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Medial (Ventral) Globus Pallidus (Substantia Innominata)

From: Neuropsychiatry, Neuropsychology, Clinical Neuroscience
by Rhawn Joseph, Ph.D.
(Academic Press, New York, 2000)

Medial (Ventral) Globus Pallidus (Substantia Innominata)

Medial (Ventral) Globus Pallidus (Substantia Innominata)

By Rhawn Joseph, Ph.D.

The medial globus pallidus is known by several names, including the "Substantia Innominata" ("Great Unknown").

The medial globus pallidus is thus part of the ventral limbic striatum.

The substantia innominata, nucleus accumbens, olfactory tubercle constitute the limbic striatum. The inferior ventral globus pallidus (also referred to as the ventral pallidum or substantia innominata) is also part of the limbic (ventral) striatum and in fact eventually merges with the centro-medial amygdala and receives extensive projections from the lateral amygdala, the olfactory tubercle, and nucleus accumbens.

Catatonia, Parkinson's Disease, & Psychosis.

Lesions to the corpus striatum and lenticular nucleus (putamen and globus pallidus) can attenuate one's capacity to motorically express their emotions via the musculature; e.g. the face may become frozen and mask-like. These latter motor disturbances are well known symptoms associated with Parkinson's disease, a disturbance directly linked to dopamine deficiency (Fahn, 1999) and neuronal degeneration not only in the putamen (Goto, et al. 1990; Kish, et al. 1988; see also Hauser et al., 1999), but within the limbic striatum, i.e. the nucleus accumbens (see Rolls & Williams, 1987), as well as in the supplementary motor areas and medial frontal lobe -which maintains rich interconnections with the striatum.

However, when chemical or structural lesions extend beyond the basal ganglia and come to include the medial frontal lobe, not only might an individual suffer motor rigidity, they may become catatonic and experience extreme difficulty responding to external or internally mediated impulses (Joseph, 1999a). Various aspects of this symptom complex also characterize those with Parkinson's disease (see below).

Other disturbances associated with striatal abnormalities include Huntington's chorea, ballismus, restless leg syndrome, sensory neglect and apathy, obsessive compulsive disorders, mania, depression, "schizophrenia" and related psychotic states (Aylward et al. 1994; Baxter et al. 1992; Caplan, et al. 1990; Castellanos et al. 1994; Chakos et al. 1994; Davis, 1958; Deicken et al. 1995; Ellison, 1994; Rauch et al. 1994; Richfield, et al. 1987; Turjanski, et al., 1999). Severe memory loss and social-emotional agnosia and an inability to recongize friends or loved ones is also characteristic of striatal abnormalities, particularly disturbances involving the limbic striatum.

Thus although the basal ganglia is often viewed and described as a major motor center (detailed below), the functional capacities and symptoms associated with this group of nuclei are quite diverse, and vary depending on the nuclei and chemical neurotransmitters involved as well as the laterality, location, and extent of any lesion.


In situations involving exceedingly high levels of arousal coupled with extreme fear, the individual may simply freeze and attentional functioning may become so exceedingly narrow that little or nothing is perceived and cognitive activity may be almost completely (albeit temporarily) abolished (see chapter 30). These behaviors are apparently under the control of the amygdala which can trigger a "freezing" reaction and a complete arrest of ongoing behavior (Gloor, 1960; Kapp et al. 1992; Ursin & Kaada, 1960) via these brainstem/striatal interconnections. This is part of the amygdala attention response, which at lower levels of excitation may be followed by anxious glancing about, an increase in respiration and heart rate, pupil dilation, and perhaps cringing and cowering or flight (Gloor, 1960; Ursin & Kaada, 1960).

Among humans, the fear response is one of the most common manifestations of amygdaloid stimulation (Gloor, 1990; Halgren, 1992; Williams, 1956). However, if arousal levels continue to increase, subjects do not merely freeze in response to increased fear, they may become catatonic; a condition which may be secondary to dopamine and serotonin depletion and amygdaloid influences on the SMA as well as the striatum; nuclei which are intimately interconnected.

For example, in response to extreme fear, "one tendency is to remain motionless, which reaches its extreme form in death-feigning in certain animals and sometimes produces the waxy flexibility of catatonics" (Miller, 1951). The affected individual becomes psychologically and emotionally numb and unresponsive which is coupled with a complete blocking off of cognition. Moreover, the individual may resist and fail to respond to attempts at assistance (Krystal, 1988; Miller, 1951; Stern, 1951).

The airline industry has referred to this as "frozen panic states" (Krystal, 1988), a condition sometimes seen in air and sea disasters. For example, in mass disasters, 10-25% of the victims will become frozen, stunned, and immobile, and will fail to take any action to save their lives, such as attempting to evacuate a burning or sinking craft even though they have been uninjured (see Krystal, 1988).

According to Krystal (1988) with increasing fear "there is also a progressive loss of the ability to adjust, to take the initiative or defensive action, or act on one's own behalf... that starts with a virtual complete blocking of the ability to feel emotions and pain, and progresses to inhibition of other mental functions" (Krystal, 1988, p. 151).


The limbic striatum consists of the nucleus accumbens, olfactory tubericle, the extended (centro-medial) amygdala, as well as the ventral aspects of the caudate, putamen and globus pallidus (-substantia innomminata).

