Excitatory Fast transmission Fig. 3.4 Th alamic motor areas and their involvement in motor control. (a) Position of the thalamus in the brain showing the major anatomical subdivisions. (b) Human coronal sections through the motor regions of the thalamus. (c) Diagram showing the main corticothalamic-co rtical pathways involved in movement (see text). CM, central median; pre-SMA, pre-supplemen tary motor area; MD, medial dorsal thalamus; VA, ventral anterior thalamus; VLa, ventral la teral anterior thalamus; VLp, ventral lateral posterior thalamus. Basal ganglia regions receiving motor input Th e largest subcortical region receiving input from both supra- granular and infragranular regions of the motor cortices is the putamen ( 23). Together with the caudate nucleus, this striatal area receives information from all co rtical regions. Th e putamen passes on processed information through both a direct activati ng pathway and an indirect inactivating pathway to the basal ganglia output nuclei, the internal globu s pallidus, and the substantia nigra pars reticulata (23) (Fig. 3.5). Th ese basal ganglia regions are small in Oxford Textbook of Movement Disorders 16 comparison with the striatum (100-fold fewer neurons) and con- tain large aspiny GABAergic inhibitory projection neurons. (a) Striatal neurons also receive excitatory thalamic input from the ventral anterior, ventrola teral, and caudal intralaminar nuclei and inhibitory input from the external globus pallidu s, and are modu- lated by dopamine from the substantia nigra pars compacta and the mesencep halic tegmentum (23, 24) (Fig. 3.5). Overall, dopamine enhances activity in the direct path way and decreases activity in the indirect pathway (25). Th e striatum contains mainly GABA ergic spiny projection neurons and a small population of GABAergic and cholinergic interneu rons ( 3% of striatal neurons). Striatal spiny neurons project to the globus pallidus and s ubstantia nigra, as well as giving rise to dense local arbors which contact other spiny neu rons (23). Th ey are usually silent and discharge only when cortical information is receive d. Th e GABAergic interneu- rons establish contacts with the dendritic shaft s of neighbori ng spiny neurons and form the structural basis for feedforward striatal surround inhibition . Striatal cholinergic interneurons, in contrast, are tonically active and play a major rol e in the learning of reward behavior. Caudate (C) Putamen (P) GPe GPi Subthalamus (STN) SNC SNR (b) C P Thalamus C SNC Thalamus Th e smallest subcortical region receiving pyramidal input from layer V neurons of the moto r cortices is the subthalamic nucleus (26). Th is is the only cortical input to this nucleu s and this hyper- direct pathway conveys powerful excitatory eff ects from the motor cortic es to the globus pallidus and substantia nigra pars reticulata, bypassing the striatum, wit h shorter conduction times compared with the direct striatal pathway (26) (Fig. 3.5). It al so receives sig- nifi cant inhibitory input from the globus pallidus and striatum (27) (Fig . 3.5). Th e subthalamic nucleus contains aspiny excita- tory glutamatergic neurons that co nduct short-latency excitatory responses to the globus pallidus and substantia nigra aft er cortical excitation. P SNR C GPe STN P GPe C GPi P (c) Primary Pre-SMA Pre-motor Cortex Internal regulators of the basal ganglia Th ere is signifi cant internal modulation of the hyperdirect, direct, and indirect basal ganglia pathways. One of the basal ganglia regions most infl uencing striatal processing is the dopaminergic substantia nigra pars compacta, a s discussed above, although pal- lidal and thalamic projections also signifi cantly modify striatal out- put. Th e large tonically active aspiny dopaminergic neurons of the substanti a nigra pars compacta receive input directly from striatal spiny projection neurons which m odifi es their fi ring rate and pat- terns (25) (Fig. 3.5). Th is reinforces wanted behavio rs and sup- presses those that are unwanted. Th ese dopaminergic neurons also receive signi fi cant innervation from cortical, limbic, and brainstem regions and play a role in shift i ng attentional sets. Thalamus VA VLa CM Putamen/caudate BG input STN BG regulators GPe SNC BG output GPi/SNR Excitatory Fast transmission Fast transmission - Hyperdirect pathway Inhibitory - Direct pa thway Inhibitory - Indirect pathway Dopaminergic Superior colliculus (saccades) Th e basal ganglia region with