By Noemi Lakatos

The study of the brain dates back to at least the 17th century BC from the Egyptian period by an Egyptian battlefield doctor in the Edwin Smith Surgical Papyrus. In 355 BC Aristotle was one of many to make speculations about the brain's role in the body. If we have been venturing into the world of neuroscience for nearly 4 THOUSAND years why do we still not have a clear answer? Hopefully, you will have more clarity on this question by the end of this article.

What is Connectomics?

Imagine this: you're finally getting a week of holiday and decide to visit your friend who lives in Paris. As your plane lands you exhale the last couple of weeks of stress. This weekend is just what you need. The Hotel is booked, and you already have an array of possible activities organized for the week. As you reach down into your bag to turn your phone back on, ping, ping, ping… your notifications start rushing in. Right at the top of your screen, you spot one percent left notification. How are you meant to get to your Hotel if you can't access your maps app?

The connectome is like the brain's very own Google Maps; only, instead of streets and landmarks, it's all about mapping the biological neural network of the human brain. Just think of your brain as a giant city with billions of neurons communicating with each other. Connectomics is a subfield of neuroscience that works on creating a map of these neurons to help us understand their interactions. There is just one small problem: we don't actually have a copy of this map.

Today we are aware of many diseases that manifest in the brain. We also understand — in theory— how the brain works, but we don't know what happens in the brain to lead to the emergence of these diseases. Imagine how much we'd understand if we had our map of the brain with every street and every alley. Well, that is what the study of connectomics is aiming to achieve. Let me explain…

The Brain 🧠

At first glance, the brain is merely a homogenous glob of tissue. But this is very far away from the truth. The human brain is a highly organized and specialized structure that is divided into key regions across a vast network. The four overarching regions in the brain are the brainstem, cerebellum, thalamus, and cerebrum. Each of these structure is responsible for a specific set of tasks.

This section will outline the 4 main structures of the brain. Feel free to skip to the next section titled "Neurons" if you understand these features.

Brainstem: The brainstem is the key feature that connects the rest of the brain to the spinal cord; allowing a constant flow of information. It consists of the medulla oblongata, the pons, and the midbrain. It can be categorized as the most primitive region of the brain as it is responsible for fundamental properties of life in our bodies such as breathing, circulation, and digestion. Think of the brainstem as the gates to the brain as it decides whether the sensory information can travel up and into the brain.

Cerebellum: Located at the base of the brain, the cerebellum is responsible for motion control such as coordination, balance, and fine motor skills. Whilst it only occupies about 10% of the brain's volume, it is the home for over 50% of the brain's neurons. Yet there is still a limited understanding of how it ties into various functions.

Thalamus: Picture the thalamus as the diligent postman of the brain. It is responsible for sorting all the sensory information and delivering it to the respective part of the brain where the sensory information is then processed.

Cerebrum: As the largest part of the human brain the cerebrum plays a major role in cognitive function. It spans out over both hemispheres and is sometimes referred to as the new brain as it is evolutionarily the newest part of the brain. In the center, there is a small cluster of cells called the corpus callosum that serves as the bridge between the two hemispheres. The cerebral cortex is the region that spans the majority of the cerebrum. The parts of the cerebral cortex work in harmony to process sensory information, control movement, and manage complex thinking and problem-solving. It's that part of the brain that allows for our out-of-the-box thinking.

Neurons

Now that we've talked about the structure of the brain let's go ahead and dive into the building blocks of this structure: neurons! Neurons are a subset of brain cells along with oligodendrocytes, astrocytes, extravascular macrophages, microglia, etc. It's important to note that only 10% of the brain cells in our brains are our neurons. So then why are they so important?

The truth is that neurons are so special because they are the cells that are responsible for sending neurotransmitters — chemical substances secreted by neurons that carry information throughout the brain — across the vast neural network.

Here is a basic diagram of a neuron. The soma is the body of the cell, whereas the connection between the axon terminal and the dendrites is the synapse. The neurotransmitters are secreted by the axon terminal and travel via the synapse from neuron to neuron (this process is called synaptic transmission). Hundreds of neurons can form synapses between each other resulting in a biological neural network (note: a neuron can form a synapse with multiple other neurons). So when we are talking about mapping the brain the key players are the synapses.

Understanding how synapses work and where they are located is critical in connectomics. Think of them as the city signs on our brain's map.

Quick recap: We know that our brain is made up of a vast synaptic network, and connectomics is a subcategory of neuroscience that focuses on mapping out each synapse, and its function.

STRUCTURAL VS FUNCTIONAL CONNECTOMICS 🤔

So far the word structure and function have both been used in this article. Let's take a quick pit stop to explore these two words.

