Direct and Indirect Pathways Form Common Circuits Throughout All Functional Divisions of the Basal Ganglia
The general organization of the basal ganglia from input to output is shown in Figure 14–5. Like the cerebellum, a basic circuit describes the basal ganglia, irrespective of motor, cognitive, or emotional function. As described, the basal ganglia are divided into input, output, and intrinsic nuclei (Figure 14–5A). Beginning with all areas of the cerebral cortex, information passes through the input nuclei and then the output nuclei. Connections with the thalamus target several nuclei that, in turn, project to different areas of the frontal lobe. These differential projections confer the distinctive functions of the basal ganglia (discussed below). Connections with the brain stem motor control centers target the pedunculopontine nucleus, important in gait control, and the superior colliculus, for saccadic eye movements. As an example of the flow of information through the basal ganglia, follow the path in Figure 14–5B, from the frontal lobe, to the putamen, globus pallidus internal segment, thalamus, and back to the cerebral cortex (to primary motor cortex).
Direct and indirect paths of the basal ganglia. A. Block diagram. The input nuclei are the components of the striatum; they receive input from all cortical areas. The output nuclei are the globus pallidus internal segment, the substantia nigra pars reticulata, and part of the ventral pallidum. Blue shading is the direct path. Green shading shows the indirect path. Whereas the basal ganglia receive input from all cortical areas, the return path from the thalamus is directed only to the frontal lobe. Note, dopaminergic cell groups innervate both the cerebral cortex and the striatum. Connections to the brain stem are directed to the superior colliculus, for eye movement control, and the pedunculopontine nucleus, for gait control. B. Circuitry of the direct path. Follow the path from cortex: (1) back to cortex; and (2) to brain stem. Note how both paths eventually end in the spinal cord. Inset shows the indirect path that terminates in the internal globus pallidus. Motor pathways to the spinal cord are also shown.
There are functionally and clinically important connections with the intrinsic nuclei. The external segment of the globus pallidus and the subthalamic nucleus are part of a basal ganglia circuit that receives input from other basal ganglia nuclei and in turn projects back (Figure 14–5A). The substantia nigra pars compacta and the ventral tegmental area contain dopaminergic neurons that project to the striatum, as well as to portions of the cortex (Figure 14–5A). Dopamine has a neuromodulatory action on striatal neurons. There are many different dopamine receptor subtypes and, depending on the particular subtype present on the postsynaptic neuron, dopamine either depolarizes or hyperpolarizes striatal neurons.
The output of the basal ganglia depends on two complementary pathways
Whereas the basal ganglia have a daunting complexity, there is a logic to the connections that helps explain their overall actions. A pair of complementary circuits—termed the direct and indirect pathways—have opposing actions on their downstream structures. The connections from the striatum to the output nuclei and then to the thalamus and brain stem, described above, comprise the direct path (Figure 14–5A, B), which promotes the actions of the basal ganglia. By contrast, connections from the striatum to three intrinsic nuclei—the external segment of the globus pallidus, part of the ventral pallidum, and the subthalamic nucleus—comprise the indirect path (Figure 14–5A, B inset), which inhibits the actions of the basal ganglia. In Figure 14–5B (inset) follow the path from the striatum, globus pallidus external segment, subthalamic nucleus, and then globus pallidus internal segment. For the components of the basal ganglia that control limb and trunk movements, eye movements, and facial muscles, the direct path enables these actions and the indirect path puts the brakes on. Box 14–1 shows schematically how neuronal activity changes in the direct and indirect paths as information from the cortex is processed from one structure to the next. Aberrant direct path functions in many movement disorders appear to drive excessive muscle tone, tics, and habitual behaviors, and aberrant indirect path functions produce debilitating akinesia, bradykinesia, and rigidity in Parkinson disease. It is thought that similar facilitatory and suppressive actions influence the nonmotor functions of the basal ganglia as well. We consider below how the complementary actions of the direct and indirect paths occur, in the context of the diversity of neurotransmitter actions in the basal ganglia.