the most internal connections is the external segment of the globus pallidus (23) (Fig. 3.5). Th ese pallidal neurons receive most input from the stria tum and the sub- thalamic nucleus, as well as a small dopaminergic projection from the subs tantia nigra (Fig. 3.5). Individual neurons in the external globus pallidus innervate the o utput nuclei as well as the subtha- lamic nucleus and the substantia nigra pars compacta (2 3) (Fig. 3.5). About 25% of them also innervate the striatal GABAergic spiny neurons. Th es e neurons provide the anatomical substrate for the synaptic integration of functionally div erse cortical information within the basal ganglia and appear to work in parallel with the subthalamic nucleus and striatum to set up appropriate oscillatory Fig. 3.5 Anatomy of the basal ganglia and their regulation of motor cortices. (a) Position of the basal ganglia in the brain showing the major regions involved in the regulation of m ovement. (b) Human coronal sections through the basal ganglia showing the major subdivision s. (c) Diagram showing the main anatomical projections and regulatory interconnections invo lving the basal ganglia. The basal ganglia can be subdivided, based on their interactions, into input, output, and regulator nuclei (see text). BG, basal ganglia; CM, central median; pre-SMA, pre-supplementary motor area; MD, medial dorsal thalamus; SNc, substantia nigra p ars compacta; SNr, substantia nigra pars reticulata; VA, ventral anterior thalamus; VLa, ve ntral lateral anterior thalamus; VLp, ventral lateral posterior thalamus. CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist 17 activity within the basal ganglia (27). Th erefore they are in a posi- tion to provide leve l-setting control of the activity through virtually the whole of the basal ganglia system. of deep nuclei (lateral, interposed, and medial), which are the fi nal output centers for t he cerebellum (28 \200\22331). The deep nuclei are innervated by the inhibitory Purkinje cells of the cerebellar cortex (F ig. 3.6). Purkinje cells are the targets of climbing fibers originating from the inferior o livary nuclear complex and, to a lesser extent, mossy fibers from the pons, brainstem, and spinal cord relay nuclei (28 \200\22331). Although each Purkinje cell receives only a singl e climbing afferent, each climbing fiber makes multiple synapses with one Purkinje cell, fo rming one of the strongest excitatory connections in the cen- tral nervous system (32). Pur kinje cells are in turn inhibited by the stellate cells and basket cells which receive thei r predomi- nant input from the parallel fibers of granule cells (28 \200\22332). The granul e cells are the only excitatory interneurons in the cerebel- lum and are the target of moss y fibers originating from the pon- tine other large pre-cerebellar nuclei. The axons of gra nule cells bifurcate to form parallel fibers which synapse on Purkinje cells and other cere bellar interneurons (28 \200\22331). Th e cerebellar system Th e cerebellum plays an important role in motor control by mod- ula ting the primary motor cortex as well as spinally projecting brainstem regions to make move ments integrated and seamless into a coordinated whole (28 \200\22331). Th e cerebellum dir ectly excites the brainstem reticular formation, the red nucleus, and the vent- rolateral t halamus to infl uence and regulate movements (Fig. 3.6). Similarly to the basal ganglia sys tem, there are three types of sub- cortical regions to consider \200\224those receiving dir ect information from and infl uencing motor cortical regions or spinal cord, those with pro jections to these motor regions, and those performing internal monitoring and regulation. Regions receiving motor input Th e cerebellum receives input from the motor cortices throug h neurons in the pontine nuclei (28 \200\22331). Th ese neurons receive direct projections from the motor cortices through the corticopon- tine tract, and the pontine nuclei in turn project axons across the midline to the contralateral cerebellum via the middle cerebellar peduncles to form the pontocerebellar projection (Fig. 3.6). Th e cerebellum also receives input from Golgi tendon organs and mus- cle spindles, which carry information concerning mu scle tension and limb position via spinocerebellar pathways, and aff erents from the access ory cuneate nucleus (28 \200\22331) (Fig. 3.6). Both these relays enter the cerebellum via the inferior cerebellar peduncle. Lastly, the