As humans, we love organizing things and creating categories. When you think of the word connectomics imagine it branching down into two directions 1) structural connectomics, and 2) functional connectomics.

Structural connectomics refers to mapping the physical connections between the neurons of different regions of the brain, whereas functional connectomics studies the collaboration between the different parts of the brain. You may be wondering why it's so important to have both structural and functional connectomics, so here are 3 examples:

1. Helping to identify how brain regions with specialized functions collaborate with other regions to perform complex tasks
2. Seeing how brain development advances the neural networks and at what stages there is a shift in cognitive abilities
3. Understanding how brain structure impacts mental health and neurological disorders

As you can see when researching connectomics it is imperative to consider both structure and function since they are pretty co-dependant. It is nearly impossible to understand how the brain works if we don't have access to both types of data.

Oh and one more difference, this data is collected in two different ways.

Techniques to map the connectome 📷🔬

ELECTRON MICROSCOPY

Electron microscopy is the technique used for the function of the synaptic connections. It's a pretty tedious task, but it is highly effective. Here's a bit more on how it's done:

1. The brain is embedded into plastic to sustain the natural state
2. Then it is cut into tiny slices that are around 30 nanometers wide using a diamond knife (a piece of paper is 100,000 nanometers thick)
3. Each slice is placed into water to be split into different sections
4. Still in the water, the slices are floated under the electron microscope and a picture is taken
5. This action is repeated for each of the pieces.
6. The images are manually compared to form the neuron.

Whilst this technique works pretty well, scientists must be incredibly careful when dealing with the slices given how thin they are. The manual comparison at the end can also be somewhat lengthy for just one neuron. You can imagine how daunting mapping the entire connectome can be when there are close to 100 billion neurons in the brain. Needless to say, electron microscopy is impossible in living individuals so scientists must have access to human brains post-mortem, which requires consent before death. On the bright side, we do get pretty cool images. If you want to try out how the images are manually compared here is a simulation that lets you do just that: https://eyewire.org/.

Can you get past the first 3 levels without making any mistakes?

DIFFUSION TENSOR IMAGING

Diffusion tensor imaging (DTI) is a technique used to examine structure via the movement of water molecules in the brain through the use of diffusion magnetic resonance imaging (dMRI). DTI is often used to image structural connectomics, especially in the white matter (deeper part of the cerebrum). What's cool here is that we can do this with any person who is alive right now. Here are the steps with a bit more detail on how the imaging works:

1. A person must be lying down inside a dMRI machine to take a picture of their brain
2. dMRI machine creates a pulsing magnetic field around the person's head that interacts with the water molecules in the brain to create an image
3. Using the data from the dMRI a map is generated illustrating the movement of water molecules within the brain
4. Tractography (the process of reconstructing white matter pathways) algorithm is applied to the dMRI data to create a map of the white matter

DTI results in a great image of the pathways thanks to the water molecules that are constantly moving along the various nerves in the brain. images can help us understand brain connectivity in healthy individuals, investigate the connectivity changes in neurological and psychiatric disorders, and even help plan neurosurgery to avoid major damage. Compared to electron microscopy this method is a lot faster. However, we are still working on achieving higher-quality images, and it can be difficult to be accurate with complex connections.

Challenges in Mapping the Brain

Mapping a connectome is an enormous undertaking. The human brain has around 86 billion neurons. If that isn't impressive enough, keep in mind each neuron makes on average 10,000 connections (give or take depending on what type of neuron). That's around 100 trillion synapses per human. To put that into perspective there is an estimated amount of 110 trillion mosquitoes on earth.

Essentially, you have almost as many synapses in your brain as the amount of mosquitoes on the planet. THATS INSANE! The substantial size of the human connectome is the main reason why we have not yet been able to create a full map. There are simply too many synaptic connections holding large amounts of information that our technology cannot store and process. This is why connectome research tends to focus on specific sections of the neural network so the information can be adequately processed. Additionally, the method of electron microscopy is a process done manually and is therefore tedious, and a technique open to human error. If a researcher makes even one small error they might have to restart the entire process. Nonetheless, recent technological advancements such as the use of AI have created novel opportunities which may expedite the field of connectomics.

The Promise of Connectomics (real-world applications)

Why should we care about connectomics? Well, understanding the brain's wiring is vital for making sense of conditions like Alzheimer's, depression, and Huntington's. As well as unlocking the secrets of human cognition, consciousness, and creativity.

So stay with me!

Medicine 🥼

The diagnosis of psychological disorders is unfortunately still a hit or miss today. Far too many times people are misdiagnosed, or not even diagnosed at all. This is because for many many neurological disorders, we base the diagnoses on observations, and filling certain criteria. Connectomics has the potential to identify concrete biological differences leading to a lot more efficient and accurate diagnoses. Furthermore, a complete understanding of these disorders may lead us to develop novel cures.

