Neurology

On the nature of pain

Posted on by Iasmina Hornoiu

Last week, a manatee was found in Florida waters, with the word ‘Trump’ scraped on its back. Although this kind of ruthless mutilation is horrific in itself, I started wondering if the animal felt any kind of pain.

I must admit, up until I came across the news about what happened to the manatee in Florida, I knew very little about manatees, in general. And my first thought was whether, during the scraping proccess, this manatee suffered at all. To my dismay, there were not many scientific papers dealing with the somatosensory system in manatees. However, I did find something that eased my soul a little bit: one of the articles reporting on the dreadful event states that the scratch was done in the algae growing on the animal’s back. Still, in the same article it is said that manatees have sensory hairs and nerves in their skin, which means that, if the cuts had touched the skin, they could have caused pain; not to mention the infection that the skin was at risk of, due to the open wounds.

The video below shows the above-mentioned manatee swimming, with the human-made scars on its back.

After reading all these news articles, I was left with some questions that kept occupying my mind: What are manatees?; To what extent can they feel pain?; And can we talk about ‘pain’ at all in manatees, or just nociception? Lastly, how did pain evolve throughout the animal kingdom?

What are mantees?

Also known as ‘sea cows’, manatees (Trichechus manatus latirostris) are herbivorous acquatic mammals of the Order Sirenia. As the name of their order suggests, manatees are believed to be the animals behind the myths of mermaids. For those interested in how manatees inspired mermaid legends, please check out the video below.

Manatees are the largest vegetarian animal to inhabit the sea, and they communicate with each other through high-pitched sounds. They are also very gentle and lack defense mechanisms, given that they do not have any natural enemies. However, they have become and endangered species, due to human activity, which is the manatee’s greatest threat. According to the Florida Fish and Wildlife Conservation Commission, the year 2020 was a hard one for manetees as well: 637 of them died, 90 of which were victims of boat collisions, and another 15 were killed by other interactions with humans.

Although manatees do not possess a highly acute visual system, they compensate for that by the presence of tactile hairs, or vibrissae, spread all over their body, especially on the face. This distribution of vibrissae is something unique among mammals, and to manatees it is highly useful in allowing them to navigate in the water.

Since mantees rely tremendously on tactile inputs, it comes as no surprise that their brains are organised to support somatosensation. The primary somatosensory cortex of manatees occupies 25% of their neocortex. Moreover, the sixth layer of their cortex contains clusters of neurons, known as Rindenkerne, which are believed to process information related to the manatee’s facial and bodily vibrissae. Although the Rindenkerne cells of manatees are somewhat similar to other cortical representations of vibrissae, termed ‘barrels’, in rodents, shrews, opposums and hedgehogs, Rindenkerne are unique to sirenia. These neuronal aggregates become active when manatees engage in tactile exploration and object recognition.

At the subcortical level, manatees possess three types of somatosenroy nuclei in their brainstems, namely the Birchoff’s nucleus, which receives information from flukes, the cuneate-gracile nucleus, which processes inputs from flippers and body trunk, and the trigeminal nucleus, which receives sensory inputs from facial vibrissae. Figure 1. below shows the somatosentory representations of the manatee’s body parts, in a coronal section of the brainstem. The thalamus also has specialised somatosensory nuclei, which differ in size, depending on their functional relevance to somatic sensation.

Figure 1. Left diagram based on image by Isuru Pryiaranga. Right image from Sarko et al. (2007), showing functional divisions withing the brainstem, corresponding to the manetee’s body parts. 

Given that somatosensation is so developed in manatees, one burning question is whether they feel pain.

What is pain?

Pain is different from nociception. However, pain from injury cannot occur without nociception. The latter reffers to the process of detecting injury by the activation of a special class of receptors found in the skin, as well as deep tissues and organs, known as nociceptors. The detection of potentially or actually damaging stimuli is followed by a reflex withdrawal reaction, or nociceptive behaviour, mediated by nerves in the spinal cord. The nerve fibres that detect noxious stimuli are Aδ fibres and C fibres, which have their cell bodies in the dorsal root ganglion (DRG) of the spinal cord, as shown in Figure 2.

Figure 2. Illustration taken from a student presentation at Heidelberg University, Germany.

Aδ fibres are mechano-nociceptors, meaning that they are activated by high mechanical pressures. C fibres are polymodal, which means that they respond to a variety of noxious stimulations, such as noxious chemicals (e.g., acids), extreme temperatures and high mechanical pressures. They not only encode the stimulus modality (type), but also their intensity and duration, which are relayed to reflex centres in the central nervous sytem, mediating withdrawal reactions.

The nociceptive information travels from the DRG to different parts of the brain via spinothalamic tracts (from the spinal cord to the thalamus) and sensory fibres of the trigeminal tract (from the face to the thalamus). And it is within the brain that pain happens.

Pain is a complex feeling. Many brain areas are involved in not just generating pain, but also in ameliorating it. Structures from the limbic system, such as the amygdala, receive and integrate nociceptive and affect-related information. The amygdala can lead to increased nocifensive and affective pain behavior, while, under certain circumstances, it can also contribute to endogenous pain inhibition. Pain is also processed in the hypothalamus, the basal ganglia, the insula and the somatosensory cortices. Because these areas play a role in metabolism, as well as fear, pleasure and homeostasis, the nociceptive information is integrated and modulated according to the current state of the individual. In some situations, pain becomes pathological, as it is the case in neuropathic pain, where either previously innocuous stimuli become painful (aka, allodynia), or previously painful stimuli become even more painful (aka, hyperalgesia).

There are two brainstem structures, which are highly involved in controlling pain and generating analgesia. One of them is the periaqueductal grey (PAG) and the other is the rostral ventromedial medulla. These regions exert control over pain to prioritise competing stimuli, and to maintain homeostasis and survival. You might have noticed that, in highly stressful situations you do not feel pain. This is known as stress-induced analgesia, a phenomenon whereby the brain responds to stress by the production of endogenous opioids that act as natural analgesics in the nervous system. The opioid receptors found in the brain are the same ones which analgesic drugs, such as synthetic opioids and morphine, act on to relieve pain.

The evolution of pain

Many animal taxa have nociceptors. A schematic of the evolutionary development of nociceptors and the types of noxious stimuli they respond to is presented in Figure 3. In order to process nociceptive inputs, animals need a central nervous system (spinal cord and brain). It might come as a surprise that such a system, though at different levels of complexity, is found in all kinds of animals, including insects (like Drosophila melanogaster, the fruit fly), C. elegans (a type of worm highly studied in neurosciences), fish, amphibians, reptiles, birds and, of course, mammals.

Figure 3. The different types of nociceptors across animal taxa, from an evolutionary perspective.
Taken from Sneddon (2017)

Life-history shapes pain perception. A very interesting example is the African naked mole rat, which lives in underground burrows that are poorly ventilated, hence contain high carbon dioxide levels. As a result, the C fibres of the naked mole rat are unresponsive to acid, which means that, while other mammals find acidic environments nociceptive, the African naked mole rat does not.

When it comes to acquatic animals, such as manatees, they are expected to have differences in their sensory system compared to terrestrial ones, due to distinct ecological and evolutionary pressures. In water, any chemicals become dilluted, shifts in temperatures are less common, and there is no mechanical damage due to falling. Thus, acquatic animals are possibly at a lower risk of damage than terrestrial animals, which has implications on their nociceptive system.

As far as manatees go, it is still unclear to what extent they feel pain. The fact that they are an endangered species makes is difficult to study them. But given that they posses a very well-developed somatosensory system, which is even more advanced than in other mammals, it is expected that manatees are familiar with pain. Moreover, we still do not know enough about their stress, fear, memory and pleasure systems, which all play a role in pain processing.

It would be great if we managed to achieve a better understanding of these amazing marine animals. But, until then, let us enjoy their existance peacefully, without interfering violently with their lifestyles and without exposing them to any potential pains.

For a more in-depth view on pain, as well as more information about manatees, I highly encourage you to read the papers and articles listed in References.

Special thanks to Isuru Priyaranga for creating the cover image. He is a fellow blogger and YouTuber, and I highly recommend visiting his blog and YouTube Channel.

References

The biology of meditation. How meditating can change your brain

Posted on by Iasmina Hornoiu

Many of us are already familiar with what it means to meditate, in a broad sense, and we have often heard that meditation can improve our lives. Several books and articles have been written on the positive effects exerted by meditation on our bodies and minds. But what is the nature of meditation and how can it help us improve our mental states? More specifically, what happens at the level of neural networks, brain cells and molecules that results in all these beneficial actions upon meditating?

