There are two important reasons for studying neuroscience.
The first is to get a mechanistic understanding of how we think,
feel and act.
And that's the main thing that we focused on in this course.
The second important reason for studying neuroscience
is to try and alleviate the many brain diseases.
That's what we're going to focus on in this video.
It turns out that the prevalence and socio-economic costs
of brain disorders are simply staggering.
In 2011, in an important publication in the European
Neuropsychopharmacology journal, Gustavsson et al. estimate
the cost of disorders of the brain in Europe in 2010.
Gustavsson et al. investigated the overall burden of brain disorders
in 30 European countries, they have a total population
of somewhere over 500 million people and the total economic gross domestic
product of these European countries is on the order of 14 trillion euros.
The brain disorders turn out to have an economic cost
of somewhere around 800 billion euros.
That's over 5% of the total GDP of Europe and that comes out to be
somewhere around 1 trillion U.S. Dollars.
Out of this cost, about 40% are direct medical costs,
20% are direct non-medical costs, and another 40% largely relate
to the lost work hours.
The economic cost is enormous and perhaps more importantly,
the number of people suffering from brain disorders is simply staggering.
It's at around 150 million people and up, so well over a quarter
of the population of Europe are in some way affected
by brain disorders as estimated by Gustavsson et al. for the year 2010.
These numbers for Europe are comparable and in fact,
slightly lower than estimates for the United States
so there's no hint of exaggeration and the impression is that
with an aging population across the world
and certainly in Europe, the number of people
and economic costs are only going to go up
in the future.
So the scale of the problems of health related to brain disorders
is simply enormous.
Gustavsson et al. divided the analysis of brain disorders in Europe in 2010
into 19 different categories of brain disorders.
Here, I've ranked them according to their estimated economic costs.
On top of the list are mood disorders that affects some 33 million people
and cost some 113 billion euros.
In mood disorders, this is largely dominated
by depression.
Dementia, incorporating such diseases as Alzheimer's, dementia affects
some 6 million people in Europe and costs around 105 billion euros
in the year 2010.
Psychotic disorders including schizophrenia
affects some 5 million people and costs some 94 billion euros.
Anxiety disorders including panic disorders,
post traumatic stress disorder affects some 69 million people
and costs 74 billon euros and addiction,
largely drug and alcohol abuse affects 16 million people,
costing some 66 billion euros.
Just these top five brain related disorders
affect more than 100 million people in Europe
and cost over 400 billion euros as estimated by Gustavsson et al.
in the year 2010.
So the scale of the problems are rather significant.
In this video, we're going to take a look at Parkinson's disease
that affects perhaps some 1.2 million people in Europe
so that's about 1 in 500 people and costs around 13.9 billion euros
in terms of the direct and indirect costs for European countries.
Parkinson's disease was well described by Dr. James Parkinson
in 1817 in his <i>Essay on the Shaking Palsy</i>.
He described an age related, slow, progressive, neurodegenerative disorder
and the early symptoms of Parkinson's disease include bradykenisia,
so that's slowness of movements, difficulty in initiating movements,
a problem with walking and stance, tremor, shaking.
That's the shaking palsy that Parkinson described
in his essay, and rigidity.
That's contraction of muscles in an unwanted way.
These motor symptoms gradually get worse
as the neurodegenerative disease progresses and at later times,
other symptoms also become important like dementia and depression.
These are clearly very debilitating symptoms
and make it impossible for the Parkinson's patient
to have a normal life.
The symptoms of Parkinson's disease appear to be caused of the degeneration
of dopaminergic neurons in the <i>substantia nigra pars compacta (SNc)</i>.
So that's a part of the brain that we've already discussed
in previous videos.
Here you see it in the mouse brain, the location of
the substantia nigra pars compacta, the dopaminergic neurons
that send their axons to the stratum, and that's where
they release their dopamine.
This seems to be the major place of neurodegeneration
that causes the motor symptoms of Parkinson's disease.
Interestingly, the dopaminergic neurons of the ventral segmental area
seem to be less affected when they send their axons
to the nucleus accumbens and to the prefrontal cortex.
They seem to be less affected by this disease.
So there's some specificity it seems in the degeneration of the
substantia nigra pars compacta neurons.
These dopaminergic neurons have some cytoplasmic,
protein-rich inclusions that have been termed
Lewy bodies, and they contain the protein alpha-synuclein
in quite a high concentration.
That may be that alpha-synuclein aggregates are causally related
to the degeneration of these dopaminergic neurons.
