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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