Box 14–1 Knowledge of the Intrinsic Circuitry of the Basal Ganglia Helps to Explain Hypokinetic and Hyperkinetic Signs
Knowledge of dysfunction in the direct and indirect pathways in the skeletomotor loop (Figures 14–5, 14–6, 14–7) is helping to explain the mechanisms of disordered movement control in basal ganglia disease and to develop more effective therapies. As discussed earlier, the direct path promotes movements, and the indirect path inhibits movements. Projection neurons of the putamen in the direct path synapse on neurons in the internal segment of the globus pallidus, which project to the ventrolateral and ventral anterior nuclei of the thalamus. This circuit contains two inhibitory neurons, in the putamen and globus pallidus. Thus, a brief period of cortical excitation of the putamen (see neural responses in boxes marked cerebral cortex and striatum; Figure 14–7A) is transformed into an inhibitory message (pause in neural activity) in the internal segment of the globus pallidus because striatal neurons are inhibitory. However, because the output of the internal segment of the globus pallidus is also inhibitory, the amount of inhibition of the thalamus from the internal segment of the globus pallidus is reduced. Inhibition of an inhibitory signal is termed disinhibition; functionally, this double negative is equivalent to excitation. The thalamic response shown is transiently released from inhibition and fires a burst of action potentials. In a motor behavior such as reaching for a glass of water, neurons in premotor areas, as well as corticospinal tract neurons in primary motor cortex, are thought to be excited by the actions of the direct path.
The indirect path has the opposite effect on the thalamus and cerebral cortex as the direct path. Putamen neurons of the indirect path, which are inhibitory because they contain GABA, project to the external segment of the globus pallidus. Excitation of the striatal neurons inhibits the external segment of the globus pallidus (pause in action potentials). Because the output of the external segment of the globus pallidus is inhibitory, indirect path neurons of the putamen disinhibit the subthalamic nucleus (burst of action potentials). This disinhibition will excite the internal segment of the globus pallidus and substantia nigra pars reticulata (which are both inhibitory) and thereby increase the strength of the inhibitory output signal directed to the thalamus.
Dopamine excites striatal neurons of the direct path and inhibits striatal neurons of the indirect path. Despite these different actions on striatal neurons, the effect of dopamine on either path is to reduce the inhibitory output of the basal ganglia, thereby reducing inhibition of the thalamus. This effect promotes movement generation by the thalamocortical circuits.
The power of this model is that it helps to explain the mechanisms of some hypokinetic and hyperkinetic signs seen in basal ganglia disease. Dopamine is deficient in Parkinson disease, which produces hypokinetic signs. Reduced striatal dopamine in Parkinson disease would be expected to diminish the excitatory effects of the direct path on cortical motor areas and enhance the inhibitory effects of the indirect path (Figure 14–7C1). Together these effects would drastically reduce the thalamic signals to the cortex. For the premotor and motor cortical areas, this would reduce cortical outflow along the corticospinal and corticobulbar tracts and reduce production of motor behaviors (ie, hypokinesia).
In hyperkinetic disorders, the opposite changes take place (Figure 14–7C2): There are enhanced excitatory effects of the indirect path on the cortex. (Note that the output of the substantia nigra pars compactor may be normal.) In Huntington disease, recent studies suggest that striatal neurons of the indirect path, which contain both GABA and enkephalin, are lost (low neural response). This cell loss would result in greater thalamic outflow to the cortex by decreasing striatal inhibition of the external segment of the globus pallidus. Hemiballism, another hyperkinetic disorder, is produced by a subthalamic nucleus lesion. This nucleus normally exerts an excitatory action on the internal segment of the globus pallidus. When the subthalamic nucleus becomes lesioned, the internal segment of the globus pallidus would be expected to inhibit the thalamus less (thin dashed line), thereby increasing outflow to the cerebral cortex.