This being human is a guest house. Every morning a new arrival. A joy, a depression, a meanness, some momentary awareness comes as an unexpected visitor. Welcome and entertain them all! […] The dark thought, the shame, the malice. Meet them at the door laughing and invite them in. Be grateful for whatever comes. Because each has been sent as a guide from beyond.

The Guest House by Rumi. Translation by Coleman Barks

FIGURE 1 |Sigiriya rock located near the Dambulla town, in the Central Province, Sri Lanka. Own image.

An introduction to meditation ~ its styles and purposes

Meditation encompasses various emotional and attentional regulatory practices, which aim at improving an individual’s cognitive abilities. Many recent behavioral, electroencephalographic and neuroimaging studies have investigated the neuronal events related to meditation, in order to achieve an increased understanding of cognitive and affective neuroplasticity, attention and self-awareness, as well as for their possible clinical implications.

The video below shows the kind of brain changes meditation leads to, in a monk who is a long-term practitioner.

According to Raffone and Sirivasan (2010), a central feature of meditation is the regulation of attention, and as such, meditation practices can be classified into two main styles—focused attention (FA) and open monitoring (OM)—depending on how attentional processes are directed. While the FA (‘concentrative’) style is based on focusing attention on a given object in a sustained manner, the second style, OM (‘mindfulness-based’) meditation, involves the non-reactive monitoring of the content of ongoing experience. More specifically, mindfulness refers to being constantly aware of the way we perceive and monitor all mental processes, including perceptions, sensations, cognitions and affects.

FA meditation techniques imply, apart from sustaining the attention on an intended object, monitoring attentional focus, detecting distraction, disengaging attention from the source of distraction, and (re)directing attention (back) on the object. This kind of attentional stability and vividness is achieved through concentrated calmness or serene attention, denoted by the word Samatha (which literarily means quiescence) in the Buddhist contemplative tradition. Another technique which can be broadly included in the FA meditation is transcendental meditation, which centers on the repetition of a mantra.

Unlike FA meditation, OM meditation does not involve an explicit attentional focus, and therefore does not seem to be associated with brain areas that control sustained or focused attention. Instead, OM meditation engages brain regions implicated in vigilance, monitoring and detachment of attention from sources of distraction from the ongoing stream of experience. Therefore, OM meditation is based on detecting arising sensations and thoughts within an unrestricted ‘background’ of awareness, without a ‘grasping’ of these events in an explicitly selected focus. In the transition from a FA to an OM meditative state, the object as the primary focus is gradually replaced by an ‘effortless’ sustaining of an open background of awareness, without an explicit attentional selection. In the Buddhist tradition, the practice of Vipassana (insight) OM meditation requires, first of all, attentional stability and vividness (acuity), as developed in FA meditation, in order to achieve a deep and reliable introspection.

The ancient yogic practice of Yoga Nidra, which is less-known, and yet is becoming increasingly popular, can also fall into the category of OM meditation. It is said to reduce stress and improve sleep, and that it has the potential to engender a profound sense of joy and well-being.

Another type of OM meditation worth mentioning here is the loving-kindness meditation or non-referential compassion (also known as Mettā in the Pali language), which involves compassion-based mental training aimed at promoting empathy. Practicing this kind of meditation is believed to increase the capacity for forgiveness, connection to others and self-acceptance, and to boost well-being and reduce stress. For more detailed descriptions as well as a deeper and broader understanding of the neurological implications of these different meditation practices, I strongly encourage you to check out the reviews listed in the Reference section, especially Brandmeyer et al. (2019) and Raffone & Srinivasan (2010).

Of all these different kinds, mindfulness meditation, which originally stems from Buddhist meditation traditions, has received the most attention in neuroscience research over the last twenty years.

Research over the past two decades broadly supports the claim that mindfulness meditation — practiced widely for the reduction of stress and promotion of health — exerts beneficial effects on physical and mental health, and cognitive performance. 

Tang et al. (2015)

Sustained engagement with mindfulness meditative practices has been shown to have neurophysiological and psychological benefits. In healthy individuals, several months of mindfulness meditation practice correlates with improvements in self-regulation and subjective well-being. Even much shorter mindfulness meditation training, of a few days, has a positive impact on mood and executive functioning, while at the same time reducing fatigue and anxiety.

Brain structural changes following mindfulness meditation

Several recent studies have investigated the structural changes in the brain related to mindfulness meditation, and have reported alterations in cortical thickness, hippocampal volume, and grey-matter volume and/or density. However, before we dive into how meditation can change our brains, it should be mentioned that there are a few issues with the current state of meditation research. First of all, most of these studies have made cross-sectional comparisons between experienced meditators and controls. But only a few recent studies have investigated longitudinal changes in novice practitioners. These logitudinal studies are very important because they follow subjects over a long-term period of practice, and are thus able to determine whether changes induced by meditation training persist in the absence of continued practice. Therefore, more such studies would be required for a complete picture of the effects of meditation on mental health.

In addition, the studies on mindfulness meditation so far have generally included small sample sizes, of between 10 and 34 subjects per group, which leads to limitations in interpreting the results, as well as increases the chances of false-positives. Another prossible issue is that these studies use different research designs, measurements and type of mindfulness meditation. Hence, it comes as no surprise that the reported effects of meditation are diverse and cover multiple regions in the brain, including the cerebral cortex, subcortical grey and white matter, brain stem and cerebellum. That being said, these findings can also reflect the fact that the effects of meditation involve large-scale and interactive brain networks.

According to various fMRI studies, minfulness meditation exerts its effects primarily (though not exclusively) on a network of brain regions – the Default Mode Network (DMN). This network comprises structures in the medial prefrontal cortex (PFC), posterior cingulate cortex (PCC), anterior precuneus and inferior parietal lobule, which have been previously shown to have high activity during rest, mind wandering and conditions of stimulus-independent thought. These regions have been suggested to support different mechanisms by which an individual can ‘project’ themselves into another perspective.

When comparing meditators with naïve subjects, DMN regions, such as the medial PFC and PCC, have shown much less activity in meditators, across different types of meditation. This has been interpreted as indicating diminished self-referential processing. Experienced meditators also seem to exert stronger coupling between the PCC, dorsal anterior cingulate cortex (ACC) and dorsolateral PFC, both at baseline and during meditation, which indicates stronger cognitive control over the function of the DMN.

Brewer et al. (2011) investigated brain activity in experienced meditators versus meditation-naïve controls as they performed several different mindfulness meditations (Concentration, Loving-Kindness, Choiceless Awareness). They found that the main nodes of the DNM (medial PFC and PCC) were relatively deactivated in experienced meditators across all meditation types (Figure 2). Moreover, functional connectivity analysis revealed increased coupling in experienced meditators between the PCC, dorsal ACC, and dorsolateral prefrontal cortices, both at baseline and during meditation, as seen in Figure 3. This increased connectivity with medial PFC regions supports greater access of the default circuitry to information about internal states, because this region is also highly interconnected with limbic regions (such as insula and amygdala).

FIGURE 2 | Experienced meditators demonstrate decreased DMN activation during different meditation conditions: Choiceless Awareness (green bars), Loving-Kindness (red), and Concentration (blue) meditations. The decreased activation in PCC in meditators is common across different meditation types. Brain activation in meditators > controls is shown, collapsed across all meditations, relative to baseline (A and B). Activations in the left mPFC and PCC (C and D). Taken from Brewer et al. (2011)

FIGURE 3 | Experienced meditators show coactivation of mPFC, insula, and temporal lobes during meditation. Differential functional connectivity with mPFC seed region and left posterior insula is shown in meditators > controls: (A) at baseline and (B) during meditation. (C) Connectivity z-scores (±SD) are shown for left posterior insula. Choiceless Awareness (green bars), Loving-Kindness (red), and Concentration (blue) meditation conditions. Taken from Brewer et al. (2011)

Meditators also reported significantly less mind-wandering, which has been previously associated with activity in the DMN. Therefore, these results demonstrated that alterations in the DMN are related to reduction in mind-wandering. They also suggested that meditation practice may transform the resting-state experience into one that resembles a meditative state – a more present-centered default mode.

The findings from this study have several clinical implications, given that a number of pathological conditions have been associated with dysfunction within areas of the DMN, including depression. The self-referrential function of the DMN has pointed to the possibility that excessive rumination (negative inner preoccupation about the personal past, present and future) in depression involves excessive DMN activity as well as an inability to switch out of it, in response to external demands. Mindfulness meditation may prove useful in reducing distractive and ruminative thoughts and behaviors, and this ability may provide a unique mechanism by which mindfulness meditation reduces distress and improves mood.

In addition, meditation has also been shown to promote neuroplasticity, an important neuronal process that entails structural and functional brain adaptations in response to changes in environmental conditions. A key neurotrophin that promotes neuroplasticity is the brain-derived neurotrophic factor (BDNF), which is usually found in abnormally low levels in various psychiatric and neurological disorders. Meditation has been shown to increase the levels of BDNF, thus promoting neuronal development, survival and plasticity, which in turn contribute to restoring the normal functioning of brain networks.