By the time of clinical motor symptoms are diagnosed,
it's estimated that about 60% of the dopaminergic neurons here
in the <i>substantia nigra</i> are already dead.
In terms of the amount of dopamine here, in the striatal,
it's thought that there's about an 80% decrease in the dopamine content here
of striatal dopamine.
There's a massive loss of dopamine by the time clinical symptoms
of Parkinson's are diagnosed.
It's likely that they'll presumably be earlier symptoms that are more difficult
to find by the clinicians and in the future research,
it'll be important to try and study how early one can diagnose
Parkinson's disease.
In fact it seems that the neurodegeneration
may not begin in the substantia nigra pars compacta
but might be coming up
from the brainstem or from other areas
of the periphery and it's thought that maybe
alpha-synuclein in a prion-like process
might actually be spreading along different synaptic pathways.
By the time the endstage of Parkinson's disease,
it's clear that there are Lewy bodies, and degenerating neurons
even in the neocortex, and so a large part of the brain
is in fact affected by Parkinson's disease.
Nonetheless, the most important symptoms of Parkinson's disease
are thought to be caused by the degeneration here
of these dopaminergic neurons in the substantia nigra pars compacta.
The disease is probably generated by a mixture of the environmental
influences and genetic susceptibility, just like most diseases
that one can think of.
It's likely that anything that causes the degeneration of
these substantia nigra pars compacta
dopaminergic neurons, will give rise to the same motor symptoms
that are similar and common with Parkinson's disease.
In the clearest demonstration of environmental influences,
inducing Parkinsonian symptoms was through the illicit use
of intravenous drugs that were unfortunately contaminated
with <i>MPTP</i>,
<i>Methyl-phenyl-tetrahydropyridine</i>, <i>MPTP</i> was then injected
intravenously together with the illicit drug
and that relatively rapidly induced Parkinsonian-like symptoms
in quite a number of people who took this drug.
The mechanism of action of <i>MPTP</i> has then been investigated.
<i>MPTP</i> is lipophilic, it crosses the blood brain barrier
so it can enter into the brain and in the brain, it's metabolized
to another compound called <i>methyl-phenylpyridinium (MPP+)</i>
it's a cation.
And this compound, MPP+ is toxic and it appears to induce
mitochondrial toxicity and in fact, a great deal of evidence suggests
mitochondrial toxicity in the degeneration of the dopaminergic neurons
from different perspectives.
In animal models, it turns out that MPTP causes Parkinson's-like symptoms,
and also a loss of dopaminergic neurons and indeed that's one of the experimental
models that people try to mimic Parkinson's disease so that they can see
what the possible treatments are that might work.
Other environmental influences that have been recognized
include pesticides and insecticides and in rural areas,
it seems that there's in general, often an increase in the prevalence
of Parkinson's disease.
Now not everyone who lives in the environment
where pesticides or insecticides are being used gets Parkinson's disease
and so it's probably likely that it's an interaction
between the gene and the environment that causes the prevalence
of Parkinson's disease.
Indeed, it's very clear that there are genetic influences that affect
Parkinson's disease.
Somewhere between five and perhaps up to 50% of Parkinson's disease
has some genetic element associated with it.
And there have been a great number of studies carrying out
so called genome wide association studies where they look at the prevalence
of Parkinson's disease with different genetic mutations
in the population.
Many different so called susceptibility loci have been identified,
regions where there are mutations that correlate with increased prevalence
of Parkinson's disease.
Here, I'll just highlight two genomic regions
that have been associated with increased chances
of Parkinson's disease.
The first one is alpha-synuclein and that's an interesting target
that's been identified in these genome wide association studies
because alpha-synuclein is one of the key proteins
that's sitting inside the Lewy bodies and might be causally related
to the degeneration of these dopaminergic neurons.
So quite a number of different mutations have independently been found
in alpha-synuclein so that it increases the confidence that this is real
and some of the mutations turn out to be very powerful so there's a mutation here
in Amino Acid 53 of alpha-synuclein that turns out to be dominant
and that means that it's very likely that you get Parkinson's disease
if you have this mutation, whereas other mutations
for example REP1, a dinucleotide repeat expansion,
it's sitting somewhere upstream of alpha-synuclein
so it's a regulatory element and that has a much smaller effect
and might just change the timing of when Parkinson's disease might happen
or increase the chances in a small way.
So there are different mutations in the genomic area surrounding
the alpha-synuclein gene and that has varying strengths of influence
upon the probability of a person getting Parkinson's disease.
