Welcome back to this tutorial on the Modulation of Movement by the Basal Ganglia. And now we turn to part three, which is about normal and abnormal modulation of movement by the basal ganglia. So my learning objectives for you are first, that I want you to explain. The hypokinetic movement disorders in terms of the function of basal ganglia circuitry. And I want you to consider the hyperkinetic movement disorders in terms of the function of the same circuitry. So to set the stage for this discussion of abnormal function, let's first recap what we've understood about normal basal ganglia function. So, the neurons of the striatum they begin to fire just before and during the onset of movement. So this suggests that the role of the basal ganglia- Is the initiation and the suppression of movement. But the basal ganglia are much less critical during the ongoing expressions of a motor program. As we'll see in a future session, that's the function of the cerebellum. And what I want you to understand that it's the balance in the activity between the direct and the indirect pathways. That mediates the initiation and the suppression of movement. By analogy, we can think about this as a kind of center-surround antagonism, not for receptive field structure, but relative to what we can possibly do with our motor system. Let me illustrate what I mean with a highly conceptual figure. Let's imagine that we intend to make a voluntary movement. So this is where we want to be. We want to activate a specific motor program, that's appropriate for the movement goal at hand. Well, in order to do that what must happen is we need to release the activity, of the motor thalamus, which can drive the output of the cortical spinal neurons in the motor cortex. Release of the motor thalamus, means that we need to have a way of shutting down the inhibition Of the internal segment of the globus pallidus, and that's where this direct pathway comes in. So the direct pathway via the caudate and the putamen, sends inhibitory signals into the internal segment of the globus pallidus, which then removes the inhibition. Consequently, the motor thalamus is released and fires action potentials that then trigger the output of the motor cortex. So this is what happens with respect to the motor programs that we actually intend to activate. Well what I want you to appreciate is that There is a, a large surround of possible movements that could interfere or antagonize the desired motor program. So, while we have a specific program in mind to activate. Bait. We also want to enforce the suppression of all other possible motor programs that pertain to the same musculoskeletal units. And this is where this concept of surround inhibition I think might be useful. So we can think of this surrounding repertoire of movement that we want to suppress. As being under the influence of the indirect pathway. And that surround comes in play schematically by this[UNKNOWN] . So we imagine that there is a kind of movement surround being represented in the thalamus that we want to suppress. With this activation of the indirect pathway. So, if anything, to facilitate the specific expression of movement, we want to make sure that nonsynergistic movements or antagonistic movements. Are held in check. So, the activity in the indirect pathway then, serves to reinforce this inhibition of this surround of potential movement. And that's where the subthalamic nucleus comes in. So, when we activate the indirect pathway, we are driving the subthalamic nucleus to increase the inhibitory output of this internal segment of the globus pallidus. So this center surround model I think is, is a useful way of considering, how is it that we can execute a very particular movement Like a visually guided reach. So as I'm expressing this, sort of, reaching and pinching motion, I'm supressing all other kinds of activities that potentilaly could be done with the same muscular skeletal units, and so the focused activation of a very particular motor program Requires a shift in balance in favor of the direct pathway for this particular motion, and the suppression of all the other unwanted movement programs that potentially could interfere with the goal of the behavior. Now, I want to apply some of these concepts to some of the disorders of movement that you'll see clinically. And as I've suggested in our opening, there's really a continuum of movement disorders. On one end of the continuum we have disorders that produce too little movement, and on the other end of the continuum are disorders that allow too much movement. So I want to begin first on the hypokinetic side of that continuum. And used a rather familiar example unfortunately. And that's Parkinson disease or Parkinsonism which refers more to the symptoms associated with idiopathic Parkinson disease. So those symptoms involve a reduction in movement. Or perhaps, even a cessation of movement. We call this akinesia or bradykinesia. It involves a highly rigid posture, that rigidity is not exactly the same thing as the spasticity that's seen with damage to upper motor neurons. Rather, it reflects a suppression of movement. That is reinforced by the over activation of the