cerebellum receives input from other brainste m nuclei including, importantly, the inferior olive, which receives projections in turn fro m the spinal cord and from the red nucleus and motor cortex (32) (Fig. 3.6). Excitatory cerebellar output (30, 31, 33 \200\22335) Th e fastigial nucleus projects most o f its axons through the infe- rior cerebellar peduncle to brainstem nuclei, generating the reticulospinal and vestibulospinal tracts. Th e vestibulospinal tract controls balance and postural tone. Th e interposed nuclei project through the superior cerebellar peduncle to t he magnocellular component of the red nucleus and, via the ventrolateral nucleus of the tha lamus, to motor cortices, infl uencing the rubrospinal and lateral corticospinal tracts. Th e cerebrocerebellar cortex sends eff erent projections to neurons in the dentate nucleus w hich project to the ventrolateral thalamus which directly infl uences motor cor- tices. Axo ns from the dentate nucleus also project to the ipsilateral inferior olivary nucleus, the m ajor source of input to the cerebel- lum, via the parvocellular division of the red nucleus . Based on the type of motor input, the cerebellum may be functionally divided into three reg ions: the spinocerebellum, the cerebrocerebellum, and the vestibulocerebellum (30). The spi nocerebellum receives and compares motor commands with sensory information to adjust motor control and improve accu- racy between intent and action. Spinocerebellar pathways in the i nferior cerebellar peduncle synapse on neurons in the fastigial and interposed deep nuclei, as well as the cerebellar cortex. The vermis and intermediate hemispheres of the spinocere bellum project to the fastigial nucleus and the interposed nuclei, respec- tively. Purkinje cells of the vestibulocerebellum send their axons through the superior cerebral peduncle t o the vestibular nuclei (30, 31). The vestibular nuclei play a role in coordinating head an d eye movements via the medial vestibulospinal tract, as well as eye movement control via f ibers in the medial longitudinal fasciculus to extraocular motor nuclei. The cerebrocerebel lum receives input directly from the pontine nuclei through the mid- dle cerebellar peduncl e (30, 31). Brainstem and spinal pattern generators for rhythmic movements Rhythmic motor patterns (wal king, scratching, breathing) are stereotyped and complex, but are subject to continuous vol untary control. Brown (36) was the fi rst to recognize that the alternate fl exion and exte nsion of leg muscles in walking could be pro- duced by rhythmic central circuits, now known as central pattern generators (CPGs). He demonstrated this in cats with a transected spina l cord, showing that they could generate sustained rhythmic output without requiring input from either supraspinal structures or sensory receptors (36). Further work has shown that r hythmic locomotion requires activation of both CPG regions and regions responsible for gene rating muscle tone (37). Both CPG regions for the coordination of rhythmic movements and re gions respon- sible for muscle tone are located in the brainstem and spinal cord (Fig. 3.7) , and are activated and modifi ed by the integration of aff erent inputs from brain regions involved in organizing motor and autonomic activities (38). Internal anatomy of the cerebellum At the cellular level, the cerebellar cortex is uniforml y organized and based on fi ve types of neurons organized into three layers: the deep layer of granule cells, the intermediate layer of Purkinje cells, and the superfi cial layer of Golgi, stellate, and basket cells (28 \200\22331). Embedded within the white matter of the cerebellum are three pairs Muscles are in a constant state of partial contraction called mus- cle tone, which is a req uirement for their use and necessary for postural stability during all movements. Th is is the only aspect of skeletal muscle activity that cannot be controlled voluntarily, even whe n a muscle is relaxed (37). Muscle tone is regulated by excita- tory descending monoaminerg ic and other reticulospinal inputs to Oxford Textbook of Movement Disorders 18 (a) Motor cortices Golgi interneuron Corticoponto- cerebellar pathways Purkinje cell Molecular layer Thalamus Stellate cell Purkinje cell layer Red nucleus VL nucleus Granular cell layer Basket cell Granule cells Deep cerebellar nuclei White matter Cortico-olivo- cerebellar pathways Deep cerebellar nuclei To the spinal cord Inferior