In sum, there is emerging evidence that mindfulness meditation might trigger neuroplastic changes in brain regions involved in the regulation of emotion and cognition. Although, as mentioned earlier, these studies often suffer from low methodological quality and present with speculative post-hoc interpretations, this is quite common in a new field of research. Thus, further research needs to use longitudinal, randomized and actively controlled research designs and larger sample sizes, as well as to concentrate on the biological factors implicated in mental health, in order to advance the understanding of how mindfulness meditation interacts with the brain. If supported by rigorous research, the practice of mindfulness meditation might be a promising therapeutic approach for clinical disorders, such as depression, and might facilitate the cultivation of a healthy mind and improved well-being.

For the readers interested in the effects of meditation on depression, please visit my article The biological implications of meditation practices in the treatment of depression.

References

  • Brandmeyer, T., Delorme, A., Wahbeh, H. (2019). Chapter 1 – The neuroscience of meditation: classification, phenomenology, correlates, and mechanisms, Editor(s): Narayanan Srinivasan, Progress in Brain Research, Elsevier, 244: 1-29. doi: org/10.1016/bs.pbr.2018.10.020
  • Brewer, J.A., Worhunsky, P.D., Gray, J.R., Tang, Y.Y., Weber, J., Kober, H. (2011). Meditation experience is associated with differences in default mode network activity and connectivity. Proc Natl Acad Sci U S A, 108(50):20254-9. doi: 10.1073/pnas.1112029108
  • Kabat-Zinn, J. (2003). Mindfulness-based interventions in context: past, present, and future. Clin Psychol Sci Pract 10:144–156
  • Heuschkel, K., & Kuypers, K.P.C. (2020). Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review. Front. Psychiatry, 11:224. doi: 10.3389/fpsyt.2020.00224
  • Raffone, A., & Srinivasan, N. (2010). The exploration of meditation in the neuroscience of attention and consciousness. Cognitive Processing, 11:1-7. doi: 10.1007/s10339-009-0354-z.
  • Tang, Y.Y., Hölzel, B.K., Posner, M.I. (2015). The neuroscience of mindfulness meditation. Nat Rev Neurosci, 16(4):213-25. doi: 10.1038/nrn3916
  • Zeidan, F., Johnson, S., Diamond, B., David, Z., & Goolkasian, P. (2010). Mindfulness meditation improves cognition: Evidence of brief mental training. Consciousness and Cognition, 19, 597-605. doi: org/10.1016/j.concog.2010.03.014.

Fear and the amygdala

Posted on by Iasmina Hornoiu

What is fear? Why are we sometimes afraid? Can fear be inhibited? What produces fear – the brain or the heart?

It is definitely the brain! More exactly, something in the brain – a tiny, almond-shaped structure, which sits anteriorly to the hippocampus, called the amygdala. This small part of our brain is to blame for  the perception of fearful stimuli and the physiological responses (increased heart rate, electrodermal responses etc.) to fearful stimuli.

As part of the FEAR system, the amygdala connects to the medial hypothalamus and the dorsal periaqueductal grey matter (in the midbrain), which is important in pain modulation in the dorsal horn of the spinal cord, as well as to sensory and association cortices. The lateral nucleus of the amygdala receives inputs from different brain regions, thus allowing the formation of associations, required for aversive conditioning. Following the processing in the lateral nucleus, information about the stimulus is, then, projected to the central nucleus of the amygdala, where an appropriate response to the stimuli is initiated, provided that the stimuli are detected as threatening or potentially dangerous.

The amygdala is involved in emotional learning and memory, modulating implicit learning, explicit memory, attention, social responses, emotion inhibition and vigilance.

You can find the article on memory here, to brush up a bit.

  • Implicit memory is a type of learning, which cannot be voluntarily reported or remembered. It includes the memories for skills and habits, for procedural knowledge, grammar and languages, priming, simple forms of associative learning and classical conditioning. The latter is particularly important for fear. It involved a conditioned stimulus (CS) and an unconditioned, painful/fearful stimulus (US), with US preceding CS and determining a fearful response to CS. This type of fear learning is adaptive and is known as sensitisation or acquisition.

There are two different pathways in the amygdala, important for fear conditioning. The “low road” pathway: sensory information projects to the thalamus, which directly communicates with the amygdala; this pathway is fast, modulating rapid responses of the amygdala to different types of fearful stimuli. The “high road” pathway is an indirect pathway: sensory information projects to the thalamus and from there, it is conveyed to the sensory cortex for a finer analysis; the sensory cortex, then, communicates the processed information to the amygdala. This pathway ensures that the sensory stimulus is the conditioned stimulus. So the responses of amygdala to threatening stimuli are both rapid and sure.

  • Explicit memory refers to the memory of facts and events; in the case of fear is means the processing and retention for a long time, of emotional events and information. For this type of fear learning, the amygdala interacts with the hippocampus. There is a distinction between the formation of memory for aversive experience (fear conditioning), which is based on previous experience, and explicit learning (in the hippocampus), which involves learning and remembering aversive properties of different threatening stimuli. The memory in the hippocampus is enhanced by arousal produced in the amygdala. The activation of the amygdala can make different cortical areas, not just the hippocampus, more receptive to stimuli that are adaptively important, thus ensuring that unattended, but important stimuli gain access to consciousness.
  • Social responses involve the ability to recognise a stimulus as good, bad, neutral or arousing. This ability, however, does not depend on the amygdala. There is one exception here, otherwise we wouldn’t be talking about it in the context of fear mediated by amygdala – fearful facial expressions. According to Darwin, social species, like humans, use facial expressions to detect internal emotional states of other members of the group. This function, mediated by the amygdala, is crucial in the emotional regulation of human social behaviour. Damage to amygdala has been demonstrated to result in impairment of the patient to identify fearful faces correctly and, therefore, react to them, accordingly. It should also be noted there is no need for the subject’s awareness of the fearful stimulus, for the amygdala to respond. In other words, when a fearful facial expression is presented subliminally, the amygdala will still show activation.
  • Inhibition of fear – it is actually very difficult to escape your own fears, as fear proves to be resistant to voluntary control. However, there is a process called extinction, a method of classical conditioning, where a CS previously associated with an aversive US in presented alone for a number of times, until the CS no longer signals the fearful stimulus. If the US is presented again, after the passage of time, it will evoke fear responses, but in different brain areas. So, the learned fear has been retained in memory, but extinction learning eliminates the response to fear. This mechanism of extinction relies on the activity of NMDA glutamate (excitatory) receptors in the amygdala. When these receptors are blocked, extinction is inhibited (so you will react to fearful stimuli) and when they are active, extinction is augmented (you no longer respond to aversive stimuli).
  • Vigilance – the amygdala is not necessary for the conscious experience of emotional states, but it plays a major role in increasing the vigilance of cortical response systems to emotional stimuli.

Memories about fearful events, just like other types of long-term memory, become permanent through a process of gene expression and novel protein synthesis, which is known as consolidation. Upon retrieval, the memories become susceptible to change and alteration, before they are reconsolidated, which involves additional protein synthesis.

The fact that humans (and probably other animals as well, I am sure, although not widely proven) have the ability to distinguish between emotional information and unemotional information is regarded as an evolutionary advantage. Emotional stimuli signal dangers and the ability to detect and appropriately react to them increases the chance of survival. However, exacerbated fear is detrimental to the individual who experiences it and is a sign of pathology. For instance, in atypical monopolar depression, which includes anxiety as one of the main symptoms, the amygdala is overactive and it determined lowering the threshold for emotional activation and abnormal reactions to stressful stimuli. A similar pattern can be seen as a result of partial chronic sleep deprivation or complete acute sleep deprivation.

References

 Beatty, 2001. The Human Brain – Essentials of Behavioural Neuroscience, Sage Publications Ltd., pg. 293-296

Bernard et al., 2007. Cognition, Brain and Consciousness – Introduction to Cognitive Neuroscience. 1st edition. Elsevier Ltd., pg. 373-383

Gazzaniga et al., 2002. Cognitive Neuroscience – The Biology of Mind. 2nd edition. W.W Norton & Company, Inc., pg. 553-572

Image by  Saya Lohovska. You can find her arts page here.

Consciousness – Who decides, 𝘺𝘰𝘶 or your brain?

Posted on by Iasmina Hornoiu

If you were to answer the question “What differentiates humans from other organisms on Earth?”, you would probably list a number of things, including the ability of humans to make “free choices” dictated by their consciousness, rather than by something organic. Am I right?

