Dysfunction of the basal ganglia of the brain is thought to cause motor and behavioral disorders. Is it possible to alleviate the symptoms with electrical or magnetic stimulation?
Israel Benjamin Galileo
What do the base nuclei really do?” This is the title of one of the key discussions at the International Basal Ganglia Association conference held in June 2010 in New Jersey, and it illustrates the difficulty in the field: the basal ganglia, which are clusters of nerve cells deep in the brain, are not physically adjacent but are also connected to each other And also to many other parts of the brain. Although the base nuclei have been intensively studied for decades and even though much knowledge has been accumulated about them, leading scientists in the field still differ in their opinions about the roles of these nuclei, or admit that they do not know about them.
The relationship between diseases and disorders to the basal ganglia
The interest in the basic nuclei arose already about a hundred years ago. In the post-mortems, surgeons saw damage in the "substantia nigra", an area of the midbrain that is included in the group of basal ganglia and which, in terms of its volume, constitutes less than one percent of the basal ganglia, which themselves constitute about one percent of the entire brain. This damage, they discovered, is related to Parkinson's disease - the second most common degenerative brain disease (after Alzheimer's disease).
It later became clear that damage to these small areas is also associated with other neurological diseases that affect movement, such as dystonia (dystonia, manifested by involuntary movements and muscle spasms) and Huntington's disease (a hereditary degenerative disease whose first symptoms include involuntary movements, followed by cognitive and emotional disturbances ). The nuclei are also associated with neuropsychiatric problems, such as obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome (characterized by "tics" of movements and vocalizations).
The connection of the basal nuclei to these diseases and disorders explains the research efforts devoted to them. These efforts are aimed at finding treatments for diseases or symptoms of those diseases. At the same time, the diseases are a clue to the role of the basal ganglia in the healthy brain. This can be compared to the accepted practice in genetics, according to which the name of a gene may be determined according to the form in which mutations in that gene are expressed. Thus, for example, the gene in which a mutation causes Drosophila fly embryos to develop without a heart is called "tinman", for a reason that is understandable to anyone who has read "The Wizard of Oz". This finding leads to an understanding of the role of the normal gene in controlling the construction of heart tissue.
If neurologists chose names for structures in the brain in a similar way, we might find areas in the brain maps called "Parkinson's disease", "dystonia" and even "OCD". Such names, for genes or structures in the brain, do not explain the normal function but only the pathological result of a disturbance in the normal function, but sometimes this is the first clue leading to deciphering the normal function.
Small buildings, big wonders
Dr. Yizhar Bar-Gad, head of the Neural Interfaces Laboratory at Bar-Ilan University, has been researching the basic nuclei for about fifteen years. The laboratory is engaged in the study of the interaction between the central nervous system and computerized systems, in order to deepen the knowledge of the pathophysiology of nervous disorders and create the basis for electrophysiological treatment of the symptoms of these disorders. The lab's researchers combine methods from theoretical fields, such as computer models, with experimental fields such as recording neural activity in people undergoing brain surgery and in animals. Currently, research is focused on motor and behavioral disorders related to the basal ganglia, and the relief of symptoms through electrical or magnetic stimulation.
Dr. Bar-Gad points out unique and puzzling characteristics of the basic nuclei. The question we opened with illustrates that it is still unknown why damage to these structures causes such severe problems, considering that they do not directly control movement or speech, but influence through their connections to the cerebral cortex. Another puzzlement has to do with the serious effects of even minor damage to the basal ganglia. For example, damage to the substantia nigra causes extreme loss of mobility. In many parts of the brain, damage to such an extent will not be felt at all or will cause only a minor impairment of function.
Another surprising feature of the basal ganglia is their pattern of action. The electrical signals measured in these areas indicate non-stop activity. For comparison, at any given moment most of the cells in the cerebral cortex are inactive. Intense activity requires energy, so it can be assumed that even though the basal ganglia are so small, their energy consumption is a significant part of the total energy consumption in the brain. Let's remember that even though the brain makes up a few percent of the body's weight, it needs about 20% of the total oxygen consumption in the body for its operation.