Another gene that's been implicated is <i>LRRK2 Leucine-Rich Repeat Kinase 2</i>
again, many independent mutations have been found that associate
with Parkinson's disease and there's some hints
that some aberrant kinase activity might be responsible
for the deficits induced by <i>LARRK2</i> mutations.
However, I think it's important to point out that we don't know
the normal physiological function of alpha-synuclein or LRRK2
and so it's clear that a great deal of basic research needs to be done
before we can understand the link between these mutations
and Parkinson's disease.
One of the good things about Parkinson's disease
is that there are relatively efficacious treatments for many of the symptoms.
<i>L-DOPA</i> treatment is the first line of treatment in Parkinson's disease
and this was something that was developed in the 50's by Arvid Carlsson
and in the year 2000 he won the Nobel Prize
for his work both in terms of identifying dopamine as a neurotransmitter
and also for developing what ultimately is still the first
and most successful treatment against Parkinson's disease,
which is <i>L-DOPA</i>.
And <i>L-DOPA</i> treatment makes a lot of sense.
We know that Parkinson's disease results from the degeneration
of dopaminergic neurons so there's less dopamine in the brain
than there should be and one way which one might go
and try to alleviate the symptoms is to increase the amount
of dopamine in the brain.
Now dopamine doesn't pass the blood brain barrier
so you can't just give a patient dopamine but you can give the natural precursor
in the synthetic pathway of dopamine, <i>L-DOPA</i> that does cross
the blood brain barrier, it enters into the brain
and the normal enzyme used in synthesizing dopamine
<i>DOPA decarboxylase</i> can then act on the <i>L-DOPA</i>
that's been administered just as a pill that you can take.
It releases dopamine into the brain and it causes a remarkable benefit
and alleviates the symptoms of Parkinson's disease.
However, high doses and long term use of <i>L-DOPA</i> are associated
with quite serious side effects.
Including dyskinesia where unwanted movements
are initiated and in some cases also, overall changes in character of the person.
So when the drug treatments fail, then some of the symptoms
of Parkinson's disease can be alleviated by so called deep brain stimulation.
<i>DBS</i>.
Deep brain stimulation consists of implanting
electrodes into the brain, and at the tip of these electrodes
one can then drive currents and stimulate the area of the brain
that's targeted by this electrode that's implanted into the brain.
What turns out to be successful in the treatment of Parkinson's disease,
is targeting these deep brain stimulation electrodes to the so called
<i>subthalamic nucleus (STN)</i> that's colored in red here,
in the schematic coronal section of the human brain.
Also indicated are other parts of the basal ganglia.
So the sub thalamic nucleus that we haven't discussed yet
are the glutamatergic excitatory neurons of the basal ganglia,
whereas these other blue colored structures
are gabaergic neurons of the basal ganglia.
So we've already discussed the striatum and in the human brain
this can be divided into two parts the Caudate and the Putamen
they're both part of the same striatum and they're just divided in two,
by axonal pathways of cortical parametal tract
with the internal capsules, so these are largely the same types
of cells and both are part of the striatum.
The striatum as we know, projects both to the Globus pallidus
and it projects to the substantia nigra and also the so called internal segment
of the Globus pallidus.
The subthalamic nucleus provides an excitatory drive onto other parts
of the basal ganglia.
So these electrodes are implanted bilaterally into the human brain
where they are placed in the subthalamic nucleus and neurophysiologist
helps the neurosurgeon guide this electrode to the right place
in the brain, this is a small structure, it's a difficult surgery to do,
but when it's successful, the recovery in terms of alleviating the symptoms
of Parkinson's disease is really quite remarkable.
So after implantation surgery and recovery from the surgery,
then high frequency stimulation is applied to the tips of these electrodes
and there's 100 Hz stimulation, so every 10 milliseconds
there's a stimulus delivered here at the tip of these electrodes
and that's done continuously throughout the life
of the Parkinson's patient.
That turns out to provide an almost immediate relief
of the symptoms.
You can learn more about Deep Brain Stimulation from looking at YouTube videos
which I think are really quite informative and one that I like
is by Professor Hagai Bergman of the Hebrew University of Jerusalem.
He's one of the inventors of Deep Brain Stimulation and neurophysiologist
who's studied Parkinson's disease and the basal ganglia
for a long time.
You may also be interested in the self report of Andrew Johnson
a patient who has been implanted with Deep Brain Stimulation electrodes
shows how efficacious the brain stimulation is.