The nucleus accumbens is located immediately beneath the anterior portion of the caudate and from a microscopic level appears to be part of the ventral caudate (Olton et al. 1991; Zaborszky et al. 1991). However, it maintains extensive interconnections with the amygdala as well as the hippocampus via the fimbria-fornix fiber bundle (DeFrance et al. 1985), which implicates this nuclei in memory functioning and probably the learning of visual-spatial and perhaps social-affective relationships.

Similarly, the dorsal portion of the substantia innominata ("great unknown") merges (dorsally) with the ventral globus pallidus (and ventrally with the centro-medial amygdala), and maintains interconnections with the accumbens, hippocampus, lateral amygdala, and dorsal medial (DM) nucleus of the thalamus (Young et al. 1984; Zaborszky et al. 1991) -the DM being involved in regulating neocortical arousal and information reception as well as memory (see chapter 19).

Like the accumbens, the substantia innominata (SI) is also important in memory functioning and has been implicated as one of the principle sites (along with the nucleus basallis) for the initial development of Alzheimers disease (see Olton et al. 1991; Zaborszky et al. 1991, for review of related details).

The nuclei of the limbic striatum are also interconnected with the lateral and medial hypothalamus, brainstem reticular formation, and the frontal and inferior temporal lobes (Everitt & Robbins, 1992; Groenewegen, et al. 1991; Heimer & Alheid, 1991; Kelly, et al. 1982; Mogenson & Yang 1991; Olton et al. 1991; Parent & Hazrati 1995; Van Hoesen, et al. 1981; Zaborszky et al. 1991). The limbic striatum is able, therefore, to exert widespread effects on neocortical and subcortical structures.

As noted, the limbic striatum receives DA from the mesolimbic system as does the amygdala. The amygdala also sends axons that terminate in striatal neurons immediately adjacent to those innervated by mesolimbic DA neurons (Kelly et al. 1982; Yim & Mogenson, 1983, 1989). Thus, a complex interactional loop is formed between these nuclei, the integrity of which, in part is dependent on the mesolimbic DA system which can act on the amygdala, hippocampus and limbic striatum simultaneously so as to modulate striatal reception of amygdala (Maslowski-Cobuzzi & Napier, 1994) and hippocampal excitatory signals, and regulate the transmission of accumbens input into the SI. Alterations in mesolimbic DA activity, therefore, can significantly influence limbic striatal, amygdala and hippocampal activity as well as the motoric expression of limbic impulses.

For example, depletions in mesolimbic DA can disrupt motor and social-emotional memory functioning; a condition compounded by DA influences on acetylcholine (ACh) neurons, and the effects of striatal DA on the reception of hippocampal, amygala, and neocortical input.

Indeed, the limbic striatum (and limbic system) contain high densities of ACh neurons which are involved in memory as well as motor functioning (Olton et al. 1991; McGaugh et al. 1992; Zaborszky et al. 1991). In fact, of all striatal nuclei, densities of DA (and ACh) neurons are highest within the (SI) and nucleus accumbens (Meredith et al. 1989) which in turn greatly influences the SI (which is a major source of neocortical ACh), as does the amygdala (Yim & Mogenson 1983) and hippocampus; i.e. these signals converge on the SI.


Like the striatum, the hippocampus (and the amygdala) also receives meso-limbic DA input and contains D1 and D2 receptors (Camps et al. 1990) as well as ACh. ACh influences on neuronal activity can be excitory or inhibitory depending on the resting membrain potential of the receiving neuron (Ajima et al. 1990) as well as concurrent DA activity. Specifically, mesolimbic DA mediated signals are relayed from the accumbens to ACh neurons in the SI which in turn project to DM and the neocortex, the frontal lobes in particular (Mogenson & Yang 1991; Olton et al. 1991; Zaborszky et al. 1991). However, the DA and cholinergic, ACh system appear to exert counterbalancing influences.

For example, ACh is usually inhibited by DA. By contrast, DA depletion results increased ACh and neuron hyperactivity (see Aghanjanian & Bunney, 1977; Bloom et al. 1965; Klockgether, et al., 1987) which can greatly disrupt cognitive and memory functioning as well as motor activities, unless reversed by anti-cholinergic drugs. In fact, damage to this DA/cholinergic system can result in Alzheimers disease (Olton et al. 1991; Zaborszky et al. 1991).

As per memory functioning, it appears that mesolimbic DA modulates the reception of hippocampal (motor-spatial) input into the accumbens which projects to the SI (which in turn distributes these influences, perhaps via ACh) to the neocortex). DA accomplishes this via inhibitory influences on ACh and facilitation of the GABA system which appears to exert inhibitory influences within the striatum and the transmission of impulses from the nucleus accumbens (and amygdala/hippocampus) to the SI. Therefore, if the inhibitory influences of GABA and ACh on the SI are dampened, the SI becomes activated and memory functioning may be enhanced or disrupted at the neocortical level as this nucleus exerts widespread ACh influences on the cerebrum. Thus fluctuations in DA levels can either act to excite or inhibit cognitive-memory activity within the limbic striatum (see Mogenson & Yang 1991) as well as the corpus striatum (Packard & White 1991) and the neocortex.

