier in Alzheimer´s Disease. Chapter 3.

Tonegawa,S., Pignatelli, M., Roy, D.S. and Ryan, T.J. (2015). Memory engram storage and retrieval. Current Opinion in Neurobiology, 35, 101-109.

Optogenetics procedure picture: Available from: http://optogenetics.weebly.com/why–how.html.

Wavelengths of light picture: Available from: http://www.chemistryviews.org/details/news/1360543/Optogenetics__Revolutionizing_Biochemistry.html

 

Chronic Pain: Is Optogenetics The Answer?

We have all experienced some kind of pain countless times throughout our lives; be it a small paper cut that stings for days, to the agony of a severely broken limb. Despite pain being an unpleasant and unwanted experience, it is vital for our survival and wellbeing. It acts as a danger signal, informing us of injury and damage.

What is Chronic Pain?

Pain is experienced after peripheral nociception, the physical process of detecting and transducing sensory signals in response to harmful stimuli. Nociceptive nerves send electrical impulses from the damaged site via a pathway called the spinothalamic tract, which eventually terminates in the sensory cortex of our brains. It is then that pain is perceived and experienced.

Problems arise when pain is continuously felt without the presence of harmful stimuli. This pain, known as chronic pain, no longer serves a protecting role and instead becomes pathological and debilitating. Chronic pain can arise after damage to the nociceptors transducing the signals in the periphery. This neuropathy can result in the unprovoked firing of nociceptive signals, despite the original injury having healed. Chronic pain can persist for months to years and so far has proven difficult to treat pharmacologically. Up until now, over the counter painkillers such as aspirin and narcotic analgesics such as morphine have been used in pain management. However, the efficacy of drug therapies vary for individuals and issues surrounding tolerance and addiction have limited their success. Over 10% of adults in the UK are affected by chronic pain and the debilitating, stressful nature of the condition has emphasized the requirement for newer, more effective treatments.

Recently, research surrounding the management of chronic pain has diverted from pharmacological intervention and instead has focused its efforts on specifically silencing individual peripheral nociceptors that become over active in chronic pain conditions. The current approved approaches include the use of the Botulinum toxin to suppress the secretion of chemical signals called neurotransmitters from nociceptors to inhibit pain signal transmission. This strategy, however, indiscriminately blocks peripheral nerves, hence lowering its efficacy as a pain management technique. In recent years, the emergence of Optogenetics as an approach to selectively target the nociceptors using light has overcome these previous drawbacks, and proves an exciting possibility for chronic pain treatment.

What is Optogenetics?

Optogenetics is the use of light to selectively control neural activity. Light activated protein channels, known as opsins, can be targeted to enhance or disrupt neuronal firing.

When exposed to a flash of light these channels open, allowing ions to enter the cell. Depending on the type of opsin used, positive or negatively charged ions will enter. The more positive ions inside a neuron, the more likely it is to fire and send signals to other neurons. The more negative ions inside, the less likely it is to fire.

In the context of (chronic) pain transmission, researchers believe nociceptors are hyper-excitable, uncontrollably sending nociceptive signals to the sensory cortex, resulting in constant pain. In order to reduce the frequency of signals, these neurons must be inhibited. This is where Optogenetics comes into play. By inserting an ‘off’ light sensitive channel into the nociceptor, the influx of negatively charged ions leads to hyperpolarization, suppressing its activity.

The first few attempts to control nociceptors using Optogenetics were successful yet limited to in vitro preparations rather than freely moving, living mice. Further technological advances meant neuroscientists could successfully insert the genes encoding for these opsins into mice genomes. The transgenic mice produced express these channels in their nerves as if they were their own. Scientists then induce pain conditions in these mice, and via light stimulation opsins are activated and pain perception is suppressed.

Since these attempts, the technique has come a long way. The use of viral vectors to deliver the opsin genes to the target nociceptors has made the technique more accessible and applicable to humans, without the need for transgenics. In a recent study, the viral delivery of Halorhodopsin successfully resulted in the inhibition of pain when exposed to light in freely moving mice (Iyer et al, 2014). Induced pain conditions such as hyperalgesia (increased sensitivity to pain) were reversed. A simple viral injection and flash of light relieved the suffering of constant pain.

Human Application

Despite numerous animal studies yielding positive results, two major challenges limit the clinical application in humans – the light delivery method and opsin duration. Transdermal light activation avoids invasive procedures, however skin thickness and the need for constant illumination poses problems. So far, the use of short acting opsins has limited the technique to acute pain conditions only. If longer lasting opsins were used, more complex, chronic pain conditions could be targeted.

Recently this year, the sustained inhibition of nociceptors using transient transdermal light activation was achieved. In the 2016 study (Iyer et al, 2016), a newly developed inhibitory Channel rhodopsin (SwiChR) was inserted into the sciatic nerves of mice. The channel, with slow acting kinetics, leads to the persistent inhibition of pain long after the (blue) light activation. The inhibition is sustained over long periods without the need for constant illumination, something that has never been achieved before.

These significant findings take us one step closer to the clinical translation of Optogenetics as a pain management strategy in humans. Further research and improved technologies are needed before human application, and questions surrounding the longevity and practicality of Optogenetics require answers. For those suffering from chronic pain, new advances can’t come fast enough and Optogenetics proves an exciting new possibility for those with constant, untreatable pain.