olivary nucleus Mossy \201bre Climbing \201bre of inferior olive Reticular formation Excitatory Inhibitory (b) Input Output VL nucleus Red nucleus Sensory motor cortices Superior cerebellar peduncle Spinocerebellum Vestibulocerebellum Dentate Deep cerebellar nuclei Pons Pons Middle cerebellar peduncle Interposed Inferior olivary nucleus Fastigial Inferior cerebellar peduncle Vestibular nuclei Sensory relay nuclei Cerebrocerebellum Vestibular/ reticular spinal tract Fig. 3.6 Anatomy of the cerebellum and its involvement in motor control. (a) There are two main descending pathways from the motor cortex to the cerebellum: the corticopontocerebella r and the cortico-olivocerebellar pathways. Both pathways target the Purkinje cells of the cerebellar cortex (see inset) which then project through the deep cerebellar nuclei to the thalamus and red nucleus to regulate the motor cortices and spinal cord. Inset: Illustratio n of the three layers of the cerebellar cortex and the five types of neurons involved, incl uding the major inhibitory output neuron, the Purkinje cell. (b) The cerebellar cortex can be divided into three functional regions based on their connectivity and function. The spin ocerebellum is the cortical region located medially in the cerebellum (vermis and paravermi s). Spinocerebellar Purkinje cells receive input from the pons, the inferior olive, and the sensory relay nuclei in the upper spinal cord and medulla oblongata. These Purkinje cells then project to the interposed deep cerebellar nuclei which regulate motor pathways via the red nucleus and thalamocortical systems. The cerebrocerebellum comprises the cortical regi ons located in the lateral cerebellar hemispheres. Cerebrocerebellar Purkinje cells receive input from the pons and inferior olive and then project to the dentate nuclei which direct ly influence the motor cortices via the ventrolateral (VL) nucleus as well as to the red nu cleus. Inhibitory neurons in the dentate nuclei also project to the inferior olivary nucleu s. The vestibulocerebellum is the cortical region located adjacent to the fourth ventricle (flocculonodular lobe). Vestibulocerebellar Purkinje cells receive input from the pons, the inferior olive, and the vestibular nuclei. These Purkinje cells project to the fastigial n uclei which relay back to the vestibular nuclei and reticular formation to influence reticu lospinal and vestibulospinal pathways. CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist 19 Muscle tone Locomotion GPi/SNR GPi/SNR Subthalamic locomotor region Pre-SMA MLR Cerebellar locomotor region PPN Raphe nucleus Locus coeruleus Reticular formation Excitatory Inhibitory Fig. 3.7 Pathways involved in locomotor patterns and muscle tone. Locomotion (right): Subth alamic/cerebellar locomotor regions synapse on the mesencephalic locomotor region (MLR) in the pedunculopontine tegmental region, innervating the interneurons of the spinal central p attern generators (CPGs) either directly or through reticulospinal neurons. Th ese pathways are regulated by the inhibitory inputs from the basal ganglia (GPi/SNR). Muscle tone (left ): Monoaminergic locus coeruleus and raphe nuclei projections excite spinal motor neurons. Pontoreticular neurons excite inhibitory neurons in the medulla oblongata (reticulospinal n eurons) and spinal cord (spinal interneurons), both of which inhibit spinal motor neurons. Th ese two spinal projection systems have reciprocal inhibitory interactions. Cholinergic n eurons in the pedunculopontine tegmental nucleus (PPN) receive direct input from the pre-SM A of the motor cortices as well as from the basal ganglia (GPi/ SNR) to modulate muscle ton e by directly exciting the pontine reticular formation. Inset: All three pathways are in \202 uenced by external stimuli from the skin and proprioceptive a \200 erents. E, extenso r motor neurons; F, \202 exor motor neurons; GPi, internal globus pallidus; SNR, substant ia nigra pars reticulata. Proprioception CPG Extensor Muscle E F Flexor Muscle skin motor spinal neurons (Fig. 3.7), and inhibited via cholinoceptive pontine reticular formati on neurons which excite inhibitory neu- rons in the medulla oblongata (reticulospinal neuro ns) and spinal cord (spinal interneurons), both of which inhibit spinal motor neu- rons (Fi g. 3.7). Th e excitatory and inhibitory muscle tone projec- tions have reciprocal inhibitor y interactions (37). Consequently, muscle tone is achieved by the counterbalance between th