However, also of importance in this memory-striatal neural network is (5HT) serotonin (McLoughlin et al. 1994; Mogenson & Yang 1991) and (NE) norepinephrine (Roozendaal & Cools, 1994). For example, NE levels have been shown to fluctuate within the amygdala and nucleus accumbens when presented with novel stimuli (Cools et al. 1991) and during information acquisition. Presumably NE levels within the accumbens can regulate or influence the reception of amygdala and hippocampal impulses within the accumbens and SI which in turn projects to the neocortex and, in this regard, may act to shunt amygdala-hippocampal impulses to discrete or wide areas of the cerebrum.

Specifically, high alpha-NE activity is associated with reduced amygdala input, whereas low beta NE may reduce hippocampal input into the striatum. Conditions such as these, however, are most likely to result when stressed or traumatized in which case it is possible for amygdala (and thus emotional) input to be received in, learned, and expressed by the striatum in the absence of hippocampal participation (see Rozzendaal & Cools 1994). It is conditions such as these that can give rise to amnesia with preserved learning (see chapters 14, 30).

However, in some cases, it is also possible for both the alpha and beta NE system to be effected simultaneously such that amygdala and hippocampal input to the limbic striatum are inhibited in which case profound memory loss may result (see Rozzendaal & Cools 1994). Similar disturbances are associated with the serotonin (5HT) system (McLoughlin et al. 1994).

Depletion of 5HT can significantly effect the capacity to inhibit irrelevant sensory input (at the level of the brainstem, amygdala, basal ganglia, and neocortex). Hence, 5HT abnormalities or depletion typically results in confusion and sensory overload and in some instances the production of hallucinations (see chapter 30).

Thus disruption of the mesolimbic DA system and/or severe disruptions in the 5HT system in turn interferes with the hippocampal-limbic striatal memory system (Packard & White 1991) and can create neuronal hyperactivity -a condition which interferes with perceptual and hippocampal- memory-SI-amygdala functioning. In this regard it is noteworthy that the central 5HT system is severely disrupted among those with severe memory loss and Alzheimer's disease (McLoughlin et al. 1994) and that calcification of the globus pallidus/SI can induce visual and auditory hallucinations as well as cognitive deterioration (Lauterbach et al. 1994).


Alzhiemer's disease is associated with a profound loss of memory and cognitive and intellectual functioning, including, at its later stages, an inability to recognize friends, loved one's or their own personal identity. Alzhiemer's disease is estimated to afflict approximately 10% of those over age 65, and 50% of those over 85.

In its later stages, Alzhiemer's disease is associated with profound loss of cerebral functional capacity, coupled with neural degeneration and a loss of neurons and the development of amyloid (senile) plaque and neurofibrillary tangles. Because structures such as the substantia innominata, amygdala, and entorhinal cortex have been injured (Morrison et al. 1990; Gomez-Isla, et al., 2000; Rapoport 1990) it is thought that the destruction of this tissue and adjacent tissue accounts for the loss of memory, and social-emotional, facial recognition, and related visual abnormalities, including visual agnosia (Giannakoulos, et al., 1999).

However, because there is no single factor that has been implicated, and due to the number of associated disturbances, it has been argued that Alzheimer's disease and associated cognitive and memory disturbances are due to a "global cortico-cortical disconnection" syndrome (see Morrison et al. 1990; Rapoport 1990). Nevertheless, for the purposes of this chapter, the striatal contribution to this disorder will be emphasized.


As detailed in chapter 15, the amygdala and hippocampus provide massive input to the limbic striatum as well as the dorsal medial nucleus of the thalamus (DM) , the frontal lobes and reticular activating system, as does the accumbens and SI (see Heimer & Alheid, 1991; Koob et al. 1991; Mogenson & Yang 1991; Zaborszky et al. 1991). As noted, these nuclei, including the overlying entorhinal cortex, play a significant role in memory and the gating of information destined for the neocortex and appear to be part of a massive neural network designed to control information processing and to establish memory related neural networks (see also chapter 14). Presumably the nucleus accumbens apparently acts to integrate hippocampal and amygdala input, which is then transmitted to the SI which is also the recipient of limbic impulses concerned with cognitive, memory, and motoric activities (see Mogenson & Yang 1991).

In part, it appears that the accumbens and SI play an inhibitory (filtering) role on information processing, and may exert inhibitory (and counterbalancing) influences on the the medial frontal lobes, the DM, and corpus striatum (see Mogenson & Yang 1991). The amygdala exerts similar influences on these nuclei (chapter 15) and is also able to inhibit the SI and accumbens.

However, the role of the limbic striatum in cognitive and memory related activity also includes the learning of reward-related and aversion processes, the facilitation of approach and withdrawal responses and the memorization of where a reward or aversive stimulus was previously received (Everitt et al. 1991; Kelsey & Arnold 1994). In this regard the nucleus accumbens and SI are dependent on the medial and lateral amgydala, especially in the learning of negative experiences (Kelsey & Arnold 1994).

As noted, the SI is the primary source of neocortical cholinergic innervation (Carpenter 1991) and appears to be concerned with integrating social-emotional and cognitive input with motor memories and then storing them perhaps within the SI as well as within the neocortex. Hence, if the SI is lesioned the cholinergic projection system is disrupted, and cognitive as well as social-emotional memory functioning is negatively impacted.

