Monday, August 1, 2022

Understanding Human Brain- Recent Studies and Research Outcomes

              Brain,a tissue mass weighing little over a kilogram is the most marvelous organ evolution ever made. This is the only organ which has mysterious behavior. It is an electrically operated machine which can think, induce emotions, pull your muscles to make you stand erect and compose songs. It can renew and repair itself every day and unlike other organs make modifications on its cell connections all through a life time. It has many functions so could be considered many organs in one. It is a unique computer,  but excels all other super computers. 

   The complexity of neuronal connection is staggering. There are around 1000 billion neurons in our brains, each with 1000 synapses. The result is 100 trillion interconnections. It will take years to count them.  Human brain has 1011 neurons and 1014  synapses (neuronal connections) in the brain. It has 170,000 kilometers of nerve fibers laid out all over and 12 hyper-connected hubs that help direct traffic flow. This makes it extremely difficult to unravel the complex functions performed by the brain unlike other organs. Intelligence and consciousness are still mysteries for which mechanistic processes are yet to be defined. Here is a machine which renews by itself, changing its connections ever, expands and refurbishes parts which are constantly used, cleans by itself and changes its mode of operation at night. Although electrically operated there is no comparison to other such machines. Paths to knowledge regarding this machine always had been bumpy and rough. 

  Mind readers of new era

           But we know about our brain much better now than we knew twenty years ago. Rapid advances in computational neuroscience, imaging techniques, genetic manipulations and combinatorial studies using several other techniques led to the revision of many of the functional aspects of brain as a whole and as in part. Neuroscientists started shifting to scanning labs and some to molecular biology and genetics  labs. Many had to land in computer labs or needed collaborations with them.Psychiatrists and psychologists were compelled to read and study new neuroscience books or get trained under neuroscientists. Many working on computers landed unexpectedly in neuroscience laboratories.

      One of the machines, mainly used in hospitals for diagnosis caught interests of neurobiologists. That was Magnetic resonance imaging machines. Like an X- ray  of the soft tissue MRI will show detailed anatomical images. Functional MRI or fMRI  would differentiate brain areas during mental tasks such as arithmetic or reading. It displayas changes in blood supply to active areas. Diffusion MRI or diffusion imaging, also called tractography tracts would reveal brain’s long-distance connections by tracing water molecules  which can diffuse along the length of axons more freely than escaping through the layaers of fat covering them. 

fMRI-Your emotions in pictures 

Functional MRI changed the pace of investigations on brain functions changing the course of neuronal function. Invented only about 25 years ago this technique is still advancing. We could look at what is happening in the brain exactly at a moment when you are using your brain for a special purpose, for example praying, composing a song, writing creative poetry or falling in love. This facility changed the norms of functional analysis of brain in general. The underlying principle is that blood rushes to that part of the brain where it gets active. fMRI in fact detects alterations in oxygen-bound or unbound form of  hemoglobin. When neurons fire there is an increased demand for energy and the molecule which supplies immediate energy, ATP is made by the neurons. This process requires oxygen-in fact that is the reason why we breath in oxygen!-which is delivered by hemoglobin.  MRI detects this shifts and the image will display as an active spot. The process is named BOLD-blood oxygen level dependent-MRI.


   fMRI paved the way to a revision of function and  structure relationship in the brain. Besides, it helped elaborate detailed operative modalities of many of the working mechanisms of our brain. Most of the exact spots in brain helping to form and store memories were elucidated by fMRI. Although we know about centers of speech and comprehension it was fMRI which brought out the  mechanisms of relationship build- up for these functions.   fMRI can provide information on brain activity when nothing special is going on. Named ‘resting stae fMRI’ this technique would pinpoint pathophysiologiacal alterations and locations, along with regional interactions and functional connectivity of motor pathways. This has helped in the diagnosis of Parkinson’s disease and Alzhimers’s disease.  .

        The spots of emotions in our brain had been pinpointed earlier by physiological and electrical measurements and similar observations. fMRI brought in another wrinkle here, specifically picturizing the regions. In the late 1990s this did not gain much validity but as more data arrived and  many of the single observations on individuals got ratified by worldwide observations the technique gathered momentum. This was a huge leap: one could observe the brain behaviour on the spot when an emotion is felt by the subject being studied. Emotions and brain function got redefined in the sense that each emotion had a specified neuron network center getting activated and the location specified functional variations. Since it is a real-time measurement the exact working mechanism of each emotion could be studied in detail.

