24 basal ganglia and extrapyramidal system · pyramidal system whose descending fibers pass through...

24 Basal Ganglia and Extrapyramidal System

The cerebrum exerts control of voluntary somatic motor activity through several descending pathways. The direct pathway is via the pyramidal system, which includes the corticospinal (pyramidal) tract together with fibers that diverge from it to innervate cranial nerve motoneurons, the corticobulbar tract (see Fig. 24.1). The cortical neurons that form the tract are upper motoneurons. There are two other major descending pathways that arise from the cortex: the corticorubral/ rubrospinal tract and the corticoreticular/ reticulospinal tract, but these are less direct. They involve a synapse in the red nucleus and in the reticular formation of the lower brainstem, respectively. Before evolution of the cerebral cortex in mammals, voluntary somatic motor activity was mainly mediated by upper motoneurons in the red nucleus and the brainstem reticular formation. These nuclei together with the corpus striatum, the major component of the basal ganglia and the most important forebrain center for motor control in premammalian vertebrates, were designated as components of the extrapyramidal system whose descending fibers pass through the tegmentum rather than the medullary pyramid. However a dichotomy between a pyramidal and an extrapyramidal system does not really exist. The cortex that gives rise to all of these descending tract sys-

tems is anatomically, functionally, and inextri- cably interconnected with the basal ganglia.

ORGANIZATION OF THE BASAL GANGLIA

The basal ganglia are nuclear complexes in the cerebrum and midbrain that play a critical role in the integration of motor activity. Along with the cerebellum, the basal ganglia act at the interface between the sensory and motor systems. The basal ganglia integrate and process afferent input from the cerebral cortex and send the modified signals to the thalamus, which, after further alteration, relays the output back to specific areas of the cerebral cortex. Although this chapter emphasizes the role of the basal ganglia in somatic motor function, this group of nuclei also is of great importance in mechanisms involving emotional and cognitive behaviors. The following information is meant to provide a basic understanding of how the basal ganglia participates in a variety of activities and is a simplification of their functional organization and complex circuitry.

Clinically, resting movement disorders (dyskinesias), which occur when a patient is not purposefully moving, are generally ascribed to malfunctioning of the basal ganglia. Parkinson's disease and Huntington's chorea

419

420

are two well-known expressions of basal ganglia dysfunction. In order to understand the mechanisms involved, it is important to know the structures that comprise the basal ganglia, fundamentals of the circuitry, and whether the various links excite or inhibit their targets or do both.

The H u m a n Nervous System

The basal ganglia are considered to include the corpus striatum, subthalamic nucleus, substantia nigra, and the ventral tegmental area (see Table 24.1). This is based on the interrela- tionships of these structures and their roles in somatic motor function. The pedunculopontine nucleus probably should be added to this list

Caudate nucleus - - ; : i i!~i! !

Ventral anterior and ventral lateral

thalamic nuclei Putamen

Nucleus ruber - -

Rubrospinal tract

Reticular formation

: Glob us pallidus

fibers

Reticulospinal _ ~ tracts.

Corticospinal _ _ tract

Figure 24.1: The core circuit linking the cerebral cortex, basal ganglia, thalamus, and motor cortex to the descending pathways. The sequence comprises the (1) cerebral cortex to (2) striatum (putamen and caudate nucleus) to (3) globus pallidus to (4) thalamus (ventral anterior and ventral lateral nuclei) to (5) supplementary, premotor, and motor cortices, where (6) the corticospinal, cor- ticorubrospinal, corticoreticulospinal, and corticobulbar pathways originate.

Chapter 24 Basal Ganglia and Extrapyramidal System

Table 24-1: Basal Ganglia and Related Centers

421

Corpus striatum --

Striatum (neostriatum)

Globus pallidus (pallidum, paleostriatum)

~ audate nucleus

utamen

ucleus accumbens

edial (internal) segment

ateral (external) segment

ntral pallidum

Dorsal striatum

Ventral striatum

Dorsal pallidum

Substantia nigra _•pPars compacta

ars reticularis

Subthalamic nucleus

Ventral tegmental area (VTA)

because of its extensive interrelations with nuclei listed in the table.

The corpus striatum is divided into the striatum (neostriatum) and the globus pallidus (pallidum or paleostriatum). The striatum is divided into the putamen (about 55% by volume), caudate nucleus (about 35% by volume), which together form the dorsal striatum (see Fig. 1.8), and the nucleus accumbens (ventral striatum). The globus pallidus (GP) is divided into medial (GPm) and lateral (GP1) segments, and ventral pallidum. The substantia nigra consists of two parts, called the pars reticularis and pars compacta based upon differences in neuronal densities. The two parts have different connectivity and neurotransmitters and, hence, are functionally distinct. During development, the fibers of the internal capsule pass through the territory of the basal ganglia and separate (1) the putamen from the caudate nucleus and (2) the subthalamic nucleus and the substantia nigra from the globus pallidus. The putamen and the globus pallidus are collectively called the lenticular (lentiform) nucleus. The (1) caudate nucleus and putamen and the (2) medial seg-

ment of the globus pallidus and substantia nigra, pars reticularis (SNr), form two paired units; each pair has similar inputs and outputs (see Fig. 24.2). The ventral tegmental area (VTA) is a cluster of neurons in the midbrain tegmentum located just medial to the substantia nigra, pars compacta (SNc). The substantia nigra, pars compacta, and VTA both are dopaminergic.

Ventral Striatum and Ventral Pallidum (see Table 24.1 )

The ventral striatum, which we equate to the nucleus accumbens although it does encompass some of the adjacent area, is located ventral to the anterior limb of the internal capsule at the junction of the caudate nucleus and putamen. Its cytoarchitecture and histochemistry are similar to that of the dorsal striatum, which commonly is referred to simply as striatum. The ventral striatum projects to the ventral pallidum. It serves as a link with the limbic system through afferent input from the amygdala and hippocam- pal formation and output via the ventral pallidum to the dorsomedial thalamic nucleus.