Since the SI merges with and becomes coextensive with the centromedial amygdala (Heimer & Alheid 1991),and is an amygdala derivative, not suprisingly, a significant loss of neurons, neurofibrillary changes and senile plaques have been found in the amygdala (and hippocampus, Rapoport 1990), as well as in the SI, in patients with Alzheimer's disease and those suffering from degenerative disorders and memory loss (Herzog & Kemper, 1980; Mann, 1992; Sarter & Markowitsch, 1985). Degeneration in the amygdala would also account for the social-emotional agnosia and prosopagnosia that is common in the advanced states of Alzhiemer's disease; i.e. failure to recognize or remember loved ones (chapter 13).


Neuronal loss has also been reported in the entorhinal and parahippocampal areas of the inferior temporal lobe (see Morrison et al. 1990; Rapoport 1990) within which is buried the hippocampus and amygdala. Specifically, in addition to senile plaques, neurofibrillary tangles, a 40% to 60% loss of neurons during the early stages of this disease have been found in layers 4 and 2 of the entorhinal cortex (Gomez-Isla, et al., 2000)--the gateway to the hippocampus. Destruction of this tissue and adjacent tissue would also result in memory, social-emotional, facial recognition, and related visual abnormalities, including visual agnosia, as recently demonstrated among those with Alzheimer's disease (Giannakoulos, et al., 1999).

Indeed, among those with Alzheimer's disease, widespread atrophy, amyloid plaques, tangles, and metabolic disturbances have been noted in a variety of cortical areas with relative preservation of the motor and primary receiving areas (Rapoport 1990). Based on these findings it has been argued that Alzheimer's disease and associated cognitive and memory disturbances are due to a "global cortico-cortical disconnection" syndrome (see Morrison et al. 1990; Rapoport 1990); i.e., a loss of neurons in and interconnections with association neocortex, which in part would account for the cognitive deterioration.

The initiation of this deteriorative process may well be in the SI, and it may be due to an olfactory borne infection due to viral or bacterial invasion. That is, these bacterial or viral agents may enter the olfactory system and invade those structures directly innervated by the olfactory nerves, i.e. the amygdala, entorhinal cortex, and SI (Joseph, 1998d). On the other hand, or perhaps related to this scenario, are findings suggesting a genetic foundation for this disorder, such that defects in at least four specific genes (located on chromosomes 1, 14, and 21) may be responsible (Levy-Lehad et al., 1995; Saunders et al., 1993).

Given the likelihood that the limbic striatum and olfactory-limbic structures may be selectively involved in the early stages of Alzheimers, and given the fact that the SI provides cholinergic input to the neocortex, then the subsequent and progressive loss of SI (and amygdala) neurons might result in a progressive deterioration and cell death within the neocortex such that otherwise healthy neurons are killed. That is, since the SI contains high concentrations of cholinergic neurons which in turn project to widespread areas throughout the neocortex (reviewed in Carpenter 1991), perhaps the initial cell loss within the SI (also referred to as the nucleus basalis), may trigger further cell death in healthy neurons (which project to or receive fibers from the affected cells) which essentially become "pruned" and drop out form disuse.

Defective Axonal Transport.

There is evidence which indicates that perhaps due to head injury, drug or toxic exposure, or perhaps the loss of synaptic junctions (due to the death of unhealthy cells and dendritic retraction), axonal transport becomes defective due to the death of its target neuron. However, if a healthy cell cannot discharge and exchange information it too may die, thus leading to a domino effect and thus widespread cell death (see Burke et al. 1992). That is, due to the loss of terminal synaptic junctions (due to cell death) or to other chemical abnormalties including defects in microtubule assembly (which participates in neuronal transmission), axonal transport becomes dysfunctional as the receiving cell and it's dendrite have died. Hence, there is a buildup of toxic oxidatative metabolites and naturally occurring neurotoxins in the healthy cell body that project to the dead cell, which causes the normal cell to die as well. This would result in a progressive loss of neurons such that widespread areas of the cerebrum soon become effected.

Presumably this what may occur if the limbic striatum becomes abnormal and cells within the SI and accumbens begin to die. As the disturbance and deterioration spreads, cognitive, emotional, memory and related abnormalities including Parkinsonian symptoms begin to appear and become progressively worse as neocortical, striatal, and limbic neurons die and drop out.


The limbic and corpus striatum are richly interconnected and send projections to many of the same brain areas. However, due to differential input from the amygdala and DA systems, these nuclei exert tremendous counterbalancing influences on each other and their associated neural networks. For example, the centro-medial as well as the basolateral amygdala projects to and exerts excitatory influences on the the limbic striatum (Maslowski-Cobuzzi & Napier, 1994; Yim & Mogenson 1982), whereas the medial and posterior-lateral amygdala projects to the corpus striatum and the ventral and dorsal globus pallidus. Via these dual interconnections, the amygdala can exert simultaneous and even oppositional influences on these nuclei.

In addition, the corpus striatum receives the bulk of its DA from the nigrostriatal systems, whereas the limbic striatum receives DA from the mesolimbic DA system (see Fibiger & Phillips, 1986 for review) -transmitter systems which interact at the level of the brainstem, limbic system, striatum, and neocortex (Maslowski-Cobuzzi & Napier, 1994). For example, it has been shown mesolimbic DA can act on the amygdala and limbic striatum simultaneously so as to modulate striatal reception of amygdala excitatory signals (Maslowski-Cobuzzi & Napier, 1994).

