Primate basal ganglia system

Corticostriatal connection

A major output from the cortex, with axons from most of the cortical regions connecting to the striatum, is called the corticostriatal connection. In the primate most of these axons are thin and unbranched. The striatum does not receive axons from the primary olfactory, visual or auditory cortices. The corticostriatal connection is an excitatory glutamatergic pathway. One small cortical site can project many axon branches to several parts of the striatum.

Striatum

The striatum is the largest structure of the basal ganglia.

Neuronal constitution

Medium spiny neurons (MSN)s, account for up to 95 per cent of the striatal neurons. There are two populations of these projection neurons, MSN1 and MSN2, both of which are inhibitory GABAergic. There are also various groups of GABAergic interneurons and a single group of cholinergic interneurons. These few types are responsible for the reception, processing, and relaying of all the cortical input.

Most of the dendritic spines on the medium spiny neurons synapse with cortical afferents and their axons project numerous collaterals to other neurons. The cholinergic interneurons of the primate, are very different from those of non-primates. These are said to be tonically active.

The dorsal striatum and the ventral striatum have different populations of the cholinergic interneurons showing a marked difference in shape.

Physiology

Unless stimulated by cortical input the striatal neurons are usually inactive.

Levels of organisation

The striatum is one mass of grey matter that has two different parts, a ventral and a dorsal part. The dorsal striatum contains the caudate nucleus and the putamen, and the ventral striatum contains the nucleus accumbens and the olfactory tubercle. The internal capsule is seen as dividing the two parts of the dorsal striatum. There is a sensorimotor cortical input to the striatum mostly to the putamen. An associative input goes to the caudate and possibly to the nucleus accumbens.

There are two different components of the striatum differentiated by staining – striosomes and a matrix. Striosomes are located in the matrix of the striatum and these contain μ-opioid receptors and dopamine receptor D1 binding sites.

The striatopallidal fibers give a connection from the putamen to the globus pallidus and substantia nigra.

Connectomics

Unlike the inhibitory GABAergic neurons in the neocortex that only send local connections, in the striatum these neurons send long axons to targets in the pallidum and substantia nigra. A study in macaques (following another one on the rat) showed that the medium spiny neurons have several targets. Most striatal axons first target the GPe, some of these also target the GPi and both parts of the substantia nigra. There are no single axon projections to either the GPi, or to the SN , or to both of these areas; only connecting as continuing targets via axon collaterals from the striatum to the GPe.

The only difference between the axonal connectomes of the striosomes and the axons of those neurons in the matrix, is in the numbers of their branching axons. Striosomal axons cross the extent of the NS, and in macaques emit 4 to 6 vertical collaterals that form vertical columns which enter deep into the NSc; the axons from those in the matrix are more sparsely branched. This pattern of connectivity is problematic. The main mediator of the striatopallidonigral system is GABA and there are also cotransmitters. The GPe stains for met-enkephalin, the GPi stains for either substance P or dynorphin or both, and the NS stains for both. This probably means that a single axon is able to concentrate different comediators in different subtrees, depending on the target.

Selectivity of striatal territories for targets

A study of the percentage of striatal axons from the sensorimotor (putamen) and associative striatum (caudate nucleus) to the Globus pallidus found important differences. The GPe for instance receives a large input of axons from the associative territory. The GPi is strongly sensorimotor connected. The nigra is at first associative. This is confirmed by the effects of striatal stimulations.

All the projections from the primary somatosensory cortex to the putamen, avoid the striosomes and innervate areas within the matrix.