422

A Ansa lenticulads

Cau nucl

The Human Nervous System

Lenticular fasciculus (H~)

Llamic fasciculus (HO

:halamic nucleus

Putamel

B Lenticular nucleus

Caudate nucleus

N "\ Substantia \ "~ nigra

Internal capsule

Subthalamic nucleus

nucleus

Figure 24.2: Structures involved in the circuitry of the basal ganglia. (B) the location of the basal ganglia in relation to the lateral ventricle; (A) some efferent projections of the basal ganglia and cerebellum. The pallidofugal fibers from the globus pallidus form three bundles: ansa lenticularis, lenticular fasciculus, and subthalamic fasciculus. The former two bundles and the projections from the dentate nucleus of the cerebellum join to form the thalamic fasciculus that terminates in the thalamus. L and M refer to the medial and lateral segments of the globus pallidus, respectively. VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nuclei; CM, centrum medianum; ZI, zona incerta.

The substantia innominata (see Fig. 22.2) is an area located ventral to and extending rostrally from the basal ganglia. It is associated with the substantia innominata is the basal nucleus of Meynert (Chap. 25) and the ventral pallidum composed of neurons considered to

be a ventral extension of the globus pallidus. The ventral pallidum has projections that eventually affect descending motor systems. Through these connections, the ventral pallidum together with the ventral striatum are linked to the limbic system and exert a role in

Chapter 24 Basal Ganglia and Extrapyramidal System 423

planning and integrating movements that are related to motivational and emotional stimuli.

GENERAL CIRCUITRY ASSOCIATED WITH THE BASAL GANGLIA

The cerebral cortex, basal ganglia, and thalamus are interconnected via several complex neural circuits. Until recently, it was thought that the basal ganglia primarily integrated and processed diverse inputs from wide areas of the neocortex and relayed signals to "motor nuclei" of the thalamus, which projected back to motor regions of the cortex. However, It has become clear that the circuitry of the basal ganglia is in a dynamic state. Components are differentially activated, depending on conditions, and interact as required. Inhibitory and excitatory transmit- ters, involving numerous comodulators, which act on neurons with a variety of receptor subtypes to produce smooth coordinated movements and behavioral responses, exquisitely modulate activity throughout the system. Pathology of an anatomical or chemical nature can cause profound functional disturbances.

The following representation is abstracted from more complex circuitry. The basal ganglia are composed of a core circuit, which is divisi- ble into at least four functionally segregated parallel circuits (motor, association, oculomotor, limbic), and two side loops, one with the subthalamic nucleus and the other with the substantia nigra.

Generalized Core Circuit The basic core circuit comprises the cerebral

cortex --~ striatum ---) globus pallidus --) thalamus ---) cerebral cortex. Processed information then is transmitted via upper motoneuron pathways (e.g., corticospinal tract) to the lower motoneurons. Some structures associated with this circuit are illustrated in Figs. 24.1-24.4. A feedback loop goes back to the striatum via thalamostriate fibers from the intralaminar nuclei.

The general core circuit serves as a template for the other parallel cerebral cortex ~ basal

ganglia ---) thalamocortical loops that convey functionally distinct information from different cortical regions. Each circuit combines a "closed loop" and an "open loop." The "closed loop" comprises the input from a specific cortical area (e.g., supplementary motor cortex) back to the same region (e.g., supplementary motor cortex). The "open loop" component comprises input from other cortical areas (e.g., premotor area, primary motor cortex, and primary somatosensory cortex) and terminates in the cortical area of origin of the closed-loop supplementary motor cortex in the example.

PARALLEL ORGANIZATION OF FUNCTIONALLY SEGREGATED

CIRCUITS LINKING BASAL GANGLIA, THALAMUS, AND CORTEX

The basal ganglia-thalamocortical circuits include (1) a motor circuit (see Fig. 24.5A), (2) an association circuit (see Fig. 24.5B), (3) an oculomotor circuit (see Fig. 24.5C), and (4) a limbic circuit (see Fig. 24.5D). As indicated, the basic design of each circuit incorporates a central "closed loop" and an "open loop" which receives input from several partially overlap- ping functionally related cortical areas. These multiple inputs are progressively integrated in their passage through the pallidum and thalamus and back to one specific cortical area. None of the loops is a rigid self-contained pathway but, rather, receives diverse influences from the nuclei of the circuit.

The significance of the parallel circuits is that they express another level of organization and functional specificity. Subsidiary inputs and circuits modify and modulate the flow of information that passes through the major basal ganglia-thalamocortical circuits and, thus, provide additional routes for influences to be exerted on these processing centers.

Circuit 1: Motor (see Fig. 24.5A) Widespread areas of the cerebral cortex,

including the motor areas, project corticostriate fibers in a topographically organized arrange-

424 The Human Nervous System

Caudate nucleus

VA and VL thalamic nuclei

Centromedian nucleus

Putamen

Thalamic fasciculus H 1

Prerubral field H

A

Lenticular fasciculus H 2

Subthalamic.i Fascic

nigra

Gabaergic fibers

Dopaminergic fibers

al

• Lateral~ Globus r pallidus

MedialJ

,pontine

Figure 24.3: Main circuits associated with the basal ganglia are illustrated in (A) a coronal sec- tion through the cerebrum and (B,C) transverse sections through the upper and lower midbrain. Note." (1) circuit 1: cerebral cortex to striatum to globus pallidus to VA and VL of thalamus (via


Thalamocortical fibers

VL c nuclei

Subthalamic nucleus

Putame

jra

Subthalamic fasciculus

Figure 24.4: Circuits associated with the basal ganglia. Note: circuit 2: striatum (caudate nucleus and putamen) to substantia nigra to striatum and to VA and VL thalamic nuclei to motor cortex; circuit 3: globus pallidus to subthalamic nucleus to globus pallidus.

ment to the ipsilateral striatum, particularly the putamen. The motor cortices (areas 4 and 6) and primary somatosensory cortex (areas 3, 1, and 2) project bilaterally to the putamen. The closed-loop portion of the motor circuit begins and ends in the supplementary motor cortex. The open-loop portion involves the other areas.