However, because the corpus and limbic striatum are largely (but not completely) innervated by different clusters of midbrain DA neurons, reductions or increases in one DA system can exert profound influences on those neurons innervated by the others -for example, by eliminating inhibitory or counterbalancing influences. Thus depletion of DA in the nigrostriatal (but not the mesolimbic) pathways can result in increased activity within the limbic striatum (see Yim & Mogenson, 1983, 1989) and medial amygdala, but deceased activity within the corpus striatum. If this occurs, movement programming may be disrupted resulting in rigidity or tremors -a consequence, in part, of an imbalance in amygdala-DA-striatal activation.

Conversely, mesolimbic DA depletion can result in enhanced corpus striatal activity and decreased limbic striatal and lateral amygdala and hippocampal activity, such that motor and social-emotional memory functioning may be disrupted; a condition compounded by DA influences on acetylcholine (ACh) neurons and the reception of hippocampal, amygala, and neocortical input within the striatum. Hence, the functioning of the limbic or corpus striatum can be severely disrupted even when the functional integrity of its own neurotransmitter systems are otherwise intact; i.e. due to a loss of counterbalancing influences.



As noted, some studies have indicated that those with Parkinson's disease demonstrate the greatest amounts of DA depletion and related DA neuronal degeneration within the putamen. Hence, many authors have argued that Parkinson's symptoms are a consequence of damage to this nuclei (e.g. Goto et al.1990), which in turn can result in the production of unwanted movements such as tremor. Presumably, in these instances, the medial (internal) globus pallidus (which receives putamen input) ceases to inhibit irrelevant motor activity.

The putamen receives much of it's input from the caudate and in particular the SMA, the secondary and primary motor cortex, as well as areas 5 and 7 of the parietal lobe (Jones & Powell, 1970; Pandya & Vignolo, 1971). Presumably the putamen, in conjunction with the caudate, transmits this information to the medial and lateral GP which in turn projects to the motor thalamus, and brainstem. However, like the caudate, the putamen and GP also project back to the motor neocortex, thus creating a very elaborate feedback loop (see Mink & Thach, 1991; Parent & Hazrati 1995) whose origin may begin in the SMA (Alexander & Crutcher, 1990; Crutcher & Alexander, 1990) or perhaps the limbic system (chapter 13).

For example, when anticipating or preparing to make a movement, but prior to the actual movement, neuronal activity will first begin and then dramatically increase in the SMA, followed by activity in the secondary and then the primary motor area (see chapter 19), and then the caudate and last of all the putamen-GP (Alexander & Crutcher, 1990; see also Mink & Thach, 1991).

Ignoring for the moment the role of the limbic system, this indicates that impulses to move first appear in the SMA and that other motor regions are temporally-sequentially recruited in a step-wise fashion; i.e. SMA - premotor - primary motor - caudate - putamen - GP - motor thalamus/frontal motor areas - brainstem...

However, the caudate nucleus also contains neurons which become active prior to, and in anticipation of making body movements, and in response to associated auditory and visual environmental cues (Rolls, et al. 1983; Rolls & Williams, 1987). This caudate neuronal activity precedes, or occurs simultaneously with excitation in the lenticular nucleus, which also results (via feedback) in SMA activation. This is because the GP and the putamen not only receive caudate and neocortical afferents, but they project back to the frontal motor areas (as well as to the motor thalamus). Hence, parallel processing also occurs.


That is, activity in these regions quickly begins to overlap such that neurons in the motor neocortex and basal ganglia often remain activated simultaneously (Alexander & Crutcher, 1990). Moreover, the motor areas all independently send axons to the brainstem, with axons from different areas converging on the same motor neuron.

Therefore, activity in the motor areas is characterized by both temporal-sequential and parallel processing that in turn is made possible via feedback neural circuitry. Because these different networks are intimately linked and mutually interactive they make coordinated and goal directed movements possible.

Indeed, multiple feedback loops are probably also necessitated by the numerous variables and body- spatial- visual- kinesthetic- motor references, etc., that need to be computed in order to make a planned movement. Thus both temporal-sequential and parallel processing is necessitated as each area is functionally specialized to analyze specific types of information and to perform certain actions in semi-isolation as well performing other functions in parallel with yet other motor areas.


Just as different regions of the caudate appear to subserve different functions, a variety of neuronal types also characterize the lenticular nucleus. For example, preparatory and movement related neurons are segregated within the putamen (Alexander & Crutcher, 1990). This suggests that the putamen employs two different neural networks, one which executes movements, the other which prepares to make the movement; information which is normally transmitted to the GP as well as back to the motor neocortex.


The putamen appears to act at the behest of impulses arising in the neocortical motor areas (as well as the limbic system) and then only secondarily acts to prepare for and then to participate in the guidance of movement (Mink & Thach, 1991). In conjunction with the caudate, the putamen accomplishes this via signals transmitted to the medial and lateral GP, the motor thalamus, and brainstem reticular formation (Marsden & Obeso, 1994) and then back to the motor neocortex (see also Parent & Hazrati 1995, for a related review).