Constitution

The pallidonigral set comprises the direct targets of the striatal axons: the two nuclei of the pallidum and the pars compact and pars reticulata of the "substantia" nigra". One character of this ensemble is given by the very dense striato-pallidonigral bundle giving it its whitish aspect (pallidus means pale). In no ways has the pallidum the shape of a globe. After Foix and Nicolesco (1925) and some others, Cécile and Oskar Vogt (1941) suggested the term pallidum - also used by the Terminologia Anatomica (1998). They also proposed the term nigrum for replacing nigra, which is indeed not a substance; but this is generally not followed. The whole pallidonigral set is made up the same neuronal components. The majority is made up of very large neurons, poorly branched, strongly stained for parvalbumin, having very large dendritic arborisations (much larger in primates than in rodents) with straight and thick dendrites. Only the shape and direction of the dendritic arborizations differ between the pallidum and the nigra neurons. The pallidal dendritic arborisations are very large flat and discoidal. Their principal plane is parallel to the others and also parallel to the lateral border of the pallidum; thus perpendicular to the axis of the afferences. Since the pallidal discoidal discs are thin, they are crossed only for a short distance by striatal axons. On another hand, since they are wide, they are crossed by many striatalaxons from wide striatal parts. Since they are loose, the chances of contact are not very high. Striatal arborisations, in anotherhand, emit perpendicular branches participating in flat bands parallel to the lateral border, which increases the density of synapses in this direction. This is true for the striatal afferent but also for the subthalamic (see below). The synaptology of the set is uncommon and characteristic. The dendrites of the pallidal or nigral axons are entirely covered by synapses, without any apposition of glia. More than 90% of synapses are of striatal origin. One noticeable property of this ensemble is that not one of its elements receives cortical afferents. Initial collaterals are present. However, in addition to the presence of various appendages at the distal extremity of the pallidal neurons that could act as elements of local circuitry, there are weak or no functional interrelations between pallidal neurons.

Lateral pallidus

The lateral globus pallidus or external globus pallidus (GPe) is flat, curved and extended in depth and width. The branching dendritic trees are discoid, flat, run parallel to each other and to the pallidum border, and are perpendicular to those axons coming from the striatum. The GPe also receives input from the subthalamic nucleus, and dopaminergic input from the pars compacta of the substantia nigra. The GPe does not give output to the thalamus only intrasystemically connecting to the other basal ganglia structures. It can be seen as a GABA inhibitory mediator regulating the basal ganglia. Its firing activity is very fast and exhibits long intervals of up to several seconds of silence.

In monkeys an initial inhibition was seen in response to striatal input, followed by a regulated excitation. In the study this suggested that the excitation was used temporarily to control the magnitude of the incoming signal and to spatially focus this into a limited number of pallidal neurons. GPe neurons are often multi-targeted and may respond to a number of neuron types. In macaques, axons from the GPe to the striatum account for about 15%; those to the GPi, SNr and subthalamic nucleus are about 84%. The subthalamic nucleus was seen to be the preferred target which also sends most of its axons to the GPe.

Medial pallidus

The medial globus pallidus or internal segment of the globus pallidus (GPi) is only found in the primate brain and so is a younger portion of the globus pallidus. Like the GPe and the substantia nigra parts the GPi is a fast-spiking pacemaker but its activity does not show the long intervals of silence seen in the others. In addition to the striatal input there is also dopaminergic input from the nigra substantia pc. Unlike the GPe the GPi does have a thalamic output and a smaller output towards the habenula. It also gives output to other areas including the pedunculopontine nucleus and to the area behind the red nucleus. The evolutionary increase of the internal pallidus also brought an associated increase in the pallidothalamic tracts, and the appearance of the ventral lateral nucleus in the thalamus. The mediator is GABA.

Substantia nigra

The substantia nigra is made up of two parts, the pars compacta and the pars reticulata, sometimes there is a reference to the pars lateralis but that is usually included as part of the pars reticulata. The ‘’black substance’’ that the term translates as, refers to the neuromelanin found in the dopaminergic neurons. These are found in a darker region of the structure the pars compacta. There is a lighter coloured region called the pars reticulata. There are similar cells in the substantia nigra and the globus pallidum. Both parts receive input from the striatopallidal fibers.

Pars compacta

The pars compacta is the most lateral part of the substantia nigra and sends axons to the superior colliculus. The neurons have high firing rates which make them a fast-spiking pacemaker and they are involved in ocular saccades.