What if someone told you that this is not actually the case? I mean, what if instead of making decisions out of your own will, your brain is “deciding” for you and only after the decision has been made the brain offers you the illusion of conscious act, making you believe that you were the one who made the choice in the first place. But how is it possible that such a dichotomy exists within ourselves, between us and our own brains? Aren’t we our brains? Apparently not!

Now that I (hopefully) managed to capture your attention, I’d like to bore you a bit with some brain structure names and functions, which are necessary in order to begin to understand what’s going to come next.

The frontal lobe contains a few areas, which are involved in planning our movements, decision-making, emotions (usually associated with the decisions we are about to make), repeating previously memorised motor sequences etc. These are the areas involved in voluntary motor control, more specifically, these are the areas that make the difference between reflexes/automatisms and movements or actions we want to pursue. Moreover, all these motor areas are interconnected and also linked to areas that are part of the sensory pathways, such as the parietal , visual, somatosensory and temporal regions (which store different components of visual, auditory and somatic stimuli and are associated with many diseases, such as the inability to feel your own limbs, or recognising faces/objects etc.).

  • The primary motor cortex (PMC) is mainly involved with the execution of movements. Populations of neurones in there encode for the direction and amplitude of the movements we make, prior and during the execution.
  • The 6 pre-motor cortices, the ventral, medial (supplementary) and dorsal areas are mostly involved with planning our movements. They receive inputs from the cerebellum and basal ganglia, which play very important roles in motor learning (like acquiring new skills) and motor planning. Interestingly, different neurones in the pre-motor areas fire action potentials during execution and are inactive during planning of movements and others vice-versa, while some populations of neurones are active for both planning and execution.
  • The prefrontal cortex controls reasoning and decision-making and it is crucial for emotion as well: recall Phineas Gage’s story and how the damage to his prefrontal cortex resulted in a complete change in his personality (article here) as well as how the prefrontal cortex regulates the activity in the hypothalamus and is disrupted in major depressive disorder (article here). 
  • The limbic system (amygdala, anterior cingulate cortex, hippocampus) , which are located at the subcortical level and behind the frontal lobe, are involved with emotion, fear and the formation of memories, which are so important in our decision making. And these are just the main players, but there are many other areas, including sensory, which contribute to the planning of our actions and the choices we constantly make.

In a rather groundbreaking paper, Libet and colleagues showed that the neural processes leading to the initiation of voluntary movements begin several hundred milliseconds before the reported time of conscious intention to make the movements, as in before the subject is aware of the intention to move. They demonstrated using the readiness-potential (negative electrical potential recorded at the scalp) that brain activity involved in decision-making starts before our brains is conscious of the actions. This is also known as ‘preparatory set”.

Dick Swaab proposed that the unconscious brain areas are active before the conscious ones, in order to enable us to make decisions rapidly and effectively, as the conscious systems require time to process and analyse the pros and cons of every decision. And although it is good to consider the consequences of your actions, there are many other decisions about apparently insignificant things, which we make and need to be fast (like for example, running away from a car you see coming). In a dangerous situation, for example, the parts of the brain involved in consciousness might consider the state of your legs, how capable they are of moving fast at that point, your heart rate, blood pressure, levels of energy needed for that action…Well, by the time your brain finishes analysing all these, you will be most certainly dead.

Another interesting idea Swaab suggested was regarding the reason why we have consciousness of our actions and the things that happen to us in the first place. We need to be conscious of our own experiences so that we learn to avoid negative things in the future and also act upon things that require intervention, such as a wound that needs to be treated. Although the brain seems to be able to plan an action independently of our awareness of it, other brain areas are involved in the execution (as previously mentioned) and the communication between these different parts which fulfil different roles results in consciousness. Exactly why and how evolutionary biology has managed to make us more than just some purely mechanical creatures remains a mystery and still poses many challenges to this field of research, inviting philosophy to have its take on this matter, which many times has proved to be useful.

Swaab also wonders to what extent are criminals, pedophiles, murderers to blame for their bad actions, when it is in fact not them, but their unconsciousness/instincts that dictate them what to do. When considering that people with brain damage resulting in impaired or lack of consciousness (schizophrenia, dementia, multiple sclerosis etc.) sometimes hurt other and are not convicted, you might think that it is right to assume that all criminal acts should be tolerated. However, the difference here is that people not suffering from such disorders are aware of their actions and are capable of stopping them. Although pedophilia is considered a psychiatric disorder, unlike the neurodevelopmental and neurodegenerative ones, it can be controlled by the individual, so that the individual is able to refrain from acting according to his/her instincts. Libet and his team of researchers mention in their study that individuals, although only aware of the intention to make a particular action after the intention has been formed in their brains, are able to “abort the performance” of the action, meaning that they have a conscious “veto”.

They also emphasise the difference between spontaneous, rapidly performed actions, and actions in which a preplanning of the experience occurred (taking into account alternative choices, for instance). This second type of voluntary movements, involving conscious deliberation prior to the act, might actually rely on conscious initiation and control, rather than non-conscious commands. However, this hypothesis has not yet been proved experimentally, in a way the “unconsciousness before consciousness” one has.

So, as it turns out, most of the times we are aware of our brain’s decisions only after they have already been made, and free will seems to be an illusion.

References

Libet et al. paper

Antonio Damasio,1995. Decartes’ Error. Vintage Books, pp. 71-73

Dick Swaab, 2014. We are our brains – From the womb to Alzheimer’s. Penguin Books, pp.326-338

Image by Saya Lohovska. You can find her arts page here.

Depression and why some of us are SAD

Posted on by Iasmina Hornoiu

I am warning you, this is going to be a long one! But it’s interesting, I promise.

There is a lot of confusion and mixed opinions when it comes to depression. Some people use the term inappropriately, to describe what is in fact grief (the feeling of sadness that humans, and presumably other animals, experience after a loved one has died, for instance), others tend to label depressed individuals as “weak”, “selfish”, “useless”, “cowards” etc.

At the same time, for the past 30 years, there have been extremely important discoveries in the field of affective disorders, which have helped eliminate many misconceptions and laid the foundation for a better understanding of what this set of disorders (affective disorders) are and what is actually happening in the brain of the ones “affected”. Moreover, according to some new theories, depression is in fact an evolutionary advantage in situations such as physical illness and dominance. When the body is sick it needs time and energy in order to recover, so the organism experiences depression in order to avoid activity and focus on recovery; in nature, many animals with a dominant status are forced (by a variety of factors) to occupy a lower hierarchical level, in which case “depressive” behaviours such as avoiding eye contact or sexual contact helps reduce the risk of attack by other dominant, more powerful individuals. There are many theories, as you can see, and this article is meant to present and analyse some of them.

We should start by clarifying a very important aspect: depression is different from grief. While the latter is a normal reaction to some external factor(s) with a negative emotional impact on our day-to-day lives, and dissipates by itself after a certain period of time, depression is a pathological, abnormal condition (either in its own right or as a symptom of other metabolic or neurodegenerative diseases). However, it should be noted, and this is one of the key concepts in understanding depression, that the way individuals interpret and react to various external events, which affect their mood, differs, which means that some individuals have a stringer predisposition to depression than others. Now, why is that? A variety of factors, both genetic and epigenetic (developmental, such as child abuse, neglect) play a role and often act synergistically, but we will deal with them (especially, the genetic factors) a bit later in the article.

Different types of depression

Major depressive disorder, also known as “the classical depression”, which is characterised by insomnia, anorexia and lack of joy and interest in things. At the opposite side of the spectrum, there is atypical depression, which manifests itself through increased sleepiness, weight gain and anxiety. Dysthymia is another form of depression, more difficult to diagnose, due to the fact that it presents itself with mild depressive symptoms. All these types discussed so far have been categorised as monopolar.

Bipolar depression refers to a kind of depression accompanied by periods of mania – manic episodes are characterised by elevated, euphoric mood, impulsiveness, hyperactivity and even psychotic symptoms (hallucinations, delusions). A case described by Dick Swaab in his book “We are our brains – from the womb to Alzheimer’s” portrays a woman, who developed mania following the death of her husband. She would talk and laugh hysterically, call the police in the middle of the night for no reason and eventually began to make up stories about people whom she had never met before, but who she believed were longtime friends of hers. After her manic episodes disappeared as a result of treatment, she developed severe depression. Luckily, her story has a happy ending, as she made a full recovery.

Bipolar depression is also associated with Seasonal Affective Disorder (SAD), characterised by extreme mood seasonal swings. In this article, I have dedicated an entire section to SAD, so I am not going to delve into it for now. Given all these particularities of BD, it is often regarded as a separate disorder (bipolar disorder or manic disorder), rather than another type of depression. As there are so many things to mention about depression, I will leave BD for future article.