As noted, the putamen and globus pallidus are also coextensive (the lenticular nucleus) and in many respects function as a prepatory motor unit involved in the guidance, and perhaps even the learning of various motor activities (Crutcher & DeLong, 1984; Kimura, 1987). For example, alterations in neuronal activity have been demonstrated in the globus pallidus and the putamen during tasks involving learned body movement (Crutcher & DeLong, 1984). Lenticular neurons also become highly active when learned facial or limb movements are triggered in response to a particular auditory or visual stimulus associated with that movement (Kimura, 1987).

Some putamen and GP neurons also fire in response to reward but not to movement and vice versa (Kimura, et al. 1984). However, these same neurons do not respond when the same learned and rewarded movements are made spontaneously and in the absence of associated cues, or when they were no longer rewarded. These findings raise the possibility that specific neurons within these nuclei are responsive to motivational cues associated with movement and that these neurons utilizes these cues in preparation to make a movement (Kimura, 1987).


Neurons in the GP also selectively respond and change their activity when making ballistic movements, particularly those which are visually guided (Mink & Thach, 1991). However, activation occurs too late for these neurons to be involved in the initiation or planning of the movement (Mink & Thach, 1991). Conversely, destruction or massive inhibition of the GP can result in difficulty turning off a movement (see Mink & Thach, 1991) -thus giving each movement a ballistic quality. Similarly, destruction or massive inhibition of the GP can make it exceedingly difficulty to rapidly alternate between movements and thus switch from an ongoing to a different motor program (Hore & Vilis, 1980). This loss of control over motor programming with GP impairment extends even to attempts to make purposeful ballistic reaching or stepping movements (Horak & Anderson, 1984; Hore & Vilis, 1980), and the velocity and amplitude of these movements may in fact be significantly slowed and reduced (Mink & Thach, 1991).


The medial and lateral GP appear to play different and counterbalancing roles in the execution, inhibition and excitation of different motor programs (Crossman, et al. 1987; Marsden & Obeso, 1994). For example, the medial GP is believed to provide positive/excitatory feedback to the neocortical motor areas, whereas the lateral GP provides indirect "negative" and inhibitory feedback so that unwanted movements are prevented. Moreover, DA inhibits the medial GP, but excites the lateral GP (reviewed in Marsden & Obeso, 1994).

In consequence (at least in theory), reduced nigrostriatal DA levels can result in an overexcitation of the medial GP, which inhibits cortically mediated or initiated movements thereby producing akinesia (loss of movement), bradykinesia (reduction in movement) and hypokinesis (slowness of movement) coupled with tremor.

On the other hand excessive lateral GP (and limbic striatal) activity can also result in gross involuntary and excessive hyperkinetic and ballistic movements usually involving the limbs on the contralateral side of the body, along with choeriform movements and tremors. However, surgical destruction of the fibers tracts leading to and from the lateral and medial GP can significantly diminish such disturbances, including hemiballismus, tremor, dystonia, chorea and athetosis (see Carpenter & Sutin, 1983).

As noted above, lesions to the amygdala prior to the development of Parkinsonian and related symptoms, can also prevent the development of these motor abnormalities, which in part is due to the extensive interconnections maintained with these regions and the fact that the amygdala becomes coextensive with the ventral GP.

In addition, because the putamen projects to the GP, lesions restricted or localized to the putamen can also result in abnormal competition between atagonist and agonist muscles, due to the release of the GP (and associated neural circuitry) from putamen control. Patients or primates so effected suffer from severe dystonia as well as rigidity and increased muscle tone sometimes accompanied by chorea (Segawa, et al. 1987). Similarly, among those with Parkinson's disease, activity within the putamen is significantly reduced (Playford et al. 1992), and reduced functional activity is also seen in the caudate which merges with the putamen.


As noted, the motor thalamus evolved in tandem with the basal ganglia and is richly interconnected with the caudate nucleus and globus pallidus in particular (Crossman, et al. 1987; Parent & Hazrati 1995; Powell & Cohen, 1956; Royce, 1987). It is an integral aspect of the motor circuit and becomes activated when making a variety of movements and in response to kinesthetic and proprioceptive stimuli (Vitek et al. 1994).


The motor thalamus consists of the ventromedial, ventrolateral, ventralis intermedius, centromedian and parafascicular (posterior) intralaminar thalamic nuclei, and receives input from the brainstem, cerebellum, and neocortex, and maintains reciprocal projections with the GP and SMA (Carpenter 1991; Brodal, 1981; Kemp & Powell, 1970; Narabayashi, 1987; Royce, 1987; Vitek et al. 1994). These thalamic "motor" nuclei also receive input from the facial, leg, and arm regions of the motor and somatosensory cortex (Kunzle, 1976; Vitek et al. 1994) and maintains reciprocal interconnections with the amygdala, cingulate gyrus, substantia nigra, and superior colliculus (Jones et al. 1979; Mesulam et al. 1977; Royce, 1987; Vogt et al. 1979).

Thus the motor thalamus is intimately associated with limbic and motor nuclei throughout the brain and is able to influence as well as receive multiple inputs from a variety of nuclei which in turn are interlinked. For example, some intralaminar thalamic nuclei send collateralizing axons which project to both the striatum and the neocortex, whereas some motor neocortical axons project to both the striatum and the intralaminar nuclei (Royce, 1987). Hence, a richly interconnected neural circuit is maintained by these nuclei so as to control and guide motor functions.