ese exci- tatory and inhibitory systems. CPGs in the spinal cord are composed of interneuronal cir- cuits that evoke rhythmic moveme nts for basic, multi-joint, and multi-limb patterns (37). Spinal cord CPGs are activated by direct corticospinal input as well as by the mesencephalic locomotor region in the peduncu lopontine region (directly and via medullary reticulospinal neurons) (Fig. 3.7). Sensory af f erents from proprio- ceptive and skin receptors can activate and modify these patterns (3 7, 39), and reticulospinal and vestibulospinal inputs select and Oxford Textbook of Movement Disorders 20 enhance the spinal repertoire by improving the control of mus- cle tone, varying the speed and quality of oscillatory patterns for locomotion (Fig. 3.7). Th e mesencephalic locomotor region and medullary reticular formation receive basal ganglia and cerebellar inputs, resp ectively, from the subthalamic and cerebellar locomo- tor regions (37) (Fig. 3.7). Th is co mplex coordination is necessary for humans to change patterns voluntarily during locomotion (e.g. when circumventing obstacles). 15. Haber S, McFarland NR. Th e place of the thalamus in frontal cortical- basa l ganglia circuits. Neuroscientist 2001; 7 : 315 \200\2232 4 . 16. Jones EG, Wise SP. Size, laminar and columnar distribution of eff erent cells in the se nsory-moto r cortex of monkeys. J Comp Neurol 1977; 175 : 391 \200\22343 8 . 17. Jones EG. Laminar distribution of cortical eff erent cells. In: A. Peters, EG Jones (eds). Cerebral cortex . New York : Plenum Press ; 1984. 18. Lemon RN, Baker SN, Davis JA, Kirkwood PA, Maier MA, Yang HS. Th e importance of the co rtico-motoneurona l system for control of grasp. Novartis Found Symp 1998; 218 : 202 \200 \2231 8 . Conclusion Movement is coordinated by a complex integrated network of brain regions. Of pri mary importance for voluntary purposeful movements is the motor neuron and its direct activ ation by the primary motor cortex. However, eff ective movement cannot be achieved without the integration of information from other motor cortices, the monitoring and modulation of this information fl ow through the thalamocortical circuits by both the basal ganglia and c erebellum, all on a background of appropriate muscle tone to enable the most time- and ener gy-eff ective inaction of the selected motion. For learned stereotyped movements some autom ation is achieved through brainstem and spinal central pattern generators. Disruption to di ff erent parts of this complex neural network pro- duces very diverse movement disorders. 19. Kurtzer I, Herter TM, Scott SH. Random change in cortical load rep- resentation suggest s distinct control of posture and movement. 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CHAPTER 4 Functional Aspects of the Basal Ganglia Th omas Wichmann Introduction Our understanding of basal ganglia function has changed sub- stantially over r ecent decades. For many years these structures were mainly associated with the control of m ovement, as many movement disorders have been related to basal ganglia patho- logy. However , there is growing recognition that these struc- tures are more broadly involved in the con trol and adaptation of behavior. Th e relevant systems-level anatomy will be reviewed here, followed by a discussion of the proposed functions of these structures. specificity. The functional separation between neighboring subcircuits appears to break dow n in dopamine-depleted ani- mals, with receptive fields of neurons in the basal ganglia and thalamus growing wider, although there are no obvious ana- tomical changes, such as altere d synaptic densities or sizes of dendritic trees (e.g. 18 \200\22321). This suggests that c ircuit separation may be a functional process rather than being entirely struc- turally det ermined. It is tempting to speculate that the active segregation of parallel circuits is a dopamine-dependent basal ganglia process, but neither the involvement of dopamine nor the r ole of the basal ganglia in this process have been directly demonstrated. Overview of basal ganglia anatomy General circuit anatomy Th e basal ganglia are components of a system of segregated par- allel circuits which originate from pre- and post-central p ortions of the cerebral cortex, traverse the basal ganglia and thalamus, and then return to the frontal area of origin (1 \200\2239). Th e circuits were designated \200\230motor \200\231, \200\230oculomotor \200\231, \200\230associative \200\231, and \200\230limbic \200\231 circuits (1), refl ecting the functions of the cortical areas involved. As shown i n Fig. 4.1, these circuits are functionally distinct although they are thought to utilize t he same basic anatomical building blocks. Studies have shown that at least some of the larg er circuits (e.g. the motor circuit) are comprised of parallel subcircuits (e.g. individual subcircuits for diff erent parts of the body) (4, 10, 11). Th e circuitry within the basal ganglia has also been studied. As shown in Fig. 4.2, the ne uronal connections seem to form a compli- cated system of negative (and positive) feedback circuits. However, it is important to recognize that most of the connections are very speci fi c within each of the brain structures involved. Th erefore it is not known whether they truly form closed feedback loops or whether, instead, they serve to connect closely related neighbor- ing basal ganglia territories. Figure 4.2 shows that the striatum (including the putamen and caudate nucleus) and the subt halamic nucleus (STN) function as input structures, receiving topographically organized pro jections from cortex, while the internal segment of the globus pallidus (GPi) and the subst antia nigra pars reticulata (SNr) are the basal gan- glia output structures, projecting to the thalamus and brainstem. Th e striatum is connected to the output structures via two dif f er- ent pathways, a monosynaptic GABAergic pathway (the so-called \200\230direct \200 \231 pathway), and a polysynaptic connection ( \200\230indirect path- way \200\231), consis ting of a GABAergic projection from the striatum to the external pallidal segment (GPe), wh ich then projects to the GPi and SNr either directly or via the intercalated STN. An interesting long-standing debate concerns the question of the degree of functional conve rgence of these parallel basal gan- glia \200\223thalamocortical circuits or subcircuits (d iscussed in refs 12, 13). It is obvious that anatomical convergence must occur, as cortical projections outnumber the striatal neurons that receive such inputs, and striatal projecti ng neurons , in turn, outnumber the neurons in other portions of the basal ganglia. Moreove r, the dendritic trees of many basal ganglia neurons are large and obvi- ously receive inpu ts from multiple axons. However, studies have demonstrated little functional convergence in healthy animals (14 \200\22317), with individual neurons showing very high functional Th e separation of the direct and indirect pathways has been intensively debated. Separatio n of these pathways was initially proposed on the basis of tract-tracing and immunohistoche mi- cal studies, showing that the indirect (striato-GPe) pathway origi- nated from striatal neurons that express encephalin, while the direct (striato-GPi/SNr) pathway originated in striatal neurons Oxford Textbook of Movement Disorders 22 Motor Oculomotor Prefrontal Limbic SMA, PMC CMA, M1 FEF SEF DLPFC LOFC MOFC ACA Cortex Caudate (ventr.) VS Putamen Caudate Caudate Striatum SNr/GPi (oculom. territory) SNr/GPi (assoc. territory) SNr/GPi (limbic territory) SNr/GPi (motor territory) Pallidum Subst. nigra VApc, VAmc VLcr, MDpl VAmc, VLm MD MDpl, VLcr VApc VLo, VLm VApc Thalamus Fig. 4.1 Circuit anatomy of the cortex \200\223basal ganglia \200\223thalamocortical circui ts. Th e basal ganglia are part of multiple segregated circuits that involve speci \201 c territories in the basal ganglia and associated areas of thalamus and cortex. ACA, anterior cingulate area; CMA, cingulate motor area; DLPFC, dorsolateral prefrontal cortex; FEF, fro ntal eye \201 elds; LOFC, lateral orbitofrontal cortex; M1, primary motor cortex; MD, med iodorsal nucleus of the thalamus; MDpl, mediodorsal nucleus of thalamus, pars lateralis; MO FC, medial orbitofrontal cortex; PMC, pre-motor cortex; SMA, supplementary motor area; SEF, supplementary eye \201 eld; VApc, ventral anterior nucleus of thalamus, pars parvocellul aris; VAmc, ventral anterior nucleus of thalamus, pars magnocellularis; VLm, ventrolateral nucleus of thalamus, pars medialis; VLo, ventrolateral nucleus of thalamus, pars oralis; VL cr, ventrolateral nucleus of thalamus, pars caudalis, rostral division. See text for other abbreviations. Reproduced, with permission, from Wichmann T, Delong MR. Deep brain stimulat ion for neurologic and neuropsychiatric disorders. Neuron 2006; 52: 197 \200\223204. although it was recently shown that the interpretation