Pars reticulata

The pars reticulate or diffusa, is most often considered as a single entity with the pars compact. The term pars reticulata may thus describe either only the most medial part of the nigral ensemble, when a pars compacta is retained, or the addition of the pars compacta and reticulata. This must be carefully checked in papers. Due to major interspecific differences, the studied animal species must be verified. The name reticulata is simply an opposition to the dense pars compacta located above it. The border between the two is highly convoluted with deep fringes. Its neuronal genus is the same as that of the pallidum, with the same thick and long dendritic trees. It receives its synapses from the striatum in the same way as the pallidum. Striatonigral axons from the striosomes may form columns vertically oriented entering deeply in the pars reticulata. The ventral dendrites of the pars compacta from the reverse direction go also deeply in it. The nigra also send axons to the pedunculo-pontine complex and to the parafascicular part of the central complex. The substantia nigra reticulata is another "fast-spiking pacemaker" Stimulations provoke no movements. Confirming anatomical data, few neurons respond to passive and active movements (there is no sensorimotor map) "but a large proportion shows responses that may be related to memory, attention or movement preparation" that would correspond to a more elaborate level than that of the medial pallidum. In addition to the massive striatopallidal connection, the nigra reticulata receives a dopamine innervation from the nigra compacta and glutamatergic axons from the pars parafascicularis of the central complex. It sends nigro-thalamic axons. There is no conspicuous nigro-thalamic bundle. Axons arrive medially to the pallidal afferences at the anterior and most medial part of the lateral region of the thalamus: the ventral anterior nucleus (VA) differentiated from the ventral lateral nucleus (VL) receiving pallidal afferences. The mediator is GABA.

Striatopallidonigral connection

The striatopallidonigral connection is a very particular one. It engages the totality of spiny striatal axons. Estimated numbers are 110 million in man, 40 in chimpanzees and 12 in macaques. The striato-pallido-nigral bundle is made up of thin, poorly myelinated axons from the striatal spiny neurons grouped into pencils "converging like the spokes of a wheel" (Papez, 1941). It gives its "pale" aspect to the receiving areas. The bundle strongly stains for iron using Perls' Prussian blue (in addition to iron it contains many heavy metals including cobalt, copper, magnesium and lead).

Convergence and focusing

After the huge reduction in number of neurons between the cortex and the striatum (see corticostriate connection), the striatopallido-nigral connection is a further reduction in the number of transmitting compared to receiving neurons. Numbers indicate that, for 31 million striatal spiny neurons in macaques, there are only 166000 lateral pallidal neurons, 63000 medial pallidal, 18000 lateral nigral and 35000 in the pars reticulata. If the number of striatal neurons is divided by their total number, as an average, each target neuron may receive information from 117 striatal neurons. (Numbers in man lead to about the same ratio). A different approach starts from the mean surface of the pallidonigral target neurons and the number of synapses that they may receive. Each pallidonigral neuron may receive 70000 synapses. Each striatal neuron may contribute 680 synapses. This leads again to an approximation of 100 striatal neurons for one target neuron. This represents a huge, infrequent, reduction in neuronal connections. The consecutive compression of maps cannot preserve finely distributed maps (as in the case for instance of sensory systems). The fact that a strong anatomical possibility of convergence exists does not means that this is constantly used. A recent modeling study starting from entirely 3-d reconstructed pallidal neurons showed that their morphology alone is able to create a center-surround pattern of activity. Physiological analyses have shown a central inhibition/peripheral excitation pattern, able of focusing the pallidal response in normal conditions. Percheron and Filion (1991) thus argued for a "dynamically focused convergence". Disease, is able to alter the normal focusing. In monkeys intoxicated by MPTP, striatal stimulations lead to a large convergence on pallidal neurons and a less precise mapping. Focusing is not a property of the striatopallidal system. But, the very particular and contrasted geometry of the connection between striatal axons and pallidonigral dendrites offers particular conditions (the possibility for a very large number of combinations through local additions of simultaneous inputs to one tree or to several distant foci for instance). The disfocusing of the system is thought to be responsible for most of the parkinsonian series symptoms. The mechanism of focusing is not known yet. The structure of the dopaminergic innervation does not seem to allow it to operate for this function. More likely focusing is regulated by the upstream striatopallidal and corticostriatal systems.

Synaptology and combinatory

The synaptology of the striato- pallidonigral connection is so peculiar as to be recognized easily. Pallidonigral dendrites are entirely covered with synapses without any apposition of glia. This gives in sections characteristic images of "pallissades" or of "rosettes". More than 90% of these synapses are of striatal origin. The few other synapses such as the dopaminergic or the cholinergic are interspersed among the GABAergic striatonigral synapses. The way striatal axons distribute their synapses is a disputed point. The fact that striatal axons are seen parallel to dendrites as "woolly fibers" has led to exaggerate the distances along which dendrites and axons are parallel. Striatal axons may in fact simply cross the dendrite and give a single synapse. More frequently the striatal axon curves its course and follow the dendrite forming "parallel contacts" for a rather short distance. The average length of parallel contacts was found to be 55 micrometres with 3 to 10 boutons (synapses). In another type of axonal pattern the afferent axon bifurcates and gives two or more branches, parallel to the dendrite, thus increasing the number of synapses given by one striatal axon. The same axon may reach other parts of the same dendritic arborisation (forming "random cascades") With this pattern, it is more than likely that 1 or even 5 striatal axons are not able to influence (to inhibit) the activity of one pallidal neuron. Certain spatio-temporal conditions would be necessary for this, implying more afferent axons.