Striatopallidal fibers arising from all parts of the striatum terminate in both the medial and lateral segments of the globus pallidus. The medial segment is the origin of two fiber bundles, both of which terminate in the thalamus. Fibers from the ventral portion of the globus pallidus form the ansa lenticularis, which loops under the internal capsule, whereas fibers from the dorsal portion enter the lenticularfas- ciculus, which passes across the internal cap-

sule and appears as a prominent band as it continues medially along the dorsal and rostral sur- faces of the subthalamic nucleus (see Fig. 24.3). In this location, the lenticular fasciculus forms the ventral border of the zona incerta, which is an extension of the brainstem reticular formation into the diencephalon. Fibers of the lenticular fasciculus and ansa lenticularis coa- lesce medial to the zona incerta and subthalamic nucleus, where they are just rostral to the red nucleus in what is referred to as the prerubral field. The combined fascicles pass later- ally and rostrally along the ventral border of the thalamus (dorsal to the zona incerta) as the thalamicfasciculus (see Fig. 24.3). It should be noted that dentatothalamic fibers from the cerebellum, as well as fibers of the medial lemnis-

ansa lenticularis, lenticular fasciculus, and thalamic fasciculus) to motor cortex; (2) circuit 2: striatum via GABAergic fibers to substantia nigra to striatum via dopaminergic fibers; (3) circuit 3: globus pallidus to subthalamic nucleus and back via subthalamic fasciculus; and (4) circuit 4: stria- turn to globus pallidus to centrum medianum to striatum. ZI, zona incerta.


cus and spinothalamic tract, also pass through the prerubral field and join the thalamic fasciculus. Pallidal efferent fibers turn dorsally and terminate in the ventral anterior (VA), ventral lateral (VL), and centro median (CM) nuclei of the thalamus. The VA and VL nuclei project somatotopically to lamina IV of the motor cortex (area 4), supplementary motor and premotor cortices, which occupy area 6, frontal eye field (area 8), and prefrontal cortex (areas 9 and 10).

Other connections of this circuit add to the complexity of interactions involving the nuclei of the basal ganglia (see Fig. 24.3). The globus pallidus, for example, projects to CM and other intralaminar thalamic nuclei; the former, in turn, projects to the putamen as well as dif- fusely to the cortex. Thus, the intralaminar nuclei are incorporated into a circuit of striatum to globus pallidus to intralaminar nuclei and back. In addition, the globus pallidus has reciprocal connections with the pedunculopontine nucleus of the midbrain (see Fig. 24.3). The latter does not project caudally. This is consistent with the evidence that none of the basal ganglia has fibers projecting to the lower brainstem or spinal cord. Rather, the output from the basal ganglia is directed toward the cerebral cortex. Several neurotransmitters have been identified with these circuits.

Circuit 2: Association (see Fig. 24.5B) The association circuit is different from the

motor and oculomotor circuits in that the widespread association areas of the frontal, parietal, occipital, and temporal lobes project primarily to the ipsilateral caudate nucleus. The closed loop commences and ends in the prefrontal

region (areas 9 and 10). Further, striatopallidal connections to the medial segment of the globus pallidus terminate in portions of the nucleus that project preferentially to intralaminar nuclei other than the CM, as well as to the VA and VL. In addition to diffuse cortical collaterals, these other intralaminar nuclei project back to the caudate. Also, the parts of the VA and VL receiving input forward the information to the prefrontal cortex (areas 9 and 10). Other features of this circuit are similar to those of the motor circuit.

Circuit 3: Oculomotor (see Fig. 24.5C) The closed-loop component of the oculomo-

tor circuit begins and ends in the frontal eye field (area 8). The open loop receives input from the prefrontal cortex (areas 9 and 10) and from the posterior parietal region (area 7). Fibers arising from these cortical areas project preferentially to the body of the caudate nucleus, from which, after processing, information is sent to the globus pallidus and the substantia nigra, the pars reticularis. In addition to projections from these nuclei to the thalamus as in the other circuits (VL, VA, intralaminar), nigral efferents also go to the frontal eye field (area 8) via relays in the dorsomedial nucleus of the thalamus and directly to the superior colliculus to participate in control of saccadic eye movements.

Circuit 4: Limbic (see Fig. 24.5D) There are several separate circuits that can

be described as limbic, but they have been combined into one for simplification. The closed-loop portion of a limbic circuit begins and ends in the anterior part of the cingulate

Figure 24.5: Schematic representation of segregated parallel circuits (loops) among the cerebral cortex, basal ganglia, and thalamus. (A) Motor loops. The closed loop commences with and terminates in the supplementary motor cortex (area 6). The open loop involves input to the closed loop from somatosensory cortex (areas 3, 1, and 2), primary motor cortex (area 4), and premotor cortex (area 6). (B) Association loops. The closed loop commences with and terminates in the prefrontal cortex (areas 9 and 10). The open loop involves input from premotor cortex (area 6) and posterior parietal cortex (area 7). (C) Oculomotor loops. The closed loop commences with and terminates in the frontal eye field (area 8). The open loop involves input from the prefrontal cortex (areas 9 and


CORTEX

STRIATUM

OUTPUT

MOTOR

Suppl Motor (Area 6)

Putamen

GPm, GPI SNr (caudlat)

j SS [areas 3,1,2] i iPrimary Motor (4) i

Premotor (6) [ y .................. 1

THALAMUS ~ ] VLo, VLm

A [ O

CORTEX

STRIATUM

OUTPUT

THALAMUS

ASSOCIATION

OCULOMOTOR

.~i Frontal Eye Field J (Area 8)

Putamen

GPm, GPI SNr (caudlat)

SS (areas 3,1,2) Primary Motor (4)

Premotor (6) Z .................. J

~ A . Superior Colliculus

m VAmc (lateral) DM (parvo]

] Primary Motor (4)[ ...... P.r...em..ot..o :. !..6.). .....

