Pediatric Movement Disorders - Anatomy and Physiology

Basal Ganglia

Introduction to the Basal Ganglia
The basal ganglia are composed of the caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. These areas take information from almost all regions of the surrounding cerebral cortex, process it, and then feed it back to motor areas of the cortex and down to the brainstem.

The purpose for the basal ganglia is not known; however, much is known about the types of symptoms that occur when they are damaged. There are theories that attempt to explain the function of the basal ganglia. These theories are the basis for current ideas on the selection of appropriate medications for treatment.

One recent theory suggests that a purpose of the basal ganglia is to select and accentuate certain motor patterns while inhibiting other "nearby" patterns (Mink, 1996). In particular, a desired pattern of muscle activity is selected based on the child's current goals as well as the sensory information that relates to the current state of the child's environment. Once the pattern is selected by the basal ganglia, it is then fed back onto the motor cortex and amplified in order to begin movement. At the same time, all other possible patterns are inhibited in order that only the desired pattern becomes active. This system must be very finely tuned. When it is damaged, there may be errors in the selected pattern, excessive feedback that may cause oscillations, or insufficient feedback to initiate rapid movement.

One way to understand the basal ganglia anatomy is to trace the path of a signal as it goes through them. Suppose that in the motor and sensory regions of the child's cortex (the outer part of the brain), a particular pattern is selected and sent to the basal ganglia. This pattern then arrives at the caudate and putamen via neurons using the excitatory transmitter glutamate. Amantadine may act at the glutamate receptors, and this could be the basis for its effect. The caudate is primarily concerned with patterns relating to behavior and motivation, while the putamen is primarily concerned with patterns related to lower-level sensory and motor function.

Medium Spiny Neurons
Both the caudate and putamen receive inputs from a large region of the cortex; thus, they are believed to be able to integrate much of the information and recognize large-scale patterns. Together, the caudate and putamen are referred to as the striatum. Inputs from the cortex arrive on the medium spiny-type neurons in the striatum. These neurons also have inputs from large aspiny-type neurons that use acetylcholine as their neurotransmitter. Thus, it may be the site of action of anticholinergic medications such as trihexyphenidyl (Artane®) or diphenhydramine (Benadryl®). The medium spiny neurons also have inputs from the dopamine neurons of the substantia nigra. The substantia nigra, meaning black substance, is a region in the midbrain portion of the brainstem in which certain cells synthesize large amounts of dopamine. These cells send axons to the medium spiny neurons. The medium spiny neurons are divided into two types: some have D1-like receptors and some have D2-like receptors. When dopamine activates a D1-like receptor on the medium spiny neurons, it tends to activate that neuron; however, when dopamine activates a D2-like receptor, it inhibits that neuron. In this way, dopamine has opposite effects on the two classes of medium spiny neurons. All dopaminergic medications, including L-DOPA, dopamine agonists, neuroleptics, and perhaps amantadine, are thought to operate by modifying the behavior of one or both groups of medium spiny neurons.

Medium Spiny Neurons: D1 and D2 Receptor Types
The medium spiny neurons are the outputs from the striatum; the division into two groups continues here. All medium spiny neurons project to the globus pallidus; however, the spiny neurons with D1 receptors project to the internal portion of the globus pallidus (GPi), while those with D2 receptors project to the external portion of the globus pallidus (GPe). These projections use the inhibitory neurotransmitter GABA, as well as other neurotransmitters and neuromodulators. GABA transmission is modulated by the benzodiazepines (e.g., diazepam, clonazepam, lorazepam, and clobazam) as well as by valproate. This may explain the utility of these medicines in the treatment of children and adults with movement disorders.

The GPe projects to the GPi as well as the subthalamic nucleus (STN), again using the inhibitory transmitter GABA. The subthalamic nucleus receives inputs not only from GPe but also directly from the cortex. This nucleus then sends signals to GPi using the excitatory transmitter glutamate. The GPi sends inhibitory signals using GABA to the VA/VL (ventral anterior /ventral lateral) regions of the thalamus, which send a mostly excitatory signal back to the motor regions of frontal cortex. The substantia nigra reticulata (SNr) is a portion of the substantia nigra that is not associated with dopamine production. This area also receives inputs from the striatum, GPe, and subthalamic nucleus. Therefore, it may function equivalently to GPi for signals that are intended to go to the brainstem rather than to the cortex.

Direct and Indirect Pathways
The pathway that goes from cortex to striatum (with D1 medium spiny neurons), to the GPi, to the thalamus, and back to the cortex has a total of two inhibitory GABA synapses. The pathway that goes from cortex to striatum (with D2 medium spiny neurons), to the GPe, to the subthalamic nucleus, to the GPi, to the thalamus and back to the cortex has a total of three inhibitory GABA synapses.

The first pathway is referred to as the "direct" pathway. The combination of the two inhibitory synapses means that overall this pathway has positive feedback. The second pathway is longer and is referred to as the "indirect" pathway, and the combination of the three inhibitory synapses means that overall this pathway has negative feedback. Dopamine selectively excites the direct pathway and inhibits the indirect pathway, thus determining those signals that are reinforced and those that are suppressed. This correlates well with the presumed function of dopamine, which behaves like a reinforcing signal. In animals, dopamine is released with rewards or the expectation of rewards. These pathways may provide a mechanism whereby patterns that the child perceives as rewarding or beneficial are ultimately strengthened within the basal ganglia. Disorders of this system may lead to incorrect patterns or excessive positive or negative feedback.

It is important to recognize that this is an extremely oversimplified view of the anatomy and function of the basal ganglia. In particular, it is known that there are multiple other pathways, both entering and exiting from these structures; however, the functions of these pathways are not known. As research progresses, ideas of the function of this important, but perplexing structure, will continue to evolve.

Surgical lesions and deep brain stimulation (DBS) block transmission through the basal ganglia. Lesions or DBS in the GPi blocks the output traveling back to cortex. Lesions or DBS in the subthalamic nucleus selectively block signals through the indirect pathway, while providing a general decrease in GPi activity. The exact mechanism by which these procedures are beneficial is not yet known. It is presumed that interruption of abnormal activity leads to the improvement in symptoms.