Pallidonigral outmaps

What is described above concerned the input map or "inmap" (corresponding to the spatial distribution of the afferent axons from one source to one target). This does not correspond necessarily to the output map or outmap (corresponding to the distribution of the neurons in relation to their axonal targets). Physiological studies and transsynaptic viral markers have shown that islands of pallidal neurons (only their cell bodies or somata, or trigger points) sending their axons through their particular thalamic territories (or nuclei) to one determined cortical target are organized into radial bands. These were assested to be totally representative of the pallidal organisation. This is certainly not the case. Pallidum is precisely one cerebral place where there is a dramatic change between one afferent geometry and a completely different efferent one. The inmap and the outmap are totally different. This is an indication of the fundamental role of the pallidonigral set: the spatial reorganisation of information for a particular "function", which is predictably a particular reorganisation within the thalamus preparing a distribution to the cortex. The outmap of the nigra (lateralis reticulata) is less differentiated.

Substantia nigra compacta (SNc) and nearby dopaminergic elements

In strict sense, the pars compacta is a part of the core of basal ganglia core since it directly receives synapses from striatal axons through the striatopallidonigral bundle. The long ventral dendrites of the pars compacta indeed plunge deep in the pars reticulata where they receive synapses from the bundle. However, its constitution, physiology and mediator contrast with the rest of the nigra. This explains why it is analysed here between the elements of the core and the regulators. Ageing leads to the blackening of its cell bodies, by deposit of melanin, visible by naked eye. This is the origin of the name of the ensemble, first "locus niger" (Vicq d'Azyr), meaning black place, and then "substantia nigra" (Sömmerring), meaning black substance.

Structure

The densely distributed neurons of the pars compacta have larger and thicker dendritic arborizations than those of the pars reticulata and lateralis. The ventral dendrites descending in the pars reticulata receives inhibitory synapses from the initial axonal collaterals of pars reticulata neurons (Hajos and Greefield, 1994). Groups of dopaminergic neurons located more dorsally and posteriorly in the tegmentum are of the same type without forming true nuclei. The "cell groups A8 and A10" are spread inside the cerebral peduncule. They are not known to receive striatal afferences and are not in a topographical position to do so. The dopaminergic ensemble is thus also on this point inhomogeneous. This is another major difference with the pallidonigral ensemble. The axons of the dopaminergic neurons, that are thin and varicose, leave the nigra dorsally. They turn round the medial border of the subthalamic nucleus, enter the H2 field above the subthalamic nucleus, then cross the internal capsule to reach the upper part of the medial pallidum where they enter the pallidal laminae, from which they enter the striatum. They end intensively but inhomogeneously in the striatum, rather in the matrix of the anterior part and rather in the striosomes dorsalwards. These authors insit on the extrastriatal dopaminergic innervation of other elements of the basal ganglia system: pallidum and subthalamic nucleus.

Physiology

Contrarily to the neurons of the pars reticulata-lateralis, dopaminergic neurons are "low-spiking pacemakers", spiking at low frequency (0,2 to 10 Hz) (below 8, Schultz). The role of the dopaminergic neurons has been the source of a considerable literature. As the pathological disappearance of the black neurons was linked to the appearance of Parkinson's disease, their activity was thought to be "motor" . A major discovery has been that the stimulation of the black neurons had no motor effect. Their activity is in fact linked to reward and prediction of reward. In a recent review (Schultz 2007), it is demonstrated that phasic responses to reward-related events , notably reward-prediction errors, ...lead to ..dopamine release..." While it is thought that there could be different behavioral processes including long time regulation. Due to its widespread distribution, the dopaminergic system may regulate the basal ganglia system in many places.