Caudate (head) Z (dorsolateral)

GPm (dorsomed) SNr (rostra)

t VA (parvo) m DM (parvo)

B i D

LIMBIC

. 1 • Ant Cingulate (24) j'"':lremporai[.obe"'] Orbitofrontal [ (medial, lateral) [

(10,11) l i Hippo,Amygdala [ j [Entorhinal [Area 24][

. . . . . . . . . . . . . . . . . .

Ventral PallidumJ GPm, SNr

,~ VAmc DMmc

10) and posterior parietal cortex (area 7). The projection to the superior colliculus has a role in the control of saccadic eye movements. (D) Limbic loops. The closed loop commences with the anterior cingulate gyrus (area 24) and orbitofrontal cortex (areas 10 and 11) and terminates in these areas. The open loop involves input from the medial and lateral temporal lobe, hippocampus, amygdala, and entorhinal area (area 24). Ant, anterior; caudlat, caudolateral; DM, dorsomedial thalamic nucleus; mc, magnocellular part; GP1, GPm, globus pallidus, lateral, and medial segments; Hippo, hippocampus; parvo, parvocellular; SNr, substantia nigra, pars reticularis; SS, somatosensory; VA, ventral anterior thalamic nucleus; VL, ventrolateral thalamic nucleus.


gyrus (area 24) and orbitofrontal cortex (areas 10 and 11). The open-loop component receives input from the medial and lateral temporal lobe cortex, including the entorhinal area (area 28), the amygdala, and hippocampus. These regions send excitatory signals (glutamatergic) to the ventral striatum (nucleus accumbens) and part of the head of the caudate nucleus, from which, after processing, information is forwarded to the ventral pallidum, globus pallidus and reticular part of the substantia nigra. Fibers from these nuclei project to the magnocellular divi- sions of the ventral anterior and dorsomedial thalamic nuclei, which project to the cortex of the closed loop.

SIDE CIRCUITS

Circuit 5: Substantia Nigra Striatum ~ substantia nigra ---) thalamus

(VA and VL nuclei) ~ portions of the motor cortex (see Figs. 24.2 and 24.4).

This circuit involves the substantia nigra. In brief, the substantia nigra (1) receives input from the ipsilateral striatum, subthalamic nucleus, and globus pallidus and (2) projects to the ipsilateral VL and VA thalamic nuclei (see Fig. 24.5) as well as back to the striatum (see Fig. 24.2).

The substantia nigra is divided into the ven- trally located pars reticularis, or SNr (adjacent to the crus cerebri) and the dorsally located pars compacta (SNc) (see Fig. 13.15). The pars reticularis has iron-containing glial cells, serotonin, and gamma aminobutyric acid (GABA), but lacks the melanin pigment. The pars compacta has dopaminergic neurons that contain melanin (hence, its dark appearance). Neuromelanin pigment is a polymer of the catecholamine precursor dihydrophenylalanine (Dopa) and is absent in patients with Parkinson's disease as well as in infants. There is linkage between the two parts of the nigra via dendrites of pars compacta neurons, which extend into the pars reticularis.

The striatonigral fibers project almost entirely to the pars reticularis, although there

are some terminals in ventral parts of the pars compacta. The projections from the substantia nigra are directed rostrally via (1) nigrostriatal fibers from the pars compacta to the striatum and (2) nigrothalamic fibers from the pars reticularis to the VA and VL thalamic nuclei. These thalamic nuclei project to portions of the motor cortical areas. The nigral efferent projections to the VA and VL nuclei terminate in different regions of these thalamic nuclei than do projections from the globus pallidus and from the cerebellum (dentatothalamic fibers); current evidence indicates that no overlap occurs among these three projections.

The substantia nigra, pars reticularis, GPm, and the cerebral cortex are sources of descending fibers to the pedunculopontine nucleus (PPN) in the caudal midbrain (see Fig. 24.2). These fibers are the most caudal projections from the basal ganglia. Other afferents come from the cerebellar nuclei via the superior cerebellar peduncle. Different cells in PPN express acetylcholine and glutamate. Efferents from the pedunculopontine nucleus, which are directed rostrally, mainly go to the substantia nigra, pars compacta, with some to the subthalamic nucleus and to GPm. Thus, PPN is an interface between the cerebellum and the basal ganglia.

The nigrostriatal fibers from the pars compacta form a dopaminergic system, which releases dopamine in the striatum. The serotonin in the pars reticularis is derived from the dorsal tegmental nucleus of the midbrain raphe. The striatonigral fibers and the nigrothalamic fibers release GABA.

Circuit 6: Subthalamic Nucleus Globus pallidus +--) subthalamic ~ globus pallidus (lateral segment) nuc l e us (medial segment)

substantia nigra (pars reticularis)

(see Figs. 24.2 and 24.4). The subthalamic nucleus receives input

from the ipsilateral globus pallidus (lateral segment), motor cortex, and pedunculopontine nucleus. It projects output to both seg-

Chapter 24 Basal Ganglia and Fxtrapyramidal System 429

ments of the ipsilateral globus pallidus and to the pars reticularis of the substantia nigra, with which it is reciprocally interconnected; this is another side circuit. The fibers that reciprocally interconnect the globus pallidus and the subthalamic nucleus form the subthalamic fasciculus, which passes through the posterior limb of the internal capsule. Neu- rons of the subthalamic nucleus release glutamate, which is an excitatory transmitter. The subthalamic nucleus is the driving force regu- lating the output of the globus pallidus and substantia nigra by increasing or decreasing the amount of inhibition they exert on the thalamus (see later).