     There are confusions on deciding which all emotions are the basic ones. Out of many, fear, anger, joy and sadness are the basic emotions and each emotion has its own dedicated neural circuitry that are architecturally distinct. There are proposals that basic emotions comprise seven, namely fear, anger, happiness, sadness, disgust, interest, and contempt. However, many fMRI studies could not decipher them with exactness and differentiating basic  emotions with other emotions with distinct universal signals were not clear, especially the localization in the brain. This has led to more controversies about the basic emotions. The conundrum has the basis in the question whether for each of the ‘basic’ emotion we can spot a place in the brain.  Or, are those the basic emotions which could be distinctly denoted in brain?

    Happiness evoking centers have been well delineated by fMRI studies. Activation in the ventral prefrontal cortex, the cingulated cortex and the ventral striatum were associated with happiness. It is not clear whether these areas are associated with the feeling of pleasure, since damage to this area does not totally deprive the feeling of euphoria. It could be the orbitofrontal cortex which transforms pleasure stimuli into cognitive representation. Another region, ventral tegmental area also could be participating in feeling of reward and happiness. This area is responsible for the release of dopamine to locus coeruleus, prefrontal cortex and anterior cingular cortex and for the cognitive effect of positive emotion.  To create the feeling of sadness anterior cingulated cortex holds responsible and it is this area which induces vocalization for crying response , proven by imaging studies. Fear center is amygdala and many fMRI studies have supported this. Several aspects of fear processing has been attributed to amygdala including fear conditioning and initiation of fear induced behaviors. Also many studies have found that amygdala is involved with many other negative emotions such as stress or anger. Regulation of anger is manifested by the interaction of orbitofrontal cortex and amygdala and many fMRI studies have suggested this. During angry stimuli left amygdale is activated. Although amygdala is known as the fear center, communication with orbitofrontal cortex , which is involved in fear extinction may lead to anger.  Disgust and anger centers share spaces as to new imaging-insula is this key center.

Emotionotopy-Emotion perception, valuation and regulation

  Thus fMRI images are telling us how emotions could be defined and how they could be related by the location they assume in the brain. Now it is certain that emotions are deemed by the physiology of neurons in specific centers such as ventromedial frontal cortex for happiness, amygdala for fear, anterior cingulate cortex for sadness orbitofrontal cortex for anger. But with the advent of more fMRI studies it was proved that this is not the full story. It is not simple as it is. Many of the centers like amygdala respond to fear, anger and disgust. Emotions span over many of these brain centers and a single emotion cannot be exclusively assigned to a single brain area. Behavioral and physiological characteristic of emotions could be more appropriately described along a number of continuous cardinal dimensions generally one governing pleasure versus displeasure (valence) and another one the strength of the experience. (arousal). Another dimension could be dominance or unpredictability. All the aforesaid centers such as insula, amygdala, ventral striatum, anterior cingulate, ventromedial prefrontal and posterior territories of the superior temporal temporal cortex  can be activated for a variety of emotions and the intensity and geometry of activation in three dimensional planes can determine what emotion needs to be elicited.  Although we have clear understanding on the centers which constitute emotions much is not known how and where emotions are processed and where a stimulus would be initiated. Recent studies on locating where emotions are registered have brought in novel revelations on brain mapping. The investigators had the argument that it was unclear which mechanisms link descriptions of affective states to brain activity, also emotion processing is local or distributed. We know that the processing is executed in the cortex but that spot has not been clearly designated yet.They used an emotionally charged movie to be watched by the participants and recorded by fMRI.

     Such a pioneering study established that three dimensional gradients work on emotion centers and a small area designated right temporo-parietal cortex is the principal emotion coding area in the brain. The major finding was that emotions are encoded within three independent but overlapping gradients:  A. Polarity   B. Complexity C. Intensity Three orthogonal and spatially overlapping gradients encode the polarity (refers to the opposing measures of positive or negative feeling states),complexity (refers to the amount of variance between emotions when they combine) and intensity ( refers to the arousal level of each experienced emotion). Thus the current norm on emotion encoding is that specific regions of temporo-parietal cortex code unique emotional experiences by responding to the spatial position in a geometric field. The scientist who proved this have named this process as “emotionotopy”.