What's remarkable about Deep Brain Stimulation in general is that
there are more than 100,000 patients already implanted
with stimulation electrodes and so clearly, this is a successful
treatment in late stages of Parkinson's disease
that can help patients dramatically.
Unfortunately, the mechanisms by which Deep Brain Stimulation works
is more or less mysterious.
Here we put the neural circuits that connect the sub thalamic nucleus
to basal ganglia, Thalamus and Cortex, to try and put together some idea
of how it might be working.
So the basic deficit with Parkinson's disease
is the degeneration of the dopaminergic inputs to striatum
and also the subthalamic nucleus.
Now we've previously noted that dopaminergic input
tries to potentiate the <i>D1</i> pathway, the pathway from Cortex,
running through the direct striatal projection neurons but then inhibits
Substantia nigra pars reticulata and the Globus pallidus
internal [inaudible] output of the basal ganglia.
So if we now remove the dopamine then that'll cause a decrease
in the efficacy of this pathway, so in Parkinson's disease,
we think that there's going to be a deficit in this pathway,
and conversely, the <i>D2</i> pathway may well be upper regulated.
So if we remove the inhibition here, the Globus pallidus internal neurons
and Substantia nigra pars reticulata neurons are perhaps
going to be overactive.
That means that they're going to inhibit the thalamus
more than they should be doing and they'll then shut down
the overall motor output equally of course.
Substantia nigra has descending projections
to the brain stem motor areas and again, this will then
cause a decrease in movement.
And that's then consistent with much of what we know about Parkinson's disease.
There's Bradykinesia, difficulty in initiating
movements and that could then, reflect this decreased importance
of the direct striatal projection neurons mediated via
a loss of dopamine, and then a lack of stimulation
of the <i>D1</i> receptors.
Now, if we stimulate the subthalamic nucleus, and that's what we do
with the Deep Brain Stimulation.
The first notion would be that we stimulate these neurons,
cause axon potentials in the subthalamic neurons
and that would then release glutamate upon it's target structures.
That would be stimulating the Globus pallidus and Substantia nigra
and these GABAergic neurons would then be causing
further inhibition and would then apparently be doing the exact opposite
of what one would want.
So apparently that's not how Deep Brain Stimulation works
and so other ideas have come up.
One idea is that the 100 Hz stimulation of the subthalamic nucleus,
instead of stimulating this nucleus, actually inactivates it,
so high frequency stimulation might be acting to inactivate
this nucleus and that would then reduce the excitation of the Globus pallidus
and that would then allow motor output to take place.
And so that's one possible way in which the Deep Brain Stimulation
might be working.
Other hypotheses are that actually it's not the stimulation
of the subthalamic nucleus itself, but rather of the axons
that are terminating in that region that mediate the positive effects
of Deep Brain Stimulation.
So it could be that it's actually stimulation of the cortical neurons
that project here that cause the positive effects
of Deep Brain Stimulation, or perhaps it's because of
the Globus pallidus axons that are being stimulated
or dopaminergic innovation here.
There are many possible ideas as to how the Deep Brain Stimulation
occurs whether it's an activation of these neurons or an inactivation
of these neurons, or whether it's affecting the other components
that are sending the axons here or perhaps it's because there are unusual
rhythms in the Parkinsonian patient, there are high frequency, 10 to 20 Hz,
so called BETA isolations that are prominent
in Parkinsonian patients and perhaps stimulating
subthalamic nucleus disrupts those BETA osolations
and that might be how it works.
I think what's clear is that further research
is needed to understand how Deep Brain Stimulation works,
and of course, if one gains an understanding of that,
one may be able to target better therapies
or better stimulation methods to be more specific,
because of course, the Deep Brain Stimulation also comes
with a variety of side effects.
So in this video we have seen that there's a variety of brain disorders
that make a large socio-economic impact upon the world.
Neuroscientists are working hard to try and understand these brain disorders,
try to come up with cures, and at least to alleviate the symptoms.
That's what we see in the context of Parkinson's disease
where we know some of the things that go wrong in the brain,
that are associated with Parkinson's disease.
We know about environmental influences, we know about genetic
susceptibility loci.
There's still a lot of work to be done
for Parkinson's disease and also of course in terms
of alleviating the symptoms, and of course, most importantly,
would be to try to cure the disease and prevent the degeneration
of the dopaminergic neurons.
The same of course is true for the many other brain disorders
and I think what's clear is that the scale of brain disorders
in both the social and economic costs are such that it's really important
that a vast amount of brain research is carried out in the future
so that as rapidly as possible, we can help those suffering
from various brain diseases.