Diagnosing depression

In order to be diagnosed with depression, one must have at least one of the two main symptoms: persistent sadness and marked loss of interest, as well as at least five secondary symptoms: disturbed sleep (either increased or decreased), disturbed appetite (increased or decreased), fatigue, poor concentration, feeling of worthlessness and excessive guilt, suicidal thoughts.

Depending on the number of these symptoms, as well as the degree to which they manifest, monopolar depression can be sub-divided into: sub-threshold depression (fewer than five secondary symptoms; no treatment needed), mild depression (fewer than five, but in excess secondary symptoms), moderate depression (more than five, plus functional impairment between mild and severe depression) and severe depression (most of the secondary symptoms and also true psychotic symptoms – yes! they can occur in severe monopolar depression as well, not just BD).

Biochemical pathways and brain systems involved in depression

In Ancient Greece, there was a biochemical theory of depression. It was believed that depression was caused by the failure of liver to eliminate toxic substances from the digested food, resulting in the accumulation of “black bile” (melan means “black” and chole means “bile”, which give the words melancholy). Biochemical theories nowadays have at their core three monoamines, which I am sure you are all familiar with: noradrenaline (a neuromodulator very similar to adrenaline) and serotonin and dopamine.

These two substances have long and diffuse projections throughout the nervous system and in levels lower than otherwise normal, they are said to be involved in affective disorders. For example, drugs such as Reserpine, used to treat the positive symptoms of schizophrenia by depleting dopamine (and also serotonin and noradrenaline) elicited depressive symptoms in schizophrenic patients.

Therapies involving monoamines

The idea is, you want to higher levels of monoamines in order to treat depression. Enzymes involved in the monoamine re-uptake mechanism from the synaptic cleft back into the presynaptic level and enzymes involved in the monoamine metabolism, such as monoamine oxidases (MAO) are the most common targets for the majority of anti-depressants.

  • Selective serotonin re-uptake inhibitors (SSRI) and selective noradrenaline re-uptake inhibitors (SNRI) – Prozac (Fluoxetine), Zoloft (Sertraline), Celexa (Citalopram), Paxil (Paroxetine) block serotonin reuptake and Effexor/Viepax/Trevilor/Lanvexin (Venlafaxine), Cymbalta (Duloxetine) inhibit the noradrenaline reuptake enzymes. For those of you who are currently under this treatment, be careful! Side-effects such as sexual dysfunction, insomnia, increased aggression and self-harm/suicide can occur. Moreover, SSRI are not so effective. They have a very long induction, which means that it takes a long time (2-3 weeks) for the therapeutic effects to start working, during which time there is a high risk of suicide (due to depression). They also have a placebo effect of 50%, which is not necessarily a bad thing as long as it works, but raises the question whether the monoamine hypotheses is really that valid in the case of depression.
  • Tricyclic antidepressants – also block the reuptake mechanism, resulting in more monoamines in the synaptic cleft. Amitril (Amitriptyline), Aventyl/Norpress/Noritren (Nortriptyline) and Tofranil (Imipramine) are a few examples. They are derived from Phenothiazines (such as Chlorpromazine), which are antipsychotic drugs (used to treat schizophrenia). Some of the side-effects are: chronic pain and suicide overdose.
  • MAO inhibitors – Nardil/Nardelzin (Phenelzine), USAN (Thanylcypromine), Marplan/Enerzer (Izocarboxazid) and Amira/Aurorix/Clobemix (Moclobemide) are very effective and widely prescribed for in major depressive disorder, bipolar disorder and anxiety disorder, although the first three pose the high risk of hypertensive crisis and death if the patient is consuming cheese or wine.

The big problem with these drug therapies is dependence – if antidepressants, especially Paroxetine and Venlafaxine are administered for a long period of time and then stopped, the patient is likely to experience Antidepressant discontinuation syndrome, characterised by flu-like symptoms, motor and cognitive disturbances.

Non-drug therapies

An alternative to pharmaceutical treatments is represented by transcranial magnetic stimulation (TSM) of the cortex, electroshock therapy – this is, apparently, very effective, BUT might result in impaired memory – and gene therapies. The latter refers to the insertion, via a vector or a plasmid, of genes that encode neurotransmitter molecules, receptor proteins or neurotrophic and neuroprotective substances. Given that many variations in genes for chemical messengers in the brain are responsible for the predisposition of certain individuals to depression, gene therapies, although still at a developing stage, provide powerful approaches to the treatment of affective disorders.

Over-activation of the stress axis

Another theory for the development of depression, which goes hand-in-hand with the “monoamine hypothesis” is that in depressed individuals there is an exaggerate amount of cortisol (a steroid) in the blood, which can affect the brain. Basically, our brains react to stressful situations by producing some hormones in the hypothalamus and pituitary gland (hypophysis), which eventually result in the production of cortisol. In turn, cortisol acts on these structures to inhibits their activity and, thus, preventing further increases in its level – this is an example of a negative feedback mechanism.

In normal people, a stressful situation will result in increased levels of cortisol, but this steroid will then revert to its normal levels. In depressed individuals, the stress axis (hypothalamus-pituitary-adrenal axis) becomes hyperactive and, as a result, a stressful event will result in the overproduction of cortisol.

In excess, cortisol affects brain structures involved in the control of emotions and fear, such as the cingulate cortex and amygdala (which explains the anxiety symptoms experienced by people suffering from atypical depression) and memory, such as the hippocampus, which explains the cognitive dysfunctions. Moreover, the activity in the prefrontal cortex, which normally inhibits the hypothalamus (overactive in depression) is decreased by cortisol. So, really, it is like a vicious circle.

Why is the stress axis hyperactive in the first place? Possibly due to decreased sensitivity of the cortisol receptors to cortisol, which might be the result of genetic as well as developmental factors (previously mentioned).

Monoamines play a role here, as increased levels of monoamines (by the administration of antidepressants) can determine neurogenesis in the prefrontal cortex and hippocampus, so these areas can function properly again and can, thus, inhibit the hypothalamus, so no longer hyperactivity of the stress axis!

Seasonal affective disorder (SAD)

Although I am planning to write about bipolar disorders in another article, I thought it is worth discussing SAD in this article as well, given that so many people, especially those living in the Northern hemisphere, suffer from it.

In the References section there is a document called “The recent history of seasonal affective disorder (SAD)”, which is a transcript of the 2013 Witness Seminar in London. I highly recommend this reading for two reasons: it is full of remarkable, extremely important information regarding SAD and the participants at this seminar included personalities such as Prof. Josephine Arendt, Prof, Norman Rosenthal, Prof. Alfred Lewy, Prof. Rob Lucas, who are pioneers of the SAD diagnostic criteria and underlying causes (for instance, Rosenthal is the first psychiatrist who diagnosed SAD).

As many of you probably know, and sadly from personal experience, SAD is a seasonal mood change disorder, a type of bipolar disorder, which determines depression during the autumn/winter seasons and hypomania during summer. In order to understand SAD, we must remember a few things about the circadian rhythm, which I have previously discussed in two articles: Why “sleep” and Even flies sleep and learn. In short, we have an internal, genetic “clock” inside our brains (in the Suprachiasmatic nucleus – SCN), which determines the body to function in an approximately 24-hour cycle and which is also entrained by the light-dark cycle. This is not only a circadian (day-night) clock, but also a seasonal clock, which means that changes in the environment (especially light and temperature) across the year entrain this clock and determine physiological and psychological changes in our bodies.

In SAD, there is an abnormal secretion of melatonin (the hormone that triggers sleep, when it is dark outside). Light inhibits this hormone: cells in our retina, which are not coding for visual information, send projections via a distinct pathway than the rods and cones. These cells, containing  the peptide melanOPSIN, project via the retinohypothalamic tract to the SCN, “telling” the brain that it is dark outside, so the brain (SCN) determines the synthesis and release of melatonin from the pineal gland. When there is light outside, the production of melatonin is inhibited. The duration of melatonin secretion is also affected by the circannual changes – long secretion in short days and short in long days. The scientists who took part in the Witness Seminar discovered that melatonine production was increased during the depressive/winter phase and that sunlight decreased its production, thus, alleviating the symptoms of depression in SAD. A note here, sunlight is an effective treatment for SAD, not ordinary room light. This explains why, during winter, when people tend to spend more time indoors, their levels of melatonin increase. The reasons why room light does not inhibit melatonin production are the intensity of light (sunlight is five times more intense than room light) and spectral differences. More about SAD and bipolar disorder in a future article!

I hope this article made sense and that you enjoyed reading it!