The neurotransmitters of the basal ganglia are shown in relation to the organization of basal ganglia circuits. Neurons in the striatum that contain GABA, substance P, and dynorphin (purple) give rise to the direct path, projecting to the internal segment of the globus pallidus. Neurons that contain GABA and enkephalin (green) give rise to the indirect path and project to the external segment of the globus pallidus. GABA, γ-aminobutyric acid; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VP, ventral pallidum; VTA, ventral tegmental area.
Functional basal ganglia circuits in health and disease. Summary of the direct (A) and indirect (B) paths of the healthy basal ganglia. Filled neuronal cell bodies and terminals indicate inhibitory actions, and open cell bodies indicate excitatory actions. Schematic action potential records are shown by each structure. The vertical line is an action potential; the horizontal line is the baseline. Neural activity for each circuit can be followed, beginning with a phasic excitatory input from the cortex and the resulting phasic change in the thalamus. Changes in activity in the diseased circuits are shown for hypokinetic (C1) and hyperkinetic (C2) neurological signs. The thickness of the lines indicates relative changes in the number of neurons and strength of connections. Thicker means stronger connections and more activity; thinner means fewer and weaker connections. Schematic neural responses are also shown. Unlike A and B, which are the neural responses to discrete cortical input signals, the responses in C1 and C2 reflect changes in continuous activation patterns produced by disease. These paths follow only tonic changes in neural activation, because phasic changes are not well characterized. GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthala-mic nucleus.
Knowledge of Basal Ganglia Connections and Neurotransmitters Provides Insight Into Their Function in Health and Disease
Many neurotransmitters and neuromodulatory substances are present in the various basal ganglia nuclei (Figure 14–6). The excitatory neurotransmitter glutamate is used by corticostriatal neurons (the major input to the basal ganglia), thalamic neurons that project to the striatum, and the projection neurons of the subthalamic nucleus. Surprisingly, the major neurotransmitter of the basal ganglia is γ-aminobutyric acid, or GABA, which is inhibitory. In the striatum, the projection neurons, termed medium spiny neurons because they have abundant dendritic spines (see Figure 1–2), use GABA as their neurotransmitter. The axons of these neurons project to the two segments of the globus pallidus, the ventral pallidum, and the substantia nigra pars reticulata. Medium spiny neurons also contain neuropeptides, with two distinct neuron classes containing either enkephalin or substance P (and dynorphin). Enkephalin thus marks indirect path striatal neurons and substance P, direct path. When one understands that direct and indirect path neurons have a different neurochemistry, it is easier to appreciate that they can be differentially vulnerable to pathological processes. Projection neurons of the internal and external segments of the globus pallidus and the substantia nigra pars reticulata also contain GABA. Thus, the output of the basal ganglia, similar to that of the cerebellar cortex, is inhibitory. The significance of this common synaptic organization is not yet apparent.
Neurons in the substantia nigra pars compacta and the ventral tegmental area contain dopamine. The activity and function of the postsynaptic targets of these nuclei, the striatum and portions of the frontal lobe, are under important regulation by dopamine. Dopamine can be excitatory or inhibitory depending on the balance of dopamine receptor subtypes present on the postsynaptic neuron's membrane. Acetylcholine is another common neurotransmitter in the basal ganglia; it is present in striatal interneurons. Striatal cholinergic interneurons play an important role in regulating diverse basal ganglia functions, including plasticity.
Parkinson disease is a hypokinetic movement disorder
In Parkinson disease, there is a major impairment in initiating movements, termed akinesia, and a reduction in the extent and speed of movements, called bradykinesia (see Figure 14–7C1). These are called hypokinetic signs because movements become impoverished. In addition, patients exhibit a resting tremor, and when an examiner moves their limbs, a characteristic stiffness or rigidity can be noted. The dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area degenerate in Parkinson disease, and striatal dopamine is profoundly reduced. The term substantia nigra means black substance. This name derives from the presence of the black pigment neuromelanin, a polymer of the catecholamine precursor dihydroxy-phenylalanine (or dopa), which is contained in the neurons of the pars compacta. Not surprisingly, neuromelanin is not present in the substantia nigra pars compacta of Parkinson patients. Dopaminergic neurons in other parts of the central nervous system are also destroyed in Parkinson disease. Dopamine loss in the basal ganglia, however, apparently produces the most debilitating neurological signs. Dopamine replacement therapy using a precursor to dopamine, L-dopa, leads to a dramatic improvement in the neurological signs of Parkinson disease.