    With refinement, fMRI could become useful for diagnosing personality or mood disorders by showing us the brain areas being stimulated during certain periods of sadness, anger, and anxiety. Such applications could help with identifying emotional experiences in individuals with impaired awareness or compromised ability to communicate.

       A multimillion project is underway to elaborate on  human brain connectomes (all the neural connections together) using fMRI studies on a huge sample population. The BRAIN Initiative is developing techniques that will pick out the finer circuits in the brain, bridging the gap between the studies examining single neurons and the large scale fMRI maps.

Light! Optogenetics! Action!

  Activating neurons specifically used to be a cumbersome job. It doesn’t have much specificity, may last longer than you desire and would lack precision. Electrodes probing into brain tissue can cause damage. Neural circuits need to be precisely mapped and manipulating neural activity would elaborate on working mechanisms of brain activity. More importantly this could lead to treatment regimen for many of the neural diseases. By 2005 a new technique was available which integrated genetic engineering, protein biochemistry and photo-activation. Proteins called opsins, first discovered in green algae Chlamydomonas reinhardtii are light sensitive and when introduced into neurons by cloning techniques could activate them only when blue light is shone on them. The protein channelrhodopsin  (ChR2) is in fact opening a cation chanel in blue light, depolarizing (inducing electrical activity and transmission) neurons. There are opsins which could inhibit the neuron activity too. Thus activating or inhibiting specific neuron’s activity can unravel the intricacies of neuronal circuits and pinpoint the functional connections, not just structural pathways. 

   Optogenetics rapidly revealed communication details between neurons Dissecting intricate connections of neural circuits has been a long standing challenge and the new technique elucidated intricacies in circuit connectivity. Projection fibers which are bundled neuron highways had been difficult to trace all through since they traverse through many brain centers and now optogenetics has made it possible to trace their trajectories. The complexity in identifying which all neurotransmitters are being released by certain neurons has been explained. Thus, for example some neurons release dopamine and glutamate and it was not clear the same terminals release these. Many properties and functional aspects of synapse (the junction where the tail end of a neuron meets with the head end of another neuron and transmit information) have been elegantly described by optogenetic techniques. This technique is extremely powerful  tool to investigate the functional role of specific neural circuits in animal behaviour and physiology. For example now we have specificity on neuron clusters employed for hearing and vision. Exact neuron groups have been identified in the visual cortex which perform to focus images, correct the rientation and to sharpen images, just to pick some examples.

      Brain structure and function relationship studies took a surge ever since optogenetics  claimed a crucial place in the neuroscientists’ lab, either regarding neuron to neuron communication or interaction between large brain regions. Many of the questions were asked again using this tool:how memory is stored, where the location of fear is, how risk and reward are calculated, how brain is altered after a stroke are some of them. Optogenetics enables to analyze circuits and neuron conductance with unprecedented spatiotemporal precision. More information on neuron connections is revealing the functional roles of cell-type specific connections in governing sensory information processing , and learning and memory in the visual cortex, somatosensory cortex and motor cortex.  

     Optogenetics has been used to pinpoint neuron centers regulating behaviour  too. Since the stimulation is regulated by an easy manipulation of light being turned on experiments on moving animals are manageable. Studies on circuits involved in complex behaviours and neurological diseases have been performed in Rhesus monkeys, indicating a wider applicability of optogenetic techniques. Opsins other than ChR2 have been discovered and are being used, some of them acting at high speed enabling stimulation of some type of neurons for longer times. Opsins activated by different colors of lights also are very effective in stimulating different groups of neurons in tandem or in sequence.

  One major limitation in optogenetic technique is that the skull need to be broken and the light source deeply placed in the brain causing bleeding and tissue damage. New opsins with enhanced light sensitivity and stronger light sources which would reach deep brain areas have been devised recently. This avoids any intracranial surgery and now may extend to clinical situations.