References
SAD – Pdf of The Witness Seminar transcript

Beatty, 2000. The Human Brain – Essentials of Behavioural Neuroscience. Sage Publications. Inc., pg.464-471

Dick Swaab, 2014. We are our brains – From the womb to Alzheimer’s. Penguin Books, pp. 112-122

Image by Damaris Pop

Decoding autism

Posted on by Iasmina Hornoiu

About a year ago, I posted an article entitled Autism, which was meant to be more of an introduction into autistic spectrum disorders. Since then, I’ve been meaning to come back to this topic and provide more details about the mechanisms leading to autism, but I knew I need to do some proper research, which my student schedule didn’t really allow at that point.

The reason why I didn’t post any articles in the past three months is mainly my uni dissertation, which took up a lot of time. My chosen topic was Cellular mechanisms of autistic spectrum disorders. This assignment offered me the chance to read a lot of scientific papers and have a far better understanding of autism than I had before. As you probably guessed, this article draws quite a lot on my dissertation.

Some clarifications

When we refer to autism, we must be well aware that this is just an extreme end of the spectrum and that different neurodevelopmental disorders, sharing particular symptoms, are grouped under the term autistic spectrum disorders (ASD). The symptoms that characterise ASD are: impairments in social interaction, communication deficits and repetitive behaviours. Several factors have been linked to ASD, including gene dysregulations, alterations of the immune system and even environmental risk factors.

Discussing all the possible causes of ASD, could probably fit in a book, rather than a blog article, so I will only focus on gene dysregulations. However, if you have any kind of questions, feel free to post them in the comment section and I will try my best to answer them.

About glutamate and one its receptors

In biochemistry there are 20 different amino acids (the building blocks of proteins) and one of them is glutamate. This particular amino acid is very important because, apart from its role in the formation of proteins, it is also the main excitatory neurotransmitter in the brain. This means that glutamate is used to help the neurons communicate with each other and give rise to all sorts of brain activities we know about, including learning and memory.

When two neurons interact at the synapse (the space between the terminals of two interacting neurons), the neurotransmitter is released from the first neuron’s terminal and comes in contact with the second neuron’s terminal. But here’s the trick: in order for the neurotransmitter to have an effect on the second neuron, it has to activate certain structures on its terminal, called receptors. In the case of glutamate, there are three types of receptors, involved in different functions and with different mechanisms. The one we will be focusing on is the type I metabotropic glutamate receptor (mGluR). When this receptor interacts with glutamate, it leads to the translation of specific proteins involved in a process known as long-term depression (LTD), which influences learning and memory. Increased LTD is thought to play a key role in the development of ASD.

The FMRP protein

A few genes have been found to regulate the activity of mGluR and, through it, several cognitive processes. The Fragile X Mental Retardation 1 (FMR1) gene, which codes for the FMRP protein, is one of these genes. It interacts with mGluR-dependent proteins and is thought to regulate synaptic plasticity. During embryonic development, FMRP plays an important role in neural differentiation. Therefore, a mutation in the FMR1 gene leading to the absence of FMRP (a loss-of-function mutation) results in restricted brain development, impaired cognitive functions and autistic symptoms (previously mentioned). This mutation has been found in patients suffering from autism and especially from another brain disease, Fragile X Sydrome, which is the most common monogenic (determined by a mutation in a single gene) cause of autism. The activity of FMRP suppresses mGluR-dependent LTD, by inhibiting the synthesis of proteins involved in this process. Therefore, the absence of FMRP results in LTD, which primarily leads to mental disability.

Neuroligins and Neurexins

These represent transgenic protein families, which mediate synapse maturation in neurons using glutamate. Mutations affecting members of neuroligin and neurexin families have been found to be associated with autistic-like behaviours. The effects of these mutations on the brain are very specific, affecting cells in brain regions involved in learning and memory (CA1 pyramidal cells of the hippocampus, the Purkinje cells of the cerebellum), language (brainstem) and social interaction (somatosensory cortex). In normal situations, neuroligins and neurexins trigger mGluR-induced LTD, but their translation is inhibited by FMRP. The absence of FMRP leads to the loss of this inhibition, which results in mGluR-induced LTD.

Possible therapeutic strategies

Research on the links between mGluR transmission and genes involved in neural development resulted in a variety of therapeutic strategies for ASD. Genetic mGluR reduction and mGluR antagonists (drugs that act on this receptor by preventing glutamate to activate it) are the most common examples of treatments. Potential therapeutic candidates are Fenobam and Lithium, which act as antagonists at mGluR. Administered on animal models and on humans suffering from Fragile X Syndrome, these drugs have resulted in cognitive and behavioural improvements. Although there is hope in treating ASD, there is still a lot of research that needs to be done, especially since even diagnosing different autistic spectrum disorders is still a challenging task.

I hope this article gave you a little more insight into the mechanisms underlying autism and that you enjoyed reading it. As I mentioned above, any questions about this topic are welcomed.

References:

Baudouin, S. J. (2014). Heterogeneity and convergence: the synaptic pathophysiology of autism. European Journal of Neuroscience, 39(7), 1107-1113.

Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D. V. & Hagerman, R. (2009). A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. Journal of Medical Genetics, 46(4), 266-271.

Espinosa, F., Xuan, Z., Liu, S. & Powell, C. M. (2015). Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner. Frontiers in synaptic neuroscience, 7, 11-11.

Etherton, M., Foeldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., Malenka, R. C. & Suedhof, T. C. (2011). Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proceedings of the National Academy of Sciences of the United States of America, 108(33), 13764-13769.

Gao, R. & Penzes, P. (2015). Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders. Current Molecular Medicine, 15(2), 146-167.

Nosyreva, E. D. & Huber, K. M. (2006). Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. Journal of Neurophysiology, 95(5), 3291-3295.

Rojas, D. C. (2014). The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. Journal of Neural Transmission, 121(8), 891-905.

Zalfa, F. & Bagni, C. (2004). Molecular insights into mental retardation: Multiple functions for the Fragile X mental retardation protein? Current Issues in Molecular Biology, 6, 73-88.

Image by Isuru Priyaranga

Even flies sleep and learn

Posted on by Iasmina Hornoiu

Sleep is a fascinating process that allows most of the creatures on Earth to function at their normal capacity and survive the environmental challenges. Recent theories support the idea that one of the main functions of sleep is not energy conservation or tissue restoration, as previously thought, but actually, enhancement of brain function. Sleep appears to be involved in consolidation of memories and improvement of learning. As you probably remember from the previous article, there are essentially to phases of sleep: REM and non-REM. The latter has been shown to be involved in consolidation of both declarative and non-declarative memories, whereas REM sleep is believed to enhance the formation of procedural and emotional (non-declarative) memories.

If you’ve ever wondered whether insects can sleep or not, the answer is yes. Several studies in Drosophila melanogaster , the fruit fly famous for Morgan’s discoveries of chromosomal inheritance, proved these flies have periods of ‘rest’. During rest , Drosophila stops moving and becomes more difficult to be aroused, which resembles what we understand by ‘sleep’. Moreover, it appears that these flies can form short-term and long-term memories, especially revealed by studies of olfactory associative conditioning. Surprising, isn’t it? Even though it is known that insects have brains, they seem too primitive, at a first glance, for complex cognitive functions such as memory and learning. Well, it’s obvious that insects are much smarter than we thought.

What’s more stunning is that, in Drosophila, just as in humans, sleep has evident effects on long term memory formation and sleep deprivation can dramatically affect this function. According to several studies, sleep homeostasis positively influences learning. During non-REM sleep, the brain shows slow oscillatory activity, which is characterised by waves of action potentials with low frequency and high amplitude. These slow waves are controlled by homeostatic processes and increase after learning tasks. Hence, sleep, which induces slow wave activity, plays a very important role in enhancing learning performances.

The homeostatic control of sleep has been somewhat elucidated by studies in our old friend, Drosophila. Organisms need not only a circadian clock (which sets a day-night rhythm, synchronising the body with the environment), but also a homeostatic system, which regulates sleep according to prior wakefulness. Just like in the circadian system, the homeostatic system seems to be genetically regulated and, eventually, resulting from neuronal activity.

Specialised sleep-promoter neurones in Drosophila, called the dorsal fan-shaped body (FB) neurones, become excited when the organism is sleep-deprived and fire action potentials (which can be surprising, given that non-REM sleep triggers reduced brain activity). It is not exactly known how the nervous system can sense lack of sleep, but it is believed that substances such as adenosine and unfolded proteins, released after prolonged wakefulness, are potential signals. Thus, after detecting too much wakefulness, dorsal FB neurones become excited and promote sleep. The gene that controls the function of the dorsal FB neurones is the crossveinless-c (cv-c) gene, which encodes for a protein that regulates different ion channels (especially potassium channels), leading to changes in electrical conductance and the excitability of the sleep-promoter neurones.

 Just to give some more information and (possibly) complicate things a bit more, another link between sleep and long term memory is represented by the notch receptors, which have been found to be involved in the restoration of long term memory formation after sleep deprivation. Their main function is to influence the development of the nervous system in the embryo, but they also play a role in memory formation.