In some respects the motor thalamus appears to act as a nexus where multiple forms of input are integrated so as to regulate motor activity. Therefore, when the motor thalamus is abnormally inhibited or activated, significant motor abnormalities result; e.g., rigidity, tremor, ballismus, catatonia, and catalepsy. For example, unilateral infarcts and hemorrhages involving the thalamus can induce unilateral thalamic ataxia and apraxia (Nadeau et al. 1994; Solomon et al. 1994).

Conversely, injuries or surgical destruction of the specific thalamic nuclei can in some instances eliminate or reduce the influences of abnormal activity received from other regions within the motor circuit (Marsden & Obeso, 1994; Narabayashi, 1987). For example, patients suffering from Parkinsonian symptoms appear to derive the greatest benefit from thalamic lesions which abolish contralateral tremor and rigidity (see Marsden & Obeso, 1994) via disruption of the GP-motor thalamus-frontal motor area motor circuit.

Specifically, there is evidence which indicates that destruction of the ventrolateral (VL) motor thalamic nuclei can reduced rigidity (if the lesion is more anterior), or tremor (if the lesion is posterior). Neurosurgical destruction of the GP to motor thalamus projection fibers can also significantly decrease rigidity, whereas section of the thalamic to brainstem/cerebellum pathway also reduces tremor (see Narabayashi, 1987). Moreover, VL lesions can significantly reduced choreic and ballistic movements such as secondary to trauma or encephalitis.

In addition, neurosurgical destruction or electrical stimulation of these nuclei (e.g. ventralis intermedius) can eliminate tremors (see Narabayashi, 1987). Indeed, neurons in the motor thalamus not only fire in tandem with tremor, but electrical stimulation of this nuclei at a frequency similar to the tremor, increases the frequency and amplitude of the tremor. However, high levels of thalamic stimulation reduces or abolishes tremor (Narabayashi, 1987).


The subthalamic nucleus is a small but densely innervated component of the basal ganglia-thalamocortical-limbic motor circuit. It maintains a very important reciporcal relationship and is richly interconnected with the medial and lateral GP (Crossman, et al. 1987; Parent & Hazrati 1995; Wichman et al. 1994) and merges medially with the lateral hypothalamus with which it is intimately linked. The subthalamic nucleus also receives extensive and topographic projections from the neocortical motor areas including inhibitory axonal fibers from the frontal lobes (Parent & Hazrati 1995). It also projects to the caduate, putamen, SI and brainstem reticular formation, and provides excitatory influences to the substantia nigra and other target nuclei (Klockgether, et al. 1987; Parent & Hazrati 1995) and thus influences the nigrostriatal dopamine system and a wide variety of brain areas via separate pathways (Wichman et al. 1994).

Due to its interconnections with so many motor related areas of the brain (as well as the limbic system), the subthalamic nucleus is able to exert significant, albeit indirect as well as direct influences on motor expression which is accomplished in conjunction with the nigro-striatal DA system and the GP which in turn modulates subthalamic activity and its reception of cortical input (Parent & Hazrati 1995; Wichman et al. 1994). Hence, the subthalamic nucleus appears to also exert modulating influences on movement (although it also serves non-movement functions), especially those involving the proximal limbs.

Specifically, subthalamic neurons are somatotopically organized, such that those representing the hand, arm, leg, or eyes, are clustered together, and these clusters change their activity during eye, or limb movements (Wichmann, et al., 1994). In fact, they increase their activity just prior to movement.

Abnormalities localized to or involving the subthalamic nucleus can therefore result in significant motor disturbances including chorea and hemiballismus (Crossman, et al. 1987) including sudden and involuntary flinging movements of the arm or leg--movements that might be appropriate if engaged in defensive maneuvers. However, patients can still make normal voluntary movements.

Chorea and hemiballismus are due presumably to interuption of the normal GABAinergic reciprocal relationship it maintains with the caudate, putamen, and in particular the GP (McGeer & McGeer, 1987; Parent & Hazrati 1995). That is, due to loss of inhibitory GP input, the patient makes sudden and involuntary movements, due to excessive activity directed, ultimately, the motor neocortex. Hence, again, these are normal movements which are abnormally produced if the subthalamic nucleus is injured or receives abnormal signals.

For example, Parent and Hazrati (1995) argue that inhibitory influences exerted on the motor thalamus, neocortex, or subthalamic nucleus by the GP can result in akinesia if GP activity is reduced, or hyperkinesia if enhanced. Similarly, Crossman et al (1987) argue that in hyperkinetic states the medial GP and subthalamic nucleus is underactive and the lateral GP is overactive. In Parkinsons and akinetic disorders, the medial GP and subthalamic nucleus is overactive whereas the lateral GP is underactive (Crossman, et al. 1987).

Conversely, lesions of the subthalamic nucleus can result in increased activity within the GP and motor thalamus, such that the motor thalamus, SMA and brainstem become hyperactivated, which results in excessive movement including ballismus. If the GP is subsequently destroyed, hemiballismus disappears. However, in one case it has been reported that a hemorrhage involving the subthalamic nucleus, resulted in the amelioration of a patients Parkinson's symptoms (Wichmann et al. 1994).