Optogenetics lights up clinics

  Optogenetics has entered the therapeutic regimen and soon will be a practical application in disease treatments, especially to cure diseases of the nervous system.  Clinical trials are already undergoing to treat blindness by optogenetics. This includes patients whose photoreceptor cells in the retina have been irreparably damaged. The retinal light sensitive cells (rods and cones) use their own opsin to convert light sensation to electrical signals which are passed on through ganglion cells to nerve fibers, finally reaching the visual cortex. But when rods and cones  are damaged the trick is to make ganglion cells light-sensitive by optogenetic techniques. Opsin gene is transfected on to ganglion cells by injecting viral vectors carrying opsin gene copies. When light strikes, these ganglion cells take up the job normally done by photoreceptor cells and transmit the signals. Handful of companies are actively pursuing clinical trials and soon this technique would be in the clinics. The same technique is being developed for the genetic disease retinis pigmentosa where partial recovery of vision has been achieved. Optogenetics is being utilized for another genetic disease –Duchenne muscular dystrophy and some early experiments in mice are promising. Neuropathic pain does not yield to most of the current drugs and optogenetic methods are being tried now. Techniques are being advanced to treat Parkinson’s disease based on neuromodulation such as opto-deep brain stimulation. Although not used in humans yet, strategies using an epidural (insertion into the spinal cord) optic fiber to deliver  light to the spinal cord and sensory nerves expressing opsins have been successful in mice, paving way to control back pain. Brain regions could be induced to recover using optogenetics after a stroke and phases of recovery could be mapped using fMRI.

Deep brain stimulation

    Although not a novel technique, deep brain stimulation has acquired precision and exactness. It has been revolutionary for the treatment of Parkinson’s disease, epilepsy, Tourette’s syndrome and even obsessive compulsory disorder. The treatment involves providing short pulses of electricity to specific areas responsible for the above said diseases where an electrode will deliver beneficial stimulation to malfunctioning brain circuitary. New electrode systems combine two recent advancements :sensing capability to monitor brain signals in real time and directional lead that enables steering of electrical current for more precise targeting. Advances in fMRI imaging has benefitted these procedures and these two methodologies together would pave new avenues.

Brain computer Interface

       Brain has been called a super computer and  it is belittling to call it so.  It is a long way for a computer to mimic all the functions of the brain. Computers facilitate gathering knowledge from sensors placed in the brain and that would unravel the intricacies of brain network  In reciprocation this would lead to regulating some of the brain functions by chips implanted inside the brain. Brain-computer interface (BCI) allows computer and the brain work side by side, translating modulation of brain signals  into computer commands and is now widely used for medical therapies and is emerging as assistive device for those with defects in brain functions or spinal cord injuries.  Tiny chips called neurograins are implanted in the brain to sense electrical pulses made by the firing neurons and send the signals to the computer wirelessly. Thus a patient who has spinal injury and cannot move his arm need just think about giving a command to move his arm and the sensors can collect these signals and move a robotic arm. Those paralyzed after a stroke who could not speak could spell words mentally and communicate with the family using brain-computer interface. The patient need to look at a computer screen and select letters or words, The sensors are able to pick up this information and decipher meaning to it. Thus we have clearer understanding on brain networks performing thought processes.

Deep learning-marriage of mind and machine

 Human brain can perceive, remember and recollect billions of images when necessary. If a computer has to do this all images should be numbered or categorized. But computer scientists are trying hard to improve on this. They are testing many models. Computers are engaged in ‘deep learning’. Deep learnng denotes a machine –learning system using artificial neural networks with multiple hidden layers. Big advances in artificial intelligence were heavily supported by deep learning. The major question is how learning occurs. Since we do not have an appropriate model for this from the studies on brain, it is expected that computer intelligence generated networks may present a model which could be used to test on brain networks. Both of these fields, brain function physiology and computer based artificial intelligence (AI) would advance by these types of novel ventures. By mimicking auditory cortex (the area in the brain for hearing) network functions computer scientists have created deep neural networks and taking this back to the brain could decipher which areas of the cortex perform speech recognition and which recognize music. The distinction that brain can learn unsupervised is still a challenge to computers but artificial intelligence is creating smart machines which are capable of doing this. The impact AI is going to have on neuroscience is huge.