General Organization of the Basal Ganglia On the basis of their neural connections, the

nuclei of the basal ganglia are organized as input nuclei, intrinsic nuclei, and output nuclei (see Table 24.2). The input nuclei receive afferent information from outside the basal ganglia and project their output to the intrinsic nuclei. The intrinsic nuclei interact and have connections with both other input nuclei and output nuclei. After neural processing within the basal ganglia, the output nuclei send inhibitory signals to nuclei outside the basal ganglia.

The striatum (caudate nucleus, putamen, and nucleus accumbens) comprises the input nuclei. It receives its major input from the cerebral cortex as well as afferents from the intralaminar nuclei of the thalamus; both pathways are glutamatergic. The globus pallidus (lateral segment), subthalamic nucleus, substantia nigra (pars compacta), and ventral tegmental area comprise the intrinsic nuclei. The circuitry linking these nuclei together and with the input and output nuclei is mainly inhibitory, with GABA as the major neurotransmitter; an important exception is the subthalamic nucleus, whose glutamatergic output is entirely excitatory (see Fig. 24.6A). A second rather unusual and very important exception, to be discussed, involves the substantia nigra, pars compacta. The globus pallidus (medial segment), substantia nigra (pars reticu-

laris), and ventral pallidum comprise the output nuclei. The GABAergic projections from these nuclei are largely directed to the thalamus and are inhibitory (see Fig. 24.6).

Cytoarchitectural and Compartmental Organization of the Striatum

Cell Types. The striatum contains two major neuronal population projection neurons whose axons terminate in other nuclei and interneurons whose axons remain within the striatum. The medium spiny neuron, which receives most of the extrastriatal input, is, by far, the most numerous cell type, constituting over 90% of the total population. These cells have axons that project out of the striatum; GABA is the major neurotransmitter. Two classes of this cell type, with different projections, are recognized. Striatonigral neurons, including those with collaterals to the medial pallidal segment, corelease substance P and dynorphin; this is referred to as the direct pathway to the output nuclei. Striatopallidal neurons to the lateral segment (indirect pathway) corelease enkephalin. Both types of spiny neuron have dopamine receptors. There are several different dopamine receptor subtypes; D~ and D2 receptors, which activate different intracel- lular pathways, have been studied most. Recent evidence shows that D1 and D2 receptors are colocalized on most spiny neurons, supersed-

Table 24-2: Categories of Basal Ganglia Nuclei Input nuclei

Caudate nucleus Putamen Nucleus accumbens

Intrinsic nuclei Globus pallidus (lateral segment) Subthalamic nucleus Substantia nigra (pars compacta) Ventral tegmental area (VTA)

Output muclei Globus pallidus (medial segment) Substantia nigra (pars reticularis) Ventral pallidum


A Normal

I

a

D Early Huntington's Chorea

X J

:ii

7

F

f

t 7

Figure 24.6: Simplified model depicts functional connections of the basal ganglia with the thalamus and cortex whence to lower motoneurons and shows relative balance/imbalance of activity in different parts of the circuitry in normal and various pathological states. Open arrows, excitatory


ing the notion that spiny neurons giving rise to the direct pathway have D~ receptors, whereas those giving rise to the indirect pathway have D 2 receptors. The two receptor subtypes interact. The dopaminergic input from the substantia nigra presumably differentially modulates the two classes of spiny projection neuron, pro- viding the basis for explaining various forms of basal ganglia-induced motor disturbances (see below). Spiny projection neuron axons emit copious collaterals, which inhibit other spiny projection neurons. This is another example of lateral inhibition. In addition, strionigral fibers form presynaptic terminals on the collaterals, adding to the complex modulatory influences on these cells. Collaterals also synapse on interneurons, which terminate on spiny projection neurons and other interneurons. Interneu- rons, whose axons do not leave the striatum, are of several types. All have dopamine receptors. Large aspiny neuron are cholinergic and form excitatory synapses on the projection neurons. In addition, there are two separate classes of intrinsic medium aspiny neurons whose major neurotransmitter is GABA. One type also colocalizes somatostatin, nitric oxide, and neuropeptide Y. Thus, different classes of interneurons directly excite or inhibit the projection neurons. Inhibitory interneurons also can indirectly disinhibit them by acting on other inhibitory interneurons, which, in turn synapse upon the projection neurons.

Patch-Matrix Compartments. Based on differences in neurochemical markers, the striatum

has been divided into smaller patch compartments (15% of the total) embedded in a matrix. The matrix, in contrast to patches, contains high levels of the enzyme acetylcholinesterase. Only matrix cells contain the calcium-binding protein calbindin D2~k and only matrix cells have ~ opi- oid receptors. Spiny projection neurons expressing primarily substance P or enkephalin occur in both compartments, but the cortical inputs to the compartments differ. Corticostriate projections from cells in more superficial parts of lamina V go principally to the matrix com- partment. Although most of the cortex projects to the matrix, afferents from sensory and motor cortex are differentially distributed to it. Patch compartments receive terminals from neurons in deep parts of lamina V in the cortex related to the limbic system (anterior cingulate and medial frontal gyri), where this lamina is well developed. The two compartments emit distinct striatonigral projections. The matrix sends fibers to the GABAergic parts of SNr, whereas the patches provide input to dopaminergic neurons located in the ventral part of SNc and in islands within SNr.