The GP receives about two thirds of its input from the putamen, and one third from the caudate (as well as some fibers from the SMA). Presumably, activation of the SMA -primary motor -caudate -putamen loop results in differential activation of the lateral and medial GP, the subthalamus, and the motor thalamus and the brainstem -nuclei which project back to the SMA and primary motor areas from which arises a massive rope of nerve fibers (the corticospinal/pyramidal tract) which directly innervates the brainstem and spinal cord. Presumably these complex feedback loops insure that coordinated and smooth continuous movements are planned, coordinated, and finally carried out. As noted, these interactions are also dependent on DA activity.

For example, Parkinson's disease, being characterized by reduced DA, is associated with a reduction in striatal inhibitory activity and thus increased GP output to the motor thalamus and brainstem which would produce tonic EMG activity and akinesia and rigidity (Kockgether, et al. 1986; Starr & Summerhayes, 1983); i.e. hypomovement due to excessive tonic excitation.

Conversely, excessive corpus stritatal DA would result in increased striatal GABA activity and thus inhibition of the GP which would lead to a disihibition of the motor thalamic and subthalamic nucleus and thus increased activation of brainstem and spinal motor neurons. Movements would become hyper, ballistic, and chorea may develop -as frequently occurs with prolonged neuroleptic treatment.

Specifically, GABA activity within the GP and subthalamus are significantly effected by DA activity within the corpus striatum. For example, deceases in striatal DA result in decreased striatal GABA neural activity (-which is normally inhibitory). As these GABA neurons project to the GP, the loss of this GABA inhibitory input would increase tonic activity within the GP. which in turn would result in increased inhibitory GP influences on the motor thalamus and brainstem thereby decreasing their activity. Hence, the modulatory influences of these latter nuclei on motor functioning would be eliminated, resulting in heightened activity levels and thus overactivation of this aspect of the feedback circuit. Brainstem and spinal motor neurons would become tonically activated thereby creating rigidity and stiffness of movement.

Conversely, the loss of GABA influences could induce choreic movements. In this regard it is noteworthy that significant GABA loss and abnormalities have been noted in the substantia nigra and basal ganglia of those with Huntington's chorea (Bird & Iversen, 1974), along with degeneration of the nigrostriatal DA projection pathway.


Chorea ("dance") is characterized by jerky, writhing, twisting, and unpredictable movements of the extremities. The two main types are Sydenham's Chorea (St. Vitus dance) and Huntington's Chorea. Sydenham's Chorea involves choreiform movements of the facial, tongue, and extremities, and is accompanied by loss of nerve cells in the caudate and putamen, as well as within the cerebral cortex, substantia nigra, and subthalamic nucleus.

Huntington's chorea is a progressive deteriorative inherited genetic disorder which is passed on by an autosomal dominant gene located on chromosome 4. It is characterized by an insidious onset that may begin during childhood or old age, with the illness beginning earlier in those who have an affected father (reviewed in Folstein et al. 1990; Young 1995). Cognitive decline, however, is gradual.

Affected individuals tend to suffer from memory and visual-spatial deficits, depression, and reduced fluent output although aphasia is not typical. Difficulty with motor coordination, planning skills, decision making, and a reduced capacity to consider alternate problem solving strategies or to shift form one mental set to another, is not uncommon (reviewed in Folstein et al. 1990). Hence, in some respects this disorder is suggestive of frontal lobe abnormalities (see chapter 19).

This syndrome is also associated with widespread neuronal loss in the caudate, putamen, brainstem, spinal cord, cerebellum, and atrophy in the GP (see Vonsattel, et al. 1987; Young 1995). Degeneration is predominantly of small striatal neurons whereas larger neurons remain intact. Opiate neurons located in the striatum are also significantly effected (Reiner et al. 1988). It is believed that the degeneration of these corpus striatal neurons, as well as the loss of GABA influences, results in reduced striatal control over the GP (see Narabayashi, 1987), thereby producing excessive movement.

It is noteworthy that some reports indicate that the posterior caudate and putamen are more severely effected than the anterior regions (Vonsattel, et al. 1987). Indeed, the posterior caudate and it's tail is usually the earliest and most severely effected part of the brain -which implicates the amygdala as a factor in the development of chorea. Indeed, in the early stages of Huntingtons chorea, atrophy and degeneration begin in the tail and spreads dorsally and anteriorally thus effecting the striatum and lenticular nucleus (Young 1995).

In this regard it is noteworthy that affective disorders and personality and mood changes are prominent early signs suggesting amygdala involvement. Indeed, disturbances of emotion may precede any motor or cognitive decline by as much as 20 years, with some patients displaying mania, depression as well as antisocial tendencies (reviewed in Folstein et al. 1990). As noted, neural degeneration tends to begin in the amygdaloid tail of the corpus striatum (Young 1995).

As per disturbances of movement, those with Huntington's disease tend to suffer from either or both voluntary and involuntary abnormalities. The involuntary aspects include the jerking and unpredictable movements of the limbs, trunk and face which may occur when at rest, walking, or while actively engaged in some task such that they may appear to be intoxicated and/or attempting to dance about.

Voluntary disorders include rigidity, slowed, clumsy, or difficulty initiating movement. Those who suffer from voluntary movement disorders are the most likely to demonstrate cognitive decline (Folstein et al. 1990).

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