 

Autor: Rachel Coneys

Editor: Molly Campbell

References

Action on Pain, 2015. About Chronic Pain [Online]. Available from: http://www.action-on-pain.co.uk

 

 

Iyer, S.M., Montogomery, K.L., Towne, C., Lee, S.Y., Ramakrishnan, C., Deisseroth, K., and Delp, S.L., 2014. Virally mediated optogenetic excitation and inhibition of pain in freely moving non-transgenic mice. Nature Biotechnology [Online]. 32(3): p274-278

 

 

Iyer, S.M., Vesuna, S., Ramakrishnan, C., Huynh, K., Young, S., Berndt, A., and Delp, S.L., 2016. Optogenetic and chemogenetic strategies for sustained inhibition of pain. Scientific Reports [Online]. 6:30570

 

 

Sim, W.S., 2011. Application of Botulinum Toxin in Pain Management. The Korean Journal of Pain [Online]. 24(1): p1-6

 

Engineered Neural Networks

Introduction to Neuroengineering

The integration of neuroscience and engineering is a relatively new discipline where scientists aim to invent unique methods of aiding patients with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, in addition to various types of brain injury. Although the human brain possesses sensory, motor and cognitive capabilities, a major limitation is the ability to repair itself in response to strokes, chronic neurodegeneration etc. This ultimately leads to a persistence of functional deficits. In an attempt to enhance and restore human function, scientists are able to collaborate Neuroscience and Engineering by creating artificial devices including neuroprosthetics and brain-computer interfaces. Such devices directly interact with the nervous system and have been used to assist research related to the understanding of coding and processing of the sensory and motor systems in both healthy and pathological states.

Central nervous system (CNS) injuries induce tissue damage, creating barriers to regeneration. One of the main barriers is the glial scar, consisting predominately of reactive astrocytes and proteoglycans. Axons cannot regenerate beyond the glial scar, and they take on a dystrophic appearance of stalled growth.1 An example of neuroengineering in action includes some relatively recent research conducted at the Penn Medicine’s department by D. Kacy Cullen (assistant professor of Neurosurgery) and his team, involving the engineering of neural networks.

Neural Networks

An axon is one of the four distinct regions of a neurone – the functional unit that makes up the mammalian nervous system. The remaining 3 regions include the dendrites, cell body and the axon terminal (Figure 1). Dendrites are outward extensions of the cell body that are specialised to receive chemical signals from the terminals of other neurones. These signals are then converted into small electric impulses which are transmitted inwardly in the direction of the cell body. The impulses travel down the axon, specialised for the conduction of an electrical impulse called the action potential, at speeds of up to 100 metres per second. The length of the axon varies, with some reaching lengths of more than a metre long in humans. A single axon has the ability to communicate with multiple neurones throughout the CNS through sites called synapses, forming complex connections that regulate the body’s signal transmission.2

 

neuron.jpg

Figure1 – The information flow through neurones. http://www.uic.edu/classes/bios/bios100/lectures/nervous.htm

Populations of neurones are connected via axons, long projections that enable complex brain function to occur. When these axon pathways are broken or damaged, the effects on the human brain are detrimental. Previous regenerative medicine strategies produced to repair the CNS focus mainly on cell-based therapies. However, these therapies lack control of differentiation and specificity required for precise reconnection of long distance pathways.2 As a result, more unique approaches have been attempted using biomaterials and cellular scaffolds to enhance axonal regrowth as discussed below.

The research performed by Cullen et al. included working on pioneering developing technologies to restore neural circuits. They created replacement connections in a lab referred to as micro-tissue engineered neural networks (micro-TENNs). This novel class of preformed tissue engineered constructs were designed for both neuronal and axonal tract replacement upon transplantation and functional integration with the brain.3 The engineered tissue can be thought of as living scaffolds that allow the combination of neural cells and biomaterials to produce constructs with a 3D axonal cytoarchitecture. The aims of the micro-TENNs were to facilitate regeneration by directly replacing and modulating neural circuits, in order to restore nervous system function. They achieved this by mimicking the structure of broken axon pathways.

Although the team were the first to demonstrate successful integration of micro-TENNS into brain structures to reconstitute altered brain pathways, further improvement was required. The main issue was the method of delivery, with the current method being invasive. The team took this on board by developing a strategy that allowed the encapsulation of fully formed engineered neural networks to insert into the brain without the use of needles. Not only did this reduce the implant footprint, but it proved to be a more hospitable environment for implanted neurones to integrate within the CNS.

Summary

Cullen et al. produced a promising strategy capable of simultaneously restoring lost neuronal populations following CNS degeneration. Their current work provides a stepping stone for in vivo studies in the future regarding the treatment of a range of neurological disorders and neurodegenerative diseases through the application of engineering techniques into neuroscience. To read the article in more depth or gain access to more research on Neuroengineering, here’s a link to the journal by Cullen et al. published in the Journal of Neural Engineering: http://www.ncbi.nlm.nih.gov/books/NBK21535/

 

Author: Aisha Islam

References

1 – Silver J & Miller J.H. 2004. Regeneration beyond the glial scar. Nature Reviews Neuroscience. [Online]. 5, pp.146-156. [Accessed 20 September 2016]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14735117

2 – https://www.sciencedaily.com/releases/2016/01/160120201330.html

3 – Cullen D.K. & Harris J.P et al. 2016. Advanced biomaterial strategies to transplant preformed micro-tissue engineered neural networks into the brain. Journal of Neural Engineering. [Online]. 13(1). [Accessed 30 July 2016]. Available from: http://iopscience.iop.org/article/10.1088/1741-2560/13/1/016019/meta;jsessionid=72E9729F95579833734F65A02B388FE0.c2.iopscience.cld.iop.org