Why do we need such a high activity level in the basal ganglia? It is likely that high energy consumption will be preserved during evolution only if it has an important role, and indeed a great deal of understanding has already been achieved regarding the importance of many parts of the brain and their need for energy. These achievements highlight the difficulty in understanding the basic kernels.
To understand the activity of a certain structure, you can try to record it and relate it to the activity patterns of other parts. In the case of the basal ganglia, no such relationships have yet been found: no correlations have been found between the electrical activity of different areas within the basal ganglia, and no cycle of activity of specific cells has been found when they are recorded over time: the activity appears to be unsynchronized or coordinated - "white noise" in terms of signal analysis.
Interfere, understand and treat
Another way to decipher the function of a part of the brain is to check what happens when that part is damaged or when its operation is disrupted by external intervention. It turns out that sometimes damage to the basal ganglia actually causes improvement: about fifty years ago, it was common practice to alleviate the tremors and difficulty in movement that appear in Parkinson's disease by brain surgery in which small parts of the basal ganglia, called the "pallid nucleus", Globus Pallidus internus (GPi - "the internal pale ball) were killed ” in Latin). This nucleus sends the output of the basal ganglia system, that is, transmits the signals to the rest of the brain.
This surgery is not common today, because of the great risk involved, and in its place came drug treatments. When these treatments lose their effect, some of the patients are treated with another surgical intervention: the insertion of a thin electrode into the subthalamic nucleus, the STN (Sub-Thalamic Nucleus), which stimulates the output nuclei of the basal ganglia. When high frequency electrical stimulation is applied through the electrode, there is usually relief in the symptoms of Parkinson's disease.
A similar phenomenon occurs due to stimulation of the GPi during dystonia. In the case of dystonia, the improvement appears gradually over several months, which suggests an adaptation process of the brain, but when the stimulation is stopped, the spasms in the limbs and neck that are characteristic of this disease immediately return. Fortunately, reintroducing the stimulus quickly alleviates the severity of the symptoms. This treatment, called DBS (Deep Brain Stimulation), was developed following the groundbreaking research in primates by Prof. Hagai Bergman (Bergman) from the Hebrew University in Jerusalem and their application in humans by Prof. Elim Benabid (Benabid) in France. In the last decade, it was found that DBS brought improvement in several cases of Tourette's, but for this disease, as well as for obsessive-compulsive disorder, the treatment is still considered experimental.
Despite the success of the DBS treatment in significantly improving the quality of life of tens of thousands of patients, it is not clear how the treatment works. The surgery that destroys parts of the GPi nucleus stops the signals passing from the basal ganglia to the cerebral cortex; The DBS treatment creates an electrical disturbance that disrupts these signals. The fact that relief of symptoms is achieved due to these actions raises a bewilderment: how is it possible that the disruption of the operation of one part of the system can lead to an improvement in the function damaged by damage to another part of the same system (as we have seen, Parkinson's disease is associated with damage to the substantia nigra)? The answer is probably related to the complex nature of control and control processes.
The complexity of control and management
In analogy to vehicle control systems, we will mention one of the explanations offered in recent months for malfunctions that caused Toyota cars to accelerate without control. According to this explanation - which Toyota completely rejects - the fault occurred in the electronic acceleration control system (ETCS). This system replaces the mechanical connection between the accelerator pedal and the throttle (which determines the amount of fuel that is fed to the engine) with electronic control circuits that determine the position of the throttle according to several parameters, which of course include the position of the accelerator pedal but also the rate of rotation of the engine, the speed of the vehicle and more. Therefore, a malfunction in these circuits may result in the loss of the ability to control acceleration.
If so, it is possible to imagine a situation where some of the dangerous effects of such a malfunction would be neutralized by disrupting the operation of another part of the ETCS circuits, so that the wrong decision that under certain conditions flows too much fuel to the engine is avoided. Similarly, it is possible that one of the functions of the basal ganglia is to suppress the activity of other parts of the brain. This is the "brake hypothesis". If this function is damaged, a change in the activity of those parts is caused. According to this explanation, this is how pathological phenomena of underactivity such as stagnation (in Parkinson's disease) are caused due to excess inhibition, overactivity such as "dancing" (in Huntington's disease), or hyperactive and obsessive-compulsive behaviors.