 As you have probably figured out by now, it is quite hard to have a complete picture of what sleep is about and how it can influence memory and learning. However, scientists are doing their best to shed some light on these wonderful phenomena. And before you close this page, don’t forget an important point: even something small like the fruit fly is able to sleep and learn!

I’d like to thank my friends Parnian Doostdar and Lee Chi Yu for sending me most of the materials I used for this article.

For further information:

Article 

Ackermann, S., Rasch, B., 2014. Differential effects of non-REM and REM on memory consolidation, Current neurology and neuroscience reports, vol. 14, p. 430

Donlea, J. M., Pimentel, D., Miesenbock, G., 2014. Neuronal machinery of sleep homeostasis in Drosophila. Neuron, vol. 81, pp. 860-872

Huber, R., Ghilardi, M. F., Massimini, M., Tononi, G., 2004. Local sleep and learning. Nature, vol. 430, pp. 78-81

Why “sleep”?

Posted on by Iasmina Hornoiu

In a previous article, we talked a bit about narcolepsy as one of the very intriguing sleep disorders. It was perhaps easy to understand why people suffering from narcolepsy could have a pretty hard time performing several normal tasks; however, most of us would probably relate less to narcolepsy. But something which almost everyone can agree to have experienced regularly, in one way or another, is sleep. In comparison with disorders associated with it or derived from its impairments, sleep itself might not seem so interesting. We all do it and we can’t deny how much we enjoy it and long for it after it stops. Yet, there is much more to sleep than we think.

Sleep is very important for the normal functioning of any being. For animals as well as for humans, sleep helps in energy conservation, body restoration, predator avoidance and learning aid. Different animals have different sleep-wake cycles, from nocturnal animals (like rodents), which sleep during the day and are active at night, and animals which sleep with only half of the brain (like dolphins), all the way to diurnal animals, like humans. Although humans are advised to sleep approximately 8 hours per night, some people sleep very little (around 2-3 hours/night) and still function perfectly fine. An example of such a situation is presented in the textbook of Rosenzweig et al. (pg. 389).

But what triggers sleep and how is it regulated?

Most of us are certainly able to recall a dream the next morning and the memory of that dream is usually accompanied by feelings and emotions we sometimes do not even experience in real life. We are often under the impression that our dream has lasted the whole night. In fact, there are two stages of sleep, one of which is associated with the formation of dreams. These stages, known as non-REM sleep and REM sleep, succeed each other in cycles lasting approximately 90 minutes. Just to define the terms, REM means rapid eye movement and represents the part of sleep with the most increased brain activity. Interestingly, during REM the brain seems to consume more oxygen than during arousal!

Normally, when we fall asleep we slip into the non-REM stage or the slow-wave sleep (SWL). This, in turn, is divided into four other stages: from light sleep to very deep sleep. During this phase, the brain is said to be truly resting and the body appears to repair its tissues. No dreams can be seen! The movement of the body is reduced, but not because the muscles are incapable of moving; it’s the brain which does not send signals to the body to move! One interesting feature of non-REM sleep is sleep-walking. This peculiar behaviour some people show while asleep usually takes place during the fourth (last) part of the non-REM sleep, when the person is the deepest sleep. This is the reason why it is very difficult to wake a sleepwalker up.

In turn, REM sleep (which starts after a 30-minute non-REM period) is the “active” part of our sleep. This time, the brain sends commands to the body, but the body seems to be in an almost complete state of atonia (immobility). The heart rate and breathing become irregular and the brain is not resting. In fact, our dreams happen during this time and more importantly, our long-lasting memories are thought to be integrated and consolidated.

FullSizeRender-2

When it comes to sleep regulation, many neuroendocrine systems and brain functions play a role. The circadian (or sleep-wake cycle), which is controlled primarily by the suprachiasmatic nuclei, in the hypothalamus, need special attention. For the purpose of this article, I won’t focus on the circadian clock now, but I will come back to this in a future article. The autonomic nervous system and parts of the brain such as the brainstem, the limbic system, especially the amygdala, and the forebrain modulate different aspects and stages of sleep. Amygdala, which I mentioned in a previous article about emotions and decision-making, is a brain region involved in the emotions such as fear. It also appears to be very active during REM-sleep and may account for the awful nightmares we often experience.

Many cognitive functions, such as intelligence, performance and emotions are associated with disrupted non-REM as well as REM sleep. To be more specific, REM-sleep loss appears to be associated with increased anxiety and stress and loss of emotional neutrality – this means that a person deprived of REM-sleep is more likely to react negatively to neutral emotional stimuli than in normal conditions. The explanations vary, but most of the studies agree that impaired REM sleep triggers increased release of noradrenaline, hyperactivity of amygdala and decreased function of prefrontal cortex (which tells “stop!” to the amygdala when it goes crazy). At the same time, people deprived of non-REM sleep could experience depression, due to deficiency in another neurotransmitter, this time an inhibitory one, called GABA (gamma-aminobutyric acid). Other problems linked to sleep deprivation are attention deficits, working memory impairments and usually affected divergent thinking (creative, innovative thinking).

Aging people seem to sleep less and this deprivation is also associated with conditions like Alzheimer’s. Moreover, sleep deprivation can kill you! Sustained sleep loss can cause low immune system and drop in body’s temperature, which can make bacterial infections fatal. Another consequence of sleep loss is increased metabolic rate, which leads to weight loss and eventually death. Don’t think this could be a good idea for a diet! More like for “die”!!! Having said that, most people should try their best to get enough hours of sleep.

I hope this article convinced you of the importance of sleep and as usual, any questions or comments are welcome 🙂

Further information:

Article 1 – about REM-sleep and emotional discrimination 

Article 2 – about non-REM sleep and GABA 

Article 3 – about how sleep loss affects behaviour and emotions

Article 4 – a review on many articles about the link between sleep deprivation and emotional reactivity and perception

Bear et al., 2006. Neuroscience – Exploring the Brain. s.l.:Lippincott Williams & Wilknins 

Rosenzweig et al., 2010. Biological Psychology – An Introduction to Behavioural, Cognitive and Clinical Neuroscience. 6th edition. Sinauer Associates Inc.,U.S., pg. 380-401

Both images by Gabriel Velichkova

Don’t be anxious about anxiety!

Posted on by Iasmina Hornoiu

I remember when I was a small child and my mum or my uncle would take me out to one of my hometown’s parks or to the shopping centre. For some reason, I so often experienced an unexplainable fear and even dizziness and the terror that I might faint. I also had the feeling I couldn’t walk in a straight line. But no one noticed. Whenever I went to an indoor show or a classical music concert where people were sat on their seats and all they had to do was watch something and not move, talk or most importantly, look at me, I was fine. Little did I know what the problem was as it never occurred to me it was a problem at all. I knew I was shy and self-conscious and in my head that was the reason for my fears of crowds.

After I hit puberty, those irrational fears and the following symptoms became amplified and I started to seek for some scientific explanations. By reading and talking to different people I finally found out about agoraphobia. As the name suggests, agoraphobia is basically the fear of open and/or crowded spaces. The most important steps, I think, in dealing with an anxiety is first of all realising you have one and identifying the type.

Anxiety disorders are very common worldwide (with about 2% of the population suffering from them) and they are characterised by the pathological expression of fear. The most common types of anxieties are: agoraphobia, panic disorder, obsessive-compulsive disorder, social phobia, specific phobia, generalised phobia, post-traumatic stress disorder.The manifestations as well as the characteristics and the severity of anxiety disorders differ from person to person. Moreover, some anxieties can derive from other anxieties, like panic disorders. No wonder it took me a while to figure out what was going on with me. Here’s the thing and I would like people who suffer or have suffered from anxiety disorders to think about it: we often do not realise we have an anxiety (because we believe the causes underling the symptoms are different, like lack of self-confidence, heart attacks, pure coincidence etc.) or we just refuse to admit the reality.

Although anxiety has been mentioned in scientific literature since the 16th century, it wasn’t until the 1800s when it started to be considered  a mental illness. Before that, people attributed physiological and hormonal causes to anxieties.

Modern medical advances like fMRI and PET have made possible the discovery of the major role of the hypothalamic-pituitary-adrenal (HPA) axis in anxiety formation and development. Through a cascade of hormones released by this three-structure system, the brain responds to stress by activating the adrenal glands to produce cortisol. This, in turn, determines physiological changes which lead to exaggerated fight-or-flight reactions.