SUMMARY

The basal ganglia are subcortical nuclei that play a primary role in the integration of somatic motor activity. The amygdala and hippocampus, nuclear complexes of the limbic system (Chap. 22) with connections to the ventral striatum, involve the basal ganglia in somatic

connections; solid arrows, inhibitory connections. Increased excitation or inhibition, thick arrows; diminished effect, thin arrows. (A) Normal: all connections are in balance (arrows are the same width throughout). The major neurotransmitters are shown. (B) Destruction of the substantia nigra, pars compacta (SNc), as in Parkinson's disease. (C) Destruction of the subthalamic nucleus (STN), as in ballism. (D) Selective loss of gabaergic striatal projection neurons to the lateral segment of the globus pallidus (GP1), as occurs in early-stage Huntington's chorea. Those projecting directly to the globus pallidus, medial segment (GPm) and to the substantia nigra, pars reticularis (SNr)-- the output nuclei of the basal ganglia--also undergo degeneration in later stages. GABA is the major neurotransmitter of spiny striatal projection neurons. Those giving rise to the direct pathway coexpress dynorphin (Dyn) and substance P (Sub P). Those giving rise to the indirect pathway coexpress enkephalin (Enk). LMNs, lower motoneurons; VL/VA, ventral lateral and ventral anterior thalamic nuclei. The striatum contains three types of interneurons. See text for description.


movements associated with responses to motivational and emotional stimuli.

The striatum is the receptive complex of the corpus striatum (see Table 24.2); its input is derived from widespread areas of the neocortex, intralaminar nuclei (centrum medianum and parafascicular nucleus) of the thalamus, substantia nigra, VTA, and dorsal raphe nucleus of the midbrain. The afferent corticostriate influences are mediated by the excitatory transmitter glutamate (see Fig. 24.6A). The intrinsic local- circuit neurons of the striatum are cholinergic and GABAergic. The striatum is divided into two compartments: 85% consists of a "matrix" and 15% consists of small "patches." The con- centration of acetylcholine is much higher in the matrix than in the patches. The matrix receives major input from the motor and sensory cortices. Patches receive major input from the limbic cortex. Two classes of GABAergic medium spiny projection neurons give rise to two separate striatal output pathways: direct and indirect. The direct pathway, which arises from neurons that coexpress substance P and dynorphin, makes monosynaptic connections with the output nuclei of the basal ganglia, the medial segment of the globus pallidus, and the substantia nigra (pars reticularis). The indirect pathway, which arises from neurons that coexpress enkephalin, goes to the lateral segment of the globus pallidus. The GP1 sends fibers to the subthalamic nucleus, whose glutamatergic excitatory efferents go to the output nuclei. Striatal projection neurons and interneurons have dopamine receptors. Although there are a variety of subtypes of dopamine receptor, the D1 and D2 subtypes, which appear to be colocalized in virtually all projection neurons, have been most thoroughly studied. They are associated with second-messenger systems (Chap. 3). The DI receptors act to increase and the D2 receptors to decrease cAMP formation.

The output of the basal ganglia is derived from neurons of the medial segment of the GP, the substantia nigra (pars reticularis), and ventral pallidum. The projections from these sources to VL and VA thalamic nuclei are distinct and their terminations do not overlap. The

thalamic neurons receiving these inputs do not exert major effects on the primary motor cortex (area 4), but, rather, mainly project their outputs to premotor and supplementary motor areas (Chap. 25). The pallidothalamic and nigrothalamic fibers primarily exert inhibitory effects on the thalamus.

The substantia nigra receives input from both the striatum and globus pallidus of the corpus striatum, subthalamic nucleus, pedunculopontine nucleus, and dorsal nucleus of the midbrain raphe. A major output from the substantia nigra (pars compacta) terminates as dopaminergic endings in the striatum. The subthalamic nucleus receives input from the lateral segment of the globus pallidus and the motor cortex and projects to both segments of the globus pallidus, the substantia nigra (pars reticularis), and ventral pallidum. Excitatory influences from the glutamatergic subthalamic nucleus acting on the medial segment of the pallidum and on the substantia nigra (pars reticularis) is regarded as the driving force reg- ulating the output of the basal ganglia.

The basal ganglia along with the cerebellum act as the interface between our sensory systems and many motor responses. The pallidothalamic projections in the thalamus do not overlap the cerebellar projections from the deep cerebellar nuclei. No convergence from the pallidal and cerebellar inputs has been demonstrated on a single thalamic neuron.

The precise role of the basal ganglia in the regulation of normal movements is still a mat- ter of speculation. They are thought to be involved in the regulation of background muscle tone and posture and in the initiation, control, and cessation of automatic movements such as in locomotion (running) and in athlet- ics (throwing a ball). The basal ganglia are apparently involved in the transfer and modi- fication of information from widespread neocortical areas to the motor cortex, especially the premotor and supplementary motor areas. Via circuitry linking the ventral striatum with the limbic system, the basal ganglia participate in behavioral responses related to the emotions.


FUNCTIONAL CONSIDERATIONS

Formerly, the cerebral cortex, especially the motor cortex, was hierarchically placed at the highest level for orchestrating motor integration, and subcortical structures were placed at another level and thought to function solely in a feedback capacity. The newer view states that both the basal ganglia and the cerebellum are crucial in the initial and early processing stages resulting in motor activity. The circuitry involving the sensory cortical areas, basal ganglia, and cerebellum act through the ventral anterior and ventral lateral nuclei, known as the motor nuclei of the thalamus. They serve as the main gateway through which these circuits become involved in generating activity in the motor cortical areas; they fire well in advance of and during each volitional movement. In addition, these circuits act as bridges between the sensory cortical areas and the motor cortical areas. In a real sense, these circuits are active partici- pants during all phases of a movement, from initiation to completion.