Researchers have an important tool in the study of Parkinson disease. They discovered that a certain kind of synthetic heroin produces a permanent clinical syndrome in humans that is remarkably similar to Parkinson disease. This substance contains the neurotoxin MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which is a meperidine derivative that kills the dopaminergic neurons of the substantia nigra pars compacta (as well as other dopaminergic neurons in the central nervous system). When monkeys are given MPTP, they too develop parkinsonian signs, including akinesia, bradykinesia, rigidity, and tremor.
There are several hyperkinetic movement disorders
Huntington disease is a hyperkinetic disorder (see Figure 14–7C2). One hyperkinetic sign of this disorder is chorea, which is characterized by involuntary rapid and random movements of the limbs and trunk. Involuntary distal limb movements, such as writhing of the hand, or athetosis, may also occur. Patients with Huntington disease also develop dementia. Huntington disease is inherited as an autosomal dominant disorder. In most patients, Huntington disease presents during midlife. The Huntington gene is located on the short arm of chromosome 4 and codes for a protein, huntingtin, whose function is not yet known. The gene mutation that causes Huntington disease is an expansion of the nucleotide sequence of CAG (>35 repeats) at the 5′ end. This is translated into huntingtin having an excessively long polyglutamine repeat that makes medium spiny neurons particularly vulnerable to cell death. This mutation, which is present in all cells of the body but apparently affecting primarily medium spiny neuron function, also leads to the dysfunction and death of neurons in other brain regions, including the cortex. Although neurodegeneration is widespread in Huntington disease, pathological changes occur earliest in striatal neurons that contain enkephalin, which are part of the indirect path (Figure 14–6). Interestingly, several neurodegenerative diseases are associated with a polyglutamine repeat mutation.
Another hyperkinetic disorder is hemiballism (see the clinical case in this chapter). This remarkable clinical disturbance occurs after damage to the subthalamic nucleus, an intrinsic basal ganglia nucleus. Hemiballism causes patients to make uncontrollable, rapid ballistic (or flinging) movements of the contralateral limbs. These movements are produced by motion at proximal limb joints, such as the shoulder and elbow.
Parallel Circuits Course Through the Basal Ganglia
One important aspect of basal ganglia circuitry is that they comprise parallel anatomical loops. Three important points relate to the general organization of these parallel circuits:
Each loop originates from multiple cortical regions that have similar general functions.
Each loop passes through different basal ganglia and thalamic nuclei, or separate portions of the same nucleus. These include the motor thalamic nuclei—the ventrolateral nucleus (a part distinct from the one receiving cerebellar input), and the ventral anterior nucleus—and the medial dorsal nucleus, which serves cognition, emotions, and eye movements.
Each loop targets separate portions of the frontal lobe.
Through their diverse connections, each loop mediates a different set of functions. Although many parallel loops originate from various cortical areas, anatomical and physiological studies have focused on four major loops (Figure 14–8): the skeletomotor, oculomotor, prefrental cortex (or cognitive), and limbic loops. Each of these loops comprises many subcircuits. The skeletomotor loop plays important roles in the control of facial, limb, and trunk musculature (Figure 14–8A1). Inputs originate from the primary somatic sensory and frontal motor areas and project back to the frontal motor areas (Figure 14–8B). Animal experiments show separate circuits within the skeletomotor loop, originating from the different motor, premotor, and somatic sensory areas, passing through different parts of the globus pallidus, and ultimately terminating in different premotor and motor areas. The oculomotor loop plays a role in the control of saccadic eye movements. Key inputs derive from the frontal eye field, which is important in the production of rapid conjugate eye movements through brain stem projections, and the posterior parietal association cortex, which processes visual information for controlling the speed and direction of eye movements (Figure 14–8A2). The output of this loop is to the frontal eye movement control centers (Figure 14–8; see Chapter 12). More is known about the organization of these two movement control loops than about the other two loops.