Gut bacteria can regulate brain function

  Once considered a parasite, later found to be of minor function in the intestine, gut bacteria have now dominated as a regulator of our physiology, especially our brain. Gut bacteria have a hot wire to the brain:the vagus nerve which descends down from the brain to stomach and intestine which could be taking messages from gut bacteria to the brain and probably backwards too. Now they are known to alter the brain, designated as a major influencer and could be key for treating Parkinson’s disease and Alzheimer’s disease.

    Neurotransmiiters, the essential message conveyors between neurons could be made by gut bacteria. A large proportion of serotonin is produced in the gut and another one which controls feelings of fear and anxiety, gamma-amino butyric acid also is made by them. Thus certain probiotics (supplemental bacterial pill you can swallow) can reduce anxiety and depression at least in laboratory mice. These bacteria make copious amounts of short-chain fatty acids (SCFA) by digesting fiber and these chemicals are known to affect appetite, alter the brain  in such a way that reward sensation from high energy food is limited. Another SCFA, butyrate can affect blood brain barrier. By affecting inflammation through immunity alterations gut bacteria can induce brain disorders like depression and Alzheimer’s disease.

   In Parkinson’s disease the neurons start to die at a spot and this is because a protein called synuclein misfolds. A particular gut bacteria also has this tendency and the current theory is that through vagus nerve the protein moves to brain to cause Parkinson’s disease. In people whose vagus nerve has been severed to curb acid production in the stomach, Parkinson’s disease is rarely seen. Another debilitating brain malady ALS (  amyotropic lateral sclerosis) also has been shown to be influenced by gut microbiome. Transplantation of certain bacteria has been shown to ameliorate mouse ALS.

  The influence of gut bacteria in infants is being studied in detail and causes of autism spectrum disorder (ASD) is believed to be originating from gut bacteria. Infection in a mother during preganancy seems to increase the risk of ASD, having a 79% higher risk of being diagnosed with ASD. In mice some of the ASD like behaviour could be reversed by a certain kind of bacteria (Lactobacillus), which produce a certain kind of metabolite which affect the brain. Now these bacteria are used to test whether treatment as probiotic would alleviate the symptoms of ASD. For premature babies the risk of brain damage is high and it has been found that the overgrowth of the bacterium Klebsiella in the gastrointestinal tract is the cause. These bacteria alter the immune system in such a way that brain development is affected. It is becoming clearer that gut-immune-brain axis is crucial in proper development of brain structure and function.

New findings on memory formation

       Electrophysiological recordings and optogenetics are facilitating the elucidation of memory formation. Specific types of neurons within the memory center have been identified for associative memories. Most of our memories are associative, meaning we relate one memory with the memory of an unrelated thing or event. You may remember a song along with a particular event or a smell and a location being remembered together.  It was not known how exactly this happens and now it has been clearly shown that specific cells of the medial temporal lobe, called fan cells are controlled by dopamine, a chemical involved in our experience of pleasure or reward. Fan cells compute and represent the association of the two new unrelated items, odor and reward but they need dopamine too.  Without these particular cells memories could be formed but during a recall two memories may not arise together. Since these kind of disjointed memories happen during Alzheimer’s disease, new avenues could be opened to tackle the disease.

 Epilogue-mind reading is real!

         Now it is almost certain that advances in brain structure and function research would materialize with three supporting components-computing, imaging and molecular genetics. With the addition of micro-and nano-technologies and their integration with chemical engineering, chemistry and biomedical engineering we have been enabled with the emergence of a new discipline , namely lab-on-a-chip or micro-total analysis system. Memory chips may transcend from fiction to reality. Artificial intelligence innovations borrow heavily from brain function models but these two are now mutually dependent. Machine learning is far behind in constructive mode compared to actual brain learning. Synaptic plasticity-the ability to alter neuronal connections to the demand and refresh and update neurons-is something even a supercomputer cannot manifest and we need novel techniques for in depth studies of this phenomenon. Memory conservation, storage and retrieval mechanisms do not have a simulatable  parallel yet in the computer models. Brain-computer interface can read one’s mind, a fictitious thought until recently. Single neuron studies, once thought impossible is a routine in many of the labs, enabling holistic representation of the brain state. Such studies would unravel precise working mechanisms of the brain and lead to new therapeutic modalities for many of the deadly neural diseases.












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