Unlike car system engineers, unfortunately neuroscientists do not have access to engineering documents that explain the operation of these mechanisms and they require imagination, creativity, patience and a combination of many research tools to make progress in solving the puzzles presented to them by the brain. Due to decades of efforts, it is known that the basal ganglia participate in three main control mechanisms: control of motor functions (movement); the control of the limbic system, related to emotions, behavior, and long-term memory; and controlling the executive functions related to allocating attention, planning, choosing which sensory information to focus on and deciding which actions are appropriate for the current situation.
The French researcher Leon Tremblay published a study in 2004 that showed that it is possible to temporarily paralyze and reverse the parts of the basal ganglia responsible for each of these control mechanisms, by injecting a substance that disrupts the operation of the cells. When the motor control in green monkeys is damaged, involuntary movements appear similar to the chorea movements that Huntington's patients suffer from. Damage to the control of the limbic system causes compulsive behavior, such as monotonous repetition of touching a certain object or body part, and damage to the control of executive functions causes phenomena reminiscent of human hyperactive behavior. After the effect of the substance wears off, the symptoms also disappear.
Neural correlates of involuntary behavior
One of the studies of the laboratory headed by Dr. Bar-Gad is designed to examine the changes in neural activity that appear due to the disruption of the control processes for which the basal ganglia are responsible. In a manner similar to Tremblay's research, a substance was injected into the motor part of the nucleus of the striatum ("striated nucleus") that neutralizes the activity of GABA, a neurotransmitter used in the central nervous system to transmit an inhibitory signal, i.e. a signal that allows one nerve cell to suppress the action of another cell Another sadness.
In the long-tailed macaque monkeys (Macaca fascicularis) who received these injections, involuntary movements - "tics" - appeared, mainly in the facial area, which appeared both when the monkey was at rest and when engaged in some routine activity. These tics are similar to Tourette's symptoms, and other findings, such as fMRI studies in Tourette's patients linking the disease to the same brain regions, support the hypothesis that this is an appropriate model for this disease. The abnormal symptoms stopped about 90 minutes after the injection of the substance.
The main innovation in this experiment was the recording of the local electrical activity of the brain at several sites in the basal ganglia system to test the change in activity due to the injection and the relationship between the pattern of activity and the appearance of tics. At the time when involuntary action was observed, the electrical activity at sites recorded in the basal ganglia showed that the cells were acting together, in a synchronized manner. On the other hand, in normal brain activity, as mentioned, there is no correlation or synchronization between the actions of different cells in the basal ganglia.
The editors of the prestigious scientific journal Brain found that the results of the experiment were important enough to justify publication in this journal, even though they usually only publish research on the functions of the human brain. The study points for the first time to correlations between neural activity deep in the brain and the appearance of involuntary movements, in a way that is probably similar to the manifestation of neurological diseases in humans. The authors of the article conclude by raising the possibility that these findings will help to understand the mechanism that causes tics, as well as the principles of operation of the basal ganglia in their normal state.
However, the core cores continue to insist on maintaining their reputation, providing new mysteries with each discovery. It is not clear why the synchronized activity of 80-70% of the neurons in the motor part of the striatum causes a tic in a well-targeted area of the face, when in normal operation these neurons are related to the control of movement throughout the body. It is also difficult to understand why a treatment such as DBS, which acts on cycles of synchronized electrical stimulation, does not usually cause involuntary movements but alleviates phenomena such as tremor (although there are many differences between the stimulation initiated in DBS and the spontaneous appearance of synchronized activity in the experiment described Here).
What is the true function of the basal nuclei? The discussion at the conference in New Jersey did not lead to a consensus among the scientists working on the subject either, but the importance of the question and the scientific challenges it raises ensure that the research will continue. In this journey, the State of Israel has an important part, which is an important research center in the field of nuclear weapons. The next conference of the International Nuclear Association will be held in three years in Israel, under the direction of Prof. Hagai Bergman and Dr. Yizhar Bar-Gad. If the past predicts the future, surprising new findings will be discovered by then that will answer some of the questions but will raise new puzzles.
The writer works at ClickSoftware developing advanced optimization methods.