As we have seen, the role of the basal ganglia, cerebellum, and associated nuclei is to modulate motor activities through circuits, which directly and indirectly feed back to the cerebral cortex. In turn, the cortex projects its influences to the brainstem and spinal levels through the descending motor pathways, upon the local circuitry that activates the alpha and gamma motor neurons. The malfunction of various nuclear complexes results in an imbalance in the interactions within the circuitry of the basal ganglia, disrupting the output, which ultimately is manifest at the level of the motor units. This is a plausible explanation for the variety and assortment of symptoms and signs noted in the disorders involving control of posture and movements. In some disorders, there is an increase in muscle tone to a similar degree in the agonists and antagonists of a muscle group without an accompanying increase in reflex activity, called rigidity. Rigidity (Chap. 8) is a form of hypertonus in which the muscles are continuously or intermittently tense, and it

is associated with hyperactive static fusiform gamma motoneurons. In contrast, spasticity (Chap. 12) is a form of hypertonus in which the muscles are in phasic hyperactive activity when the muscles are stretched. This is associated with hyperactive dynamic fusiform gamma motoneurons.

Clinical Manifestations The abnormal involuntary movements called

dyskinesias can be rhythmic or arrhythmic, generally without paralysis of the muscles. They can be classified as hypokinetic or hyperkinetic. The motor disorders result from improper functioning of the basal ganglia, and associated nuclei, including, among others, paralysis agitans (Parkinson's disease), athetosis, choreas, and ballism.

Paralysis agitans (Parkinson's disease, parkinsonism), which has a mean onset at age 60, is characterized by rigidity and tremor. The rigidity is essentially the same in all muscles; it is accompanied by poverty of movements and cogwheel rigidity. Cogwheel rigidity is expressed when the examiner flexes and extends a limb joint of the patient; during movement, an increased resistance suddenly gives way, and as the movement continues, this sequence is repeated, as in a cogwheel. From a standing position, a patient has difficulty taking initial steps. The subject also has the same problem arresting a movement. During forward locomotion, short, shuffling steps are taken. The "masked" face has a fixed expression, accompanied by no overt spontaneous emotional response. The tremor, with a regular frequency (three to six per second) and amplitude, occurs while the subject is at rest; it is lost or reduced during voluntary movement. Degener- ative changes in the nigrostriatal pathway, raphe nuclei, locus ceruleus, and motor nucleus of the vagus nerve are present in parkinsonian patients; in addition, there is a marked reduction to absence of dopamine, serotonin, and norepinephrine. It has been shown that Parkin- son-like symptoms can be elicited by toxins, such as 1-methyl-4-phenyl-l,2,3,6-tetrahy- dropyridine (MPTP), that selectively destroy


nigrostriatal dopamine neurons. Administration of L-dihydroxyphenylalanine (L-dopa) in low doses can ameliorate the rigidity, and in high doses, it can ameliorate the tremors. L-Dopa is a precursor of melanin and dopamine.

Although the placement of small lesions in the globus pallidus and VA nucleus of the thalamus in some patients alleviates the symptoms of rigidity and tremor, slowness in the initiation and execution of movement (bradykinesis) does not change. Moreover, the tremor and rigidity often recur a few years after surgery. Modern therapy for parkinsonism includes administration of can -dopa, certain anticholinergics, and/or other agents. Another therapeutic approach being explored is the transplantation of fetal midbrain tissue, including the substantia nigra into the striatum. In primate models of Parkinson's disease, caused by injecting MPTP, subsequent lesions produced in the subthalamic nucleus have been shown to reverse the signs. This is attributed to re-establishment of the appropriate balance of activity within the circuitry of the basal ganglia. A newer treatment option involves deep brain stimulation, in which high-frequency electrical currents are delivered via electrodes implanted bilaterally in the subthalamic nucleus. This produces overexcitation of the globus pallidus, causing it to increase its inhibition of the thalamus and reduce activity in the thalamocortical and descending corticofugal pathways to the lower motoneurons. Clinical trials also have been initiated using gene therapy. One strategy is to transfer glutamic acid decarboxylase, which catalyzes synthesis of GABA, into neurons of the subthalamic nucleus that normally produce glutamate. Increased excitation of the output nuclei is regarded as one aspect causing Parkinson's disease.

Tardive dyskinesia is a form of dyskinesia that occurs in some patients following the chronic administration of phenothiazines (antipsychotic and tranquilizing drugs) as therapy for such psychoses as schizophrenia. The symptoms can include facial grimacing, lip smacking, and choreoathetotic movements of the limbs and trunk. Treatment is to stop giving

the drug. Suggested causes include alteration of the dopaminergic receptors, resulting in their hypersensitivity to dopamine. The consequen- tial alteration in the balance among the dopaminergic, intrastriatal, cholinergic, and GABAergic agents results in the involuntary movements.

Choreas (dances) are characterized by jerky, irregular, brisk, graceful movements of the limbs accompanied by involuntary grimacing and twitching of the face. Primarily, the distal segments of the extremities express these movements. In advanced cases, the patient is almost always in motion when awake. There is no reduction in muscle power. Huntington's disease (chorea) is a hereditary autosomal dominant disorder (chromosome 4). From its initial subtle symptoms that might not appear until the late thirties, the affliction features pro- gressive increases in the severity of chorea (choreiform movements) and dementia. Death generally occurs 15-20 years after onset. The early stages of the disease have been correlated with a preferential loss, mainly in the caudate nucleus, of the neurons that express enkephalin that project to the lateral segment of the globus pallidus, with a relative sparing of those that project to the substantia nigra and to the medial pallidal segment. The latter are affected in later stages. Although not markedly degenerated, the cholinergic interneurons clearly are damaged in later stages, as evidenced by a significant reduction in the amount of striatal cholines- terase. A reduction in substance P and enkephalin in the globus pallidus and substantia nigra also occur. The involuntary choreiform movements are presumed to result from disturbances in metabolism and outputs of the neuronal loops involving the GABAergic spiny projection neurons, dopaminergic nigrostriatal, and cholinergic intrastriatal neurons. The impaired cognitive function is attributed to a concomi- tant loss of neocortical neurons.