indirect pathway. Somewhat paradoxically, there is a resting tremor that's seen in Parkinson's Disease, particularly in the hands. Sometimes this is called a pill rolling tremor, as if The hands of the patient are trying to roll a pill in the fingertips. But sometimes, the tremor can be a little bit more approximate. And can be expressed at rest. So it seems somewhat paradoxical that we might have a slowness of movement or an absence of movement together with a positive sign like a tremor. But it reflects the activity that is disordered in different parts of the basal ganglia. Well, the bradykinesia doesn't only affect the appendicular movements that we do with our limbs. But it also affects our facial expressions. So, people who are afflicted with Parkinson's disease. They tend to have a reduction in facial expressions. So with the problems attending bradykinesia it's not surprising that there would be disorders of gait. And there's a very characteristic gait pattern that's seen in people with parkinsonism. It is a shuffling of the feet with very small steps. And very little elevation of the foot above the walking surface. So, one of the characteristic signs of Parkinsonism is difficulty initiating and terminating movements. So it's very, very difficult to get a motor program started and then once that program is started It's difficult to terminate it precisely. So we can think of this as a real challenge in shifting from one mode of program to another. From go to stop and to go again. Eventually there are changes that afflict not just the motor system But other parts of the brain as well, so quite tragically, advanced Parkinson's disease often leads to the development of cognitive decline and dementia. Now in idiopathic Parkinson's disease, we typically see these symptoms setting on after the fifth decade of life. So, the underlying neuropathology that makes it appropriate to consider this disorder here, in this discussion of the basal ganglia, is that in Parkinson's Disease, there is a loss of these dopamine neurons that are so important for regulating the balance between direct and indirect pathways. So in order for a patient to present clinically they need to lose some 75- 80% of the dopamenurgic neurons. So sot here is a bit of redundancy built into this dopamenurgic system thankfully but nevertheless with loss of these dopamine neurons beyond that critical threshold one can see the development of the signs and symptoms that I just described for you. So, let's look at the circuitry of the basal ganglia and consider the consiquences of losing this input from the Substantia nigra pars compacta. What we would find is the inability to facilitate the activity of the direct pathway. And then inability to supress the activity of the indirect pathway. These two factors synergize in a rather unforturnate way that results in an increase in the tonic output Of inhibition from the internal segment of the global pallidus to the motor thalamus. So, the problem in Parkinsonism is bradykinesia. A slowness of movement, an absence of movement. That's because the motor thalamus is tonically suppressed, and it's very difficult to overcome that suppression. As a consequence, there is decreased excitation of the motor cortex. And tremendous difficulty initiating movement. So now, let's back up into the basal ganglia, and see why that would be. So if there's too much tonic inhibition. That suggests that the activity in the eternal segment of the globus pallidus is, is too high. And, again, the reason why it's too high is that we have a severe reduction in our ability to inhibit the inhibition. So we have a failure of disinhibition. matters are made worse by the absence of dopamine on our d2 receptors. Which means that we cannot suppress the activity of this indirect pathway. So we have a lot of inhibition coming out of the indirect pathway which will shut down the external segment of the globus pallidus and that means that it's likely that we will have disinhibition. Of the subthalamic nucleus. So the subthalamic nucleus is the main culprit here because it's driving the increased tonic outflow from the internal segment of the globus pallidus. Well, really the principal culprit is the loss of these dopaminergic neurons. But we can see the importance now of the subthalamic nucleus in modulating the output of the basal ganglia, because if we cannot reduce the tone of the subthalamic nucleus we will see a marked elevation in the inhibitory output of the internal segment onto the thalamus. The end result of all of this is bradykinesia. Perhaps even akinesia. Well thankfully collaborations between basic scientists be they neuroscientists or biomedical engineers and the clinical communities have led to the development of new interventions. One that I would invite you to read more about is deep brain stimulation. Now, the idea with deep brain stimulation is to stimulate strategic locations in the circuitry of the brain that will produce a desired clinical outcome. Now, one might imagine that stimulation means an increase in excitatory activity. For the neurons at the tip of the electrode, but that isn't necessarily the case. What we see with deep brain