Psychology 🧠

Psychology is a prevalent field in today's world. According to the World Health Organization (WHO), approximately 1 billion people worldwide are suffering from some type of neurological disorder. With such a high number of the population being affected it's impossible to ignore the issue, right?

Possible classifications of neurological disorders are neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Let's dive into how connectomics can develop each of these.

Neurodevelopmental disorders (NDDs): Neurodevelopmental disorders encompass a group of conditions that are caused by early damage to the central nervous system, and therefore affect the development and function of the nervous system. NDDs often include autism spectrum disorders, cerebral palsy, attention deficit hyperactivity disorder (ADHD), and impairments in vision or hearing. Common characteristics are difficulties in cognition, communication, behavior, and social interaction. Diagnosing NDDs can prove as a difficult task as there is no set medical test. Through mapping the connectome disrupted neural pathways and connectivity patterns associated with NDDs can be identified, and lead to direct indicators.

Neurodegenerative disorders: Neurodegenerative disorders are a group of conditions characterized by progressive degeneration in the nervous system (synaptic pruning). Conditions like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) all fall under this category.

The causes of neurodegenerative disorders are often complex and multifaceted. Common causes include a combination of genetic, environmental, and age-related factors. Similarly to NDDs, the diagnoses of these disorders are challenging as the symptoms typically overlap with other conditions. These conditions tend to be confirmed via post-mortem examinations. Additionally, treatments for these disorders are focused on symptomatic relief and management rather than a distinct cure. A concrete map of the brain can provide specific insight into what causes these disorders. Such information could help us prolong human life.

Neuropsychiatric disorders: Neuropsychiatric disorders affect both the brain and the mental well-being. Anxiety, depression, bipolar disorder, and schizophrenia are all examples. Diagnosing them often involves a clinical assessment, psychological testing, and looking for guidance in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) which provides extensive diagnostic criteria. Once diagnosed the treatment is management-based, with psychotherapies, medication, a focus on lifestyle, support groups, and in extreme cases Electroconvulsive Therapy (ECT) or Transcranial Magnetic Stimulation (TMS).

Considering the tendency of comorbidity of these disorders, individuals often try various forms of treatment, and still may not be able to find one that works for them. Access to the human connectome could reveal intricate neural circuits responsible for these neurological disorders. As we enhance our understanding of them neuropsychiatric disorders will be able to have personalized treatments majorly improving the process of receiving treatment for neuropsychiatric disorders.

Artificial Intelligence (AI) 🤖

AI is a field of computer science that has the purpose of carrying out tasks that generally would need human intelligence. Neural networks are a key component of AI as it sustains its human-like capabilities. These neural networks are constructed of interconnected and biased nodes that mimic the neural activity in our brains. Simply put AI learns from data by adjusting the connections and nodes. This allows neural networks to recognize patterns, and make decisions similarly to humans.

They can get extremely complex as all the different nodes are connected in the network. Although the first advances in AI happened before the understanding of synaptic connections; knowledge about how our biological neural network functions has the potential for great advancements in AI. For instance, understanding signal transmission can help us improve already existing learning algorithms to become faster, and more specialized. Cool right?

Where are we at right now?

The Human Connectome Project (HCP) is one of the large-scale neuroscience research initiatives working to map the entire human connectome comprehensively. It makes use of advanced neuroimaging techniques, such as dMRI and resting-state fMRI, to visualize the intricate networks of neural pathways in the brain. The project aims to grow our understanding of brain function and structure. Take a moment to explore their website. http://www.humanconnectomeproject.org/

Key Takeaways

• Connectomics is a subfield of neuroscience that focuses on mapping the biological neural network
• The brain is a highly organized structure with specific functions that are constituted by biological neural networks
• There are A LOT of neurons in the brain
• Connectomics dives into two main subcategories: structural (physical construction of the brain) and functional (collaboration between the different neurons)
• Electron microscopy is a technique to map functional connectomics by taking images of slices of the brain
• Diffusion Tensor Imaging is a technique used to make a brain tractography image that is used for studying structural connectomics
• Having a map of the human connectome will positively impact medicine, psychology, and AI
• The Human Connectome Project is working on mapping the human connectome

Conclusion

Connectomics is an incredible field studying the inner workings of the brain. It's like creating a Google Earth for our most complex organ. So next time your phone dies and you can't look at that very detailed map of the city, take a second to think of the scientists who are exploring the brain, and working on building a map to understand ourselves better. Connectomics may potentially change the way we think about the mysteries of being human.

So, there you have it, a basic introduction to connectomics! I hope this article has ignited your curiosity and given you an insight into the amazing world of connectomics.

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