The movements of athetosis are slow and exaggerated by voluntary movement. The slow, writhing character of the involuntary movements of the neck, trunk, and extremities


appear wormlike. The alternating adduction and abduction of the shoulder joint is accompanied by flexion and extension of the wrist and fingers. Usually, the wrist is flexed, and the fingers hyperextended. Facial grimaces might occur during the limb movements. This dyskinesia could be the result of a lesion in the striatum, mainly in the putamen. Athetosis is frequently associated with cerebral palsy. It occurs as the result of brain lesions during or prior to birth.

Ballism ("throwing") is characterized by violent, high-amplitude, flaillike movements originating mainly from the activity of the proximal appendicular muscles of the shoulder and pelvis. The movements cease during sleep. There is a reduction of muscle tone. These symptoms are exhibited unilaterally with a lesion in the contralateral subthalamic nucleus. Because, clinically, ballism almost always occurs on one side only and is usually the result of a vascular accident, it is also known as hemiballism. Symptoms associated with malfunctioning of the basal ganglia are usually observed bilaterally. However, like hemiballism, lesions on one side are manifest on the opposite side because the output of the basal ganglia is directed toward the ipsilateral cerebral cortex whose descending pathways pre- dominantly innervate lower motoneurons on the contralateral side.

The abnormal movements resulting from lesions in the basal ganglia circuitry are an expression of release phenomena, in which the inhibitory influences on such structures as the globus paUidus or ventral lateral nucleus of the thalamus are lost or reduced. Surgical lesions of these "released structures" (globus pallidus and VL) are known to ameliorate the symptoms in many patients. In this context, the loss of dopamine, noted in patients with parkinsonism, accounts for the reduction or loss of inhibitory influences upon the striatum. A likely underly- ing cause of disorders of the basal ganglia is that disruptions in transmitter metabolism result in an abnormal output from the circuitry of the basal ganglia.

Alterations of Inhibitory/Excitatory Activity in Movement Disorders

As indicated earlier, motor activity is modulated by the basal ganglia via their inhibitory output to the thalamus and excitatory thalamocortical-upper motoneuronal pathways. Smooth, coordinated "normal" movements require a proper balance of excitatory and inhibitory activity throughout the basal ganglia (see Fig. 24.6A). Anything that alters the usual pattern of inhibition exerted upon the thalamus is in a position to disrupt normal motor function. Thus, increased inhibition of the thalamus might be expected to diminish excitatory activity of the thalamocortical-upper motoneuronal pathways and reduce or other- wise impoverish motor activity. Conversely, decreased inhibition of the thalamus might be expected to increase excitation of the thalamocortical- upper motoneuronal pathways and produce an excess of motor activity.

Based on the circuitry of the basal ganglia and the interplay of inhibitory and excitatory neurotransmitters, the bradykinesis characteris- tic of parkinsonism is attributed to increased activity of the basal ganglia output nuclei (medial segment of the globus pallidus; substantia nigra, pars reticularis), which inhibit the VA and VL nuclei of the thalamus (see Fig. 24.6B). An unusual feature of the circuitry of the basal ganglia is that dopamine in the nigrostriatal pathway presumably inhibits the enkephalin- expressing striatal spiny projection neurons that give rise to the indirect pathway and excites the substance P- and dynorphin-containing neurons that form the direct pathway. Following this scheme, loss of dopaminergic nigrostriatal neurons, an attribute of this disease, causes reduced inhibition selectively of the striatopallidal fibers to the lateral segment of GP). Thus, the GPI receives greater than usual inhibitory input, causing its inhibitory influence on the subthalamic nucleus to be reduced. As a consequence, the excitatory influence of the subthalamic nucleus upon GPm/SNr is increased. These output nuclei inhibit the VL and VA to a greater than customary degree, ultimately reducing the


activity of the lower motoneurons. Diminished excitation of the striatal neurons that project directly to the GPm/SNr simultaneously occurs. This reduces inhibition on the GPm/SNr, leading to increased inhibition of the thalamus, as via the indirect pathway.

Conversely, lesions of the subthalamic nucleus decrease excitation of GPm/SNr, resulting in diminished inhibition of the thalamocortical part of the circuit (see Fig. 24.6C). Thus, activity of the lower motoneurons is increased above usual levels, as occurs in bal- lista. Following this line of reasoning, lesions of the subthalamic nucleus, produced in MPTP-induced models of parkinsonism, should restore the balance of activity in the internal circuitry of the basal ganglia. Indeed, this has been demonstrated to occur. With lesions of the substantia nigra, there is excessive activity in the subthalamic nucleus, regarded as an important factor in the genera- tion of Parkinson's disease. In the primate model, this excessive activity is eliminated with the secondary lesion.

As noted, Huntington's chorea in the early stages is associated with lesions of the striatum (mainly caudate) selectively involving the enkephalin-expressing GABAergic projection neurons whose axons terminate in the lateral segment of the pallidum. Reduced inhibition upon the GP1 would cause greater inhibition of the subthalamic nucleus (see Fig. 24.6D). In turn, excitation of GPm/SNr would be reduced, causing less inhibition of VL and VA, as after lesions of the subthalamic nucleus directly. Thus, the end result would be increased activity of the lower motoneurons, expressed as a hyperkinetic movement disorder. However, the pattern as well as amount of activity might be expected to be different from that elicited by other pathologies, accounting for the dissimi- larities in movement disorders.

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