We shouldn’t pin all the blame on the hypothalamus though, as it only obeys two other structures: the amygdala and the hippocampus (which respond to the information processed in the neocortex). In this case, the amygdala and the hippocampus act as antagonists – the amygdala has a positive effect on the activation of the HPA axis, whereas the hippocampus suppressed this activation. This is how the normal fight-or-flight responses are regulated. Nevertheless, in patients suffering from anxiety disorders, hippocampal damage due to continuous exposure to cortisol (probably as a result of amygdala hyperactivity) leads to more cortisol being resealed from the adrenal medulla, thus the symptoms of anxiety becoming even more pronounced.

Several treatments, ranging from anxiolytic medications (benzodiazepines, alcohol, serotonin-selective reuptake inhibitors etc.) to psychotherapy have been developed in order to heal anxieties. Psychotherapy aims to get the patient accustomed to the stressor (the stimulus that produces anxiety) and, at the same time, to assure them of the extremely low risks potentially posed by that stimulus. In time, the fear of the stressor would disappear as the neuronal connections involving the stimulus processing would be altered.

I know I put between brackets alcohol as one of the many treatments against anxiety disorders. Indeed, due to its stimulating effects on the main inhibitory neurotransmitter, GABA. Essentially all drugs that can activate this neurotransmitter are considered anxiolytic, meaning they are able to treat anxieties. Keep in mind, though: This is should not be an excuse for people to become alcoholics 😛

In my case, the anxiety went away by itself, or maybe it was just me who kept on going to crowd places and telling to myself nothing bad was ever going to happen; which, to be honest, is a bit unrealistic – bad things can actually happen, but we should try to prevent them, instead of fearing them to the point when we would refuse to leave the house.

Hopefully, this article gave you a clearer idea about what triggers anxiety disorders and also made the anxious ones more confident that their fears don’t have to last forever.

Further information:

Article about anxiety

Short video on anxiety 

Documentary about anxiety

Bear et al., 2006. Neuroscience – Exploring the Brain. s.l.:Lippincott Williams & Wilkins pp. 665-670

Picture by Damaris Pop

Narcolepsy

Posted on by Iasmina Hornoiu

Can you think of any situation when, let’s say, you were talking to someone and suddenly that person would glance at you with boredom and their eyes seemed to slowly close as if they were on the verge of nodding off? This sort of situations can be very annoying and it would be a lie to say that you didn’t feel mad or at least slightly pissed off when they happened. You probably either ignored them or chose a more aggressive approach, in order to ‘wake’ them up.

But what if instead of just a very rude or uneducated person you would have to deal with someone who suffers from narcolepsy? Not only the person you would supposedly talk to is actually asleep, but waking them up is very likely to trigger unwanted behaviours.

As odd as it sounds, there are people in this world who can fall asleep instantaneously, without any previous warning, in the middle of doing anything ranging from reading and talking to cooking and driving. These people are called ‘narcoleptics’.

So what is narcolepsy?

Narcolepsy or the so-called syndrome of excessive sleepiness is a chronic neurological disorder that affects less than one percent of the population, therefore it is considered a relatively rare disease. Due to the multiple causes that lead to this disorder, narcolepsy has been considered either an autoimmune or a neurodegenerative disease. Often it is hard to be identified and wrong diagnosis is given, such as epilepsy (because cataplexy could resemble epileptic seizures) or schizophrenia (due to visual and sometimes auditory hallucinations).

Symptoms

The most common symptoms of narcolepsy are: sleep disturbance, cataplexy (muscle weakness), excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and abnormal rapid eye movement (REM) – in narcoleptics REM occurs extremely fast (within a few minutes), whereas normally it should manifest after one hour and a half. Nevertheless, patients who suffer from narcolepsy have also experienced increased appetite, automatic behaviour, sleep apnoea and memory problems (this is not due to cortical dysfunction, but to impaired attention).

Except for cataplexy, sleep paralysis and hypnogogic hallucinations, reduced attention and disorientation after waking from daytime naps are also common. Moreover, patients could suffer from aggressive behaviour, with temper outburst and irritability especially if woken up and they might also deny their condition.

Interestingly enough, despite the fact that narcoleptics have trouble with being awake during the day, they would often experience insomnia during the night. Their sleep deficiency can be accentuated by some forms of medical treatment.

Causes

It has been demonstrated that many factors are involved in the initiation and development of narcolepsy; these range from genetic factors, including the human leukocyte antigen DQ and DR (HLA-DQ and -DR) genes and polymorphism of certain type of genes (for instance tumour necrosis factor alpha or monoamine oxidase genes, both located on chromosome 6) to environmental factors (head trauma and various infections, such as the infection with Streptococcus pyogenes). HLA genes code for the HLA complex called antigens, proteins with an essential role in the immune functions and usually associated with autoimmune diseases.

In addition, latest discoveries have shown a decrease in levels of hypocretin-1 and -2 (also known as orexin-A and-B) in the cerebrospinal fluid and hypothalamus could account for the trigger of narcolepsy. Deficiencies of this neuropeptide might produce changes in monoamine oxidases, enzymes with an important role in the degradation of amine neurotransmitters, such as serotonin and dopamine. Low levels of dopamine dramatically influence the development of some psychiatric and neurodegenerative disorders (ADHD and Parkinson’s disease, respectively) including narcolepsy.

Treatment

Given the fact that the decrease of hypocretin tone plays an important role in the production of narcolepsy, an efficient solution would involve the increase in the concentration of these peptides. One way of achieving this is by intracerebroventricular administration of hypocretin-1 peptide, which appears to reduce the frequency of cataplexy and stimulate arousal in mice. Another even more efficient and less invasive method is represented by the intranasal administration, hence the neuropeptides being directly delivered to the central nervous system.

Serotonin was also discovered to have significant role in wakefulness and REM regulation, hence decrease levels of serotonin (5-HT) might induce narcolepsy. Therefore, medicines that could increase the levels of serotonin in narcoleptic humans might be a solution for this disease.

Most of the patients diagnosed with narcolepsy are recommended pharmaceutical treatments, which usually consist of the intake of certain doses of stimulants. Nevertheless, taking into consideration the side effects of these drugs and the limited adherence of the patients to the medications, alternative methods have been discovered. One of them is represented by behavioural and psychological approaches, for instance regularly scheduled naps during the day and daily exercises (but avoidance of activities that increase body temperature).

Since treatment involving cognitive stimulants is the most wide-spread, a lot of drugs are used in order to cure narcolepsy. A very common example is represented by amphetamines (such as Ritalin), which are known to increase levels of dopamine in the brain, reduce daytime sleepiness and inhibit the monoamine oxidases. Also Mazindol, Modafil and Selegiline are used as treatment for narcolepsy, as they reduce cataplexy and inhibit the monoamine oxidases. The amino acid L-tyrosine stimulates the production of noradrenaline and dopamine, therefore it also represents a solution (although more tests of its effects are required).

Some very important drawbacks that should be considered when using pharmaceutical stimulants in treating narcolepsy, and any disorder that affects the nervous system in general, are the possible adverse effects and the chances of dependence, abuse and tolerance. Although serious addiction problems haven’t been registered, high dosages increase the risk. According to some studies, 30-40% of narcoleptic patients using medicines have developed tolerance, therefore 1-2 days per week of no medication is recommended.

The most common adverse effects of the psychostimulants are headaches, insomnia, anorexia, irritability, heart palpitation. Patients must acknowledge that these drugs cannot be taken as brain enhancers and they must also be aware of the side effects and possible risk of addiction before deciding to undergo a medicine-based treatment.

I hope you enjoyed reading this article 🙂 It is actually highly based on an essay I had to write in my first year of university and therefore I am going to add the literature I used at the time in order to gather information.

Further reading:

Aldrich, M. S. (1990). Narcolepsy. The New England Journal of Medicine, Vol.323(6), pp.389-394 ].

Allsopp, M., & Zaiwalla, Z. (2001). Narcolepsy. Archives of Disease in Childhood, Vol.67, pp.302-306.

Bassetti, C. R., & Scammell, T. E. (2011). Narcolepsy. Dodrecht: Springer.
Conroy, D., Novick, D., & Swanton, L. (2012). Behavioral Management of

Hypersomnia. Sleep Medicine Clinics, Vol.7, Issue 2.

Danis, P. (1939). Narcolepsy. The Journal of Pediatrics, Vol.15(1), pp.103-106.

De La Herrán-Arita, A., & García-García, F. (2013). Current and emerging options for the drug treatment of narcolepsy. Drugs, Vol.73(16), 1771-1781.

M.M Mitler, M.S Aldrich, G.F Koob, et al. (1994). Neuroscience and its treatment with stimulants. Sleep, Vol. 17 (4), pp. 352–371.

Thorpy, M. (2001). Current concepts in the etiology, diagnosis and treatment of narcolepsy. Sleep Medicine, Vol.2(1), 5-17.

Image edited by Isuru Priyaranga