Subthalamic nucleus, or corpus Luysi

As indicated by its name, the subthalamic nucleus is located below the thalamus; dorsally to the substantia nigra and medial to the internal capsule. The subthalamic nucleus is lenticular in form and of homogeneous aspect. It is made up of a particular neuronal species having rather long ellipsoid dendritic arborisations, devoid of spines, mimicking the shape of the whole nucleus. The subthalamic neurons are "fast-spiking pacemakers" spiking at 80 to 90 Hz. There are also about 7,5% of GABA microneurons participating in the local circuitry. The subthalamic nucleus receives its main afference from the lateral pallidum. Another afference comes from the cerebral cortex (glutamatergic), particularly from the motor cortex, which is too much neglected in models. A cortical excitation, via the subthalamic nucleus provokes an early short latency excitation leading to an inhibition in pallidal neurons. Subthalamic axons leave the nucleus dorsally. Except for the connection to the striatum (17.3% in macaques), most of the principal neurons are multitargets and ffed axons to the other elements of the core of the basal ganglia. Some send axons to the substantia nigra medially and the medial and lateral nuclei of the pallidum laterally (3-target 21.3%). Some are 2-target with the lateral pallidum and the substantia nigra (2.7%) or the lateral pallidum and the medial(48%). Fewer are single target for the lateral pallidum. If one adds all those reaching this target, the main afference of the subthalamic nucleus is, in 82.7% of the cases, the lateral pallidum (external segment of the globus pallidus. While striatopallidal and the pallido-subthalamic connections are inhibitory (GABA), the subthalamic nucleus utilises the excitatory neurotransmitter glutamate. Its lesion resulting in hemiballismus is known for long. Deep brain stimulation of the nucleus suppress most of the symptoms of the Parkinson' syndrome, particularly dyskinesia induced by dopamine therapy.

Subthalamo-lateropallidal pacemaker

As said before, the lateral pallidum has purely intrinsic basal ganglia targets. It is particularly linked to the subthalamic nucleus by two-way connections. Contrary to the two output sources (medial pallidum and nigra reticulata), neither the lateral pallidum or the subthalmic nucleus send axons to the thalamus. The subthalamic nucleus and lateral pallidum are both fast-firing pacemakers. Together they constitute the "central pacemaker of the basal ganglia" with synchronous bursts. The pallido-subthalamic connection is inhibitory, the subthalamo-pallidal is excitatory. They are coupled regulators or coupled autonomous oscillators, the analysis of which has been insufficiently deepened. The lateral pallidum receives a lot of striatal axons, the subthalamic nucleus not. The subthalamic nucleus receives cortical axons, the pallidum not. The subsystem they make with their inputs and outputs corresponds to a classical systemic feedback circuit but it is evidently more complex.

Central region of the thalamus

The central region of the thalamus is the centromedian nucleus. Contrary to the current claim it does not topographically, histologically or functionally belong to the intralaminar group. Located at the inferior part of the thalamus, it is almost everywhere surrounded by a capsule making it a closed region. In upper primates, starting from the cercopithecidae, it is made up not of two but of three parts with their own neuronal species. From there, two opposed interpretations were proposed concerning the belonging of the intermediate part: either to the centre médian or to the parafascicular nucleus. This is undecided. It has thus been proposed to group the three elements together in the regio Centralis (since it is a classical nucleus) and to name them from medially to laterally: n. centralis pars parafascicularis, pars media and pars paralateralis. The whole is parvalbumin rich. The first two medial parts are acetylcholinesterase rich. They are the source of the major, centralo-striatal, part of the thalamo-striatal connection, with glutamate as the mediator. The pars parafascicularis sends axons essentially to the associative striatum. The pars media sends axons to the matrix compartment of the sensorimotor striatum through an important bundle. In addition to cortical (see below), the pars parafascicularis receives afferences from the substantia nigra and the superior colliculus. The main afference of the pars media is the medial pallidum. The pars media is a part of the subcortical Nauta-Mehler's circuit (striatum-medial pallidum-pars media-striatum). The pars paralateralis has essentially cortical relations particularly with the motor cortex. There are thus strong interconnections of the complex with the basal ganglia. The structure of the complex being different from that of the close intralaminar formation and having different connections, it has been proposed two decades ago to remove the central complex from the intralaminar elements and to link it to the basal ganglia system, where it may be classified among the regulators of the core. Lesions of the complex have no known clinical effects. There are few physiological data in awake monkeys. For Matsumoto et al. (2001) the axons of the complex would supply striatal neurons with information about behaviorally significant sensory events. For Minamimoto and Kimura (2002) the region plays a role in attentional orienting to events occurring in the contralateral side.