stimulation is a change in the firing patterns of circuits. So in this illustration we see patterns of activity recorded in the basal ganglia prior to turning on the deep brain stimulator. During stimulation, there is obviously an increase in activity, but really fundamentally a change in the pattern. And this change in the pattern of activity in the circuitry of the basal ganglia seems to be what allows for the normalization of motor function. So, there's a lot of[INAUDIBLE] . There's a lot of ongoing study of deep brain stimulation, really trying to understand what we're doing, are we driving expiatory output, are we inhibitory input, are we just adding noise to the system, or are we depolarizing the tissue at the tips of the microelectrods to the point where the insodium channels are inactive and the signaling is lost. Well, I think we're probably doing all of the above. And the point is that it need not matter. that we target one particular type of physiological effect. What really matters for the patient is whether there's freedom of movement. And the goal of deep brain stimulation. Is to normalize patterns of activity in the basal ganglia to facilitate the expression of movement. And, thankfully many people around the world have been helped with this technology and I want to encourage you, if you have access to YouTube or other social media outlets. to go and look at some of the stories of these people who have volunteered their stories and videos of their lives to share with the world. And many of them are just really wonderful personal stories of triumph. Unfortunatly, this approach doesn't work for eveyone. And so we need to be cautious. We need to recognize that this is an invasive prodcedure. it has risks involved. And not everyone can be helped. So, as sort of my colleagues in neurology here at Duke like to say, that deep brain simulation is not going to cure Parkinsonism. But what it will do is it will increase your level of function if you are afflicted with the disease, and together with pharmacelogical approaches, behavioral approaches, excercise deep brain stimulation might actually be an important adjunct to a more multidisiplinary approach to intervention. Now, let's travel down the continuum and consider the role of the basal ganglia in creating hyperkinetic movement disorders. And the disorder that I'd like to use to illustrate this end of the continuum is Huntington disease. So, Huntington disease is characterized by involuntary movements of the body, often involving the limbs and because the flailing movements of the limbs resembles a dance-like posture or dance-like movements, this is called. A chorea, which is a, a Greek word that means dance. So involuntary, choreic movements are characteristic of Huntington's disease. Along with the disease that tends to set in in the fourth and fifth decades of life is a severe dementia that can develop. And this dementia obviously can be quite tragic and together with the unwanted movement that's being expressed can lead to a great suffering on the part of the individual inflicted with the disorder as well as that persons loved ones as a system of of support. As I mentioned, the disorder tends to first manifest itself by the fourth or fifth decade of life. And unfortunately, most patients succumb to this disorder within about 10 to 15 years of the first appearance of symptom. Now, the pathology associated with Huntington disease. actually is now traced back to a genetic origin. Huntington disease reflects an autosomal dominant mutation that results in the production of a gene product from a gene called Huntington. And this product contains a repeating sequence of CAG nucleotides. So most of us have a string of repeats maybe around 20 or so repeats of this CAG motif in our Huntington gene, but if the number of repeats exceeds about 30, 35, 40, then the likelihood of developing Huntington disease increases dramatically. Now, we don't quite understand yet, the link between this increase in these repeated motifs in the gene, and the product of the gene and how that relates to the pathology in the brain. But what we do know is that with Huntington disease, there is widespread neuronal degeneration, and among the first. Structures to experience digeneration are the medium spiny neurons of the striatum that express D2 dopamine receptors and that would be the neurons that give rise to the indirect pathway to the basil ganglia. So the consequence of Huntington disease Is a loss of this indirect pathway from the striatum to the pallidum. So this means that we lose the ability to suppress movement in the following way. With the loss of this inhibitory projection now there's way too much activity coming out of the external segment of the globus pallidus. That is going to lead to a dramatic reduction in the amount of inhibition that is being Expressed by the internal segment of the globus pallidus in the motor thalamus. With insufficient inhibition of the motor thalamus. Now we have increased excitation of this connection from the motor thalamus to the motor cortex. And that's where the unwanted movements are coming from. From the insufficient suppression of the motor thalamus.