There are four principal input-output loops through the basal ganglia. A. Block diagrams illustrating the general organization of the loops. (1) Skeletomotor loop, (2) oculomotor loop, (3) associative loop, and (4) limbic loop. GPi, internal segment of the globus pallidus; SNr, substantia nigra pars reticulata. B. Lateral and medial views of the cerebral cortex, illustrating the approximate location of the target regions in the frontal lobe. The medial orbitofrontal cortex is ventral to the lateral prefrontal cortex.
The associative loop plays a role in cognition and executive behavioral functions, such as strategic planning of behavior. Receiving inputs from diverse association areas, this loop projects primarily to the dorsolateral prefrontal cortex, and some premotor regions as well (Figure 14–8A3, B). Though principally involved in thought and reasoning and in the highest level of organizing goal-directed behaviors, the prefrontal cortex has relatively direct connections with premotor areas involved in movement planning.
The limbic loop participates in the motivational regulation of behavior and in emotions. The term limbic derives from the limbic system, the brain system that comprises the principal structures for emotions. The limbic association cortex and the hippocampal formation provide the major input to the limbic loop. The limbic loop engages the most distinct set of basal ganglia circuits: the ventral striatum—which includes the nucleus accumbens and ventromedial portions of the caudate nucleus and putamen—and the ventral pallidum (Figure 14–8A4). The limbic association cortex in the anterior cingulate gyrus is the major frontal lobe recipient of the output of the limbic loop (Figure 14–8B).
Integration of Information Between the Basal Ganglia Loops
Behaviors result from integration of complex sensory, cognitive, and motivational information. It is therefore not surprising that, in addition to the parallel loops (Figures 14–8 and 14–9A), the basal ganglia have also many different ways to integrate information between loops. Three kinds of basal ganglia integrative circuits are highlighted (Figure 14–9B). First, there is overlap in the input connections—those between the cortex and the striatum—as well as within intrinsic circuitry. Second, there appears to be integrative subregions, or "nodal points of convergence" within the basal ganglia loops. For example, while most connections of the dorsolateral prefrontal cortex are to the parts of the striatum in the associative loop, there are smaller focal projections to parts of the ventral striatum for integrating cognition with emotions and reward and to dorsal regions for linking basic eye and limb muscle control with more complex behaviors. Third, the descending corticothalamic projection, which we first examined in detail in the sensory systems (see Figure 4–11 and Figure 2–18), is more widespread than the ascending thalamocortical projection.
Integration of information in the basal ganglia. A. General organization of single parallel loop. The corticostriatal projection (top) targets the striatum (left). From the striatum, the direct path targets the output nuclei (bottom), which, in turn, project to the thalamus (right) and then back to the cortex. B. Schematic showing three circuit features where integration across loops takes place. (1) At the borders between the specific loops. (2) Special interloop connections. (3) At the level of corticothalamic terminations. GPi, internal segment of the globus pallidus; SNr, substantia nigra pars reticulata; VP, ventral pallidum.
In organizing behavior, the various parallel circuits of the basal ganglia appear to have distinct functions. This is how we think the loops function for initiating and controlling when you reach for a glass of water. The limbic loop participates in the initial decision to move, motivated by thirst. The prefrontal cortex loop participates in formulating the goal plan, for example, how, where, and when to reach for the water. The oculomotor and skeletomotor loops assist in the programming and execution of the particular behaviors to achieve the goal. For example, these loops are important in coordinating eye and limb movements to accurately direct your hand to the glass. When we are very thirsty, our movements are faster and more reactive. We think that the integrative connection from the limbic loop to the motor loop is one way for this to happen.