Pedunculopontine complex

The pedunculopontine nucleus is not a primary part of the basal ganglia. It is a part of the reticulate formation in the brainstem having strong interrelations with the basal ganglia system. As indicated by its name, it is located at the junction between the pons and the cerebral peduncle, lateral to the decussation of the superior cerebellar peduncle. The complex is not homogeneous. An important part is made up of cholinergic (Ch5)(excitatory) neurons, which is also the case for the laterodorsal tegmental nucleus (Ch6). Other neurons are GABAergic. The tracing of axons from the pedunculopontine complex has shown that they end intensively in the nigra reticulata first and to the compacta. Another strong innervation is observed in the subthalamic nucleus. Other targets are the pallidum (mainly medial) and the striatum. The complex receives direct afferences from the cortex and above all abundant direct afferences from the medial pallidum (inhibitory). It sends axons to the pallidal territory of the lateral region VO. The activity of the neurons is modified by movement, and precede it. All this led Mena-Segovia et al. (2004) to propose that the complex be linked in a way or another to the basal ganglia system. A review on its role in the system and in diseases is given by Pahapill and Lozano (2000). It plays an important role in awakeness and sleep. The complex must be left its double position and function. It is a part of the reticular formation. It is a regulator (regulating and being regulated) of the basal ganglia system.

Outputs of the basal ganglia system

In the cortico-striato-cortical loop the basal ganglia are interconnected, with little output to external targets. One target is the superior colliculus, from the pars reticulata. The two other major output subsystems are to the thalamus and from there to the cortex. In the thalamus the GPimedial fibers are separated from the nigral as their terminal arborisations do not mix.The thalamus relays the nigral output to the premotor and to the frontal cortices.

Medial pallidum to thalamic VO and from there to cortex

The thalamic fasciculus consists of fibers from the ansa lenticularis and from the lenticular fasciculus, coming from different portions of the medial globus pallidus, before they jointly enter the ventral anterior nucleus of the thalamus.

Passing above it they constitute the field H2 of Forel (1877). From there, they curve down towards the hypothalamus. At field H, they turn abruptly. This has been the cause of historical mistakes as it was thought that the bundle had to pursue its ventral course. In fact the bundle goes up in a dorsolateral direction (forming the H1 field) and reach in this manner the ventral border of the thalamus. Pallidal axons have their own thalamic territory in the lateral region of the thalamus; everywhere separated from the cerebellar and from the nigral territories. The VO nucleus remains everywhere lateral in macaques and humans. It stained for calbindin and acetylcholinesterase. The axons ascend in the nucleus where they emit branches that widespreadly distribute "bunches" of axonal branches. The distribution is such that if any somatotopical organisation exists, it may be only poor. The thalamocortical neurons of VO go preferentially to the supplementary motor cortex (SMA), to preSMA and to a lesser extent to the motor cortex. The pallidothalamic neurons also give branches to the pars media of the central complex (see above), which sends axons to the premotor and accessory motor cortex.

Nigra reticulata to thalamic VA and from there to cortex

Nigral axons go up dorsally without forming a clear distinctive bundle. They reach the inferomedial border of the thalamus. The nigral target thalamic territory (VA) is medial to the pallidal (VO). It is crossed by the mammillothalamic fasciculus. In the monkey, the nucleus is usually divided into a magnocellular part, medial and close to the mammillothalamic bundle, and a mediocellular part. In the human brain, the majority of the nucleus is composed of the magnocellular component. In any case, in macaques, the afferences from the nigra do not care about these cytoarchitectonic subdivisions. In addition to the nigral afference, VA receives axons from the tectum (superior colliculus) and from the amygdala (basal complex), which makes a singular set of afferences. Thalamocortical projections from VA travel to their own distinctive cortical territory made up of the frontal (premotor), the anterior cingulate cortex (ACC) and the oculomotor cortex (FEF and SEF), without significant connection to the motor cortex of the precentral gyrus. This set of thalamocortical outputs is different and distinct from that of the thalamic VO to which the medial pallidum connects.