of studies in the transgenic animals may require some caution (26). However, the complete separation of direct and indirect pat hways has not been confi rmed by single-cell tracing studies in which many individual stria tal neurons were, in fact, shown to project to both pallidal seg- ments in monkeys, or, in rodents, to the GP (the rodent equivalent of GPe) and the SNr (27, 28). Determining the deg ree of separa- tion between the direct and indirect pathways remains an impor- tant goal be cause some of the prominent models of basal ganglia function are built around the idea that the direct and indirect path- ways operate relatively independently on basal ganglia outpu t (see below). Such models would have to be substantially revised if col- laterals of the s ame individual axons were found to be involved in both the direct and indirect pathways. Cortex (M1, PMC, SMA, CMA) Putamen D2 D1 VA/VL CM/Pf . r i d r e p y H . r i d n . r i D SNc I GPe Besides participating in the indirect pathway of the basal gan- glia, the STN also receives monosynaptic cortical inputs (29 \200\22331). Th e corticosubthalamic pathway has been cal led the \200\230hyperdirect \200\231 pathway, to emphasize that this pathway may provide t he basal ganglia output nuclei with faster access to cortical information than is possible via the trans-striatal direct/indirect pathways (32 \200\22337). STN GPi/SNr Brainstem/ Spinal cord PPN Th e functionally relevant question of which types of cortical neu- rons provide input to t he basal ganglia (and, thus, which type of information is being processed in these nuclei) remains open. In rodents, evidence has accumulated that direct-pathway neurons receive inpu ts from inter-hemispheric projecting cortical neurons, while the striatal neurons that give rise to the indirect pathway receive collaterals of the pyramidal tract (38). However, in electro- physiological studies in primates, neurons in cortex that gave rise to the pyramid al tract were found to diff er substantially from those projecting to the striatum (39, 40) . In partial agreement with these fi ndings, single-cell tracing studies in monkeys showed two sepa- rate types of cortical neurons projecting to the striatum, includ- ing a smaller group with downstream projections and collaterals to striatal neurons, and a much larger gr oup that sends terminations exclusively to the striatum (41). Fig. 4.2 Connections between basal ganglia nuclei, thalamus, and cortex, forming the \200 \230motor circuit \200\231 of the basal ganglia. Green arrows indicate inhibitory connectio ns; gray arrows indicate excitatory connections. Abbreviations: CM, centromedian nucleus of thalamus; CMA, cingulate motor area; Dir., direct pathway; D1, D2, dopamine receptor subty pes; Indir., indirect pathway; M1, primary motor cortex; Pf, parafascicular nucleus of the thalamus; PMC, pre-motor cortex; PPN, pedunculopontine nucleus; SMA, supplementary motor ar ea. See text for other abbreviations. Reproduced, with permission, from Galvan A, Wichmann T. Pathophysiology of parkinsonism. Clin Neurophysiol 2008; 119: 1459 \200\22374. expressing substance P (summarized in ref. 22). Furthermore, in histochemical studies and s tudies in transgenic mice, striatal direct-pathway neurons express dopamine D1 receptors wh ile the indirect-pathway neurons express dopamine D2 receptors (23 \200\22325), with virtua lly no overlap between the two groups of striatal cells, CHAPTER 4 Functional Aspects of the Basal Ganglia 23 Th alamostriatal projections While nuclei of the thalamus that receive basal ganglia output are oft en considered only as a relay between the basal ganglia and cor- tex, there is acc umulating evidence that neurons in several thalamic nuclei also project back to the basal g anglia (67, 68). Th is is par- ticularly true for the caudal intralaminar nuclei (the centr omedian nucleus (CM) and the parafascicular nucleus (Pf)), which receive topographically or ganized input from the basal ganglia and send a massive projection back to the striatum (67 , 69). In primates, the CM receives collaterals of the movement-related GPi projection to t he VL, and projects to the \200\230motor \200\231 portion of the striatum (the puta- men), while the Pf receives inputs from the non-motor output pro- jections of the basal ganglia, and projects to non-motor portions of the striatum (the caudate nucleus). Although the CM and Pf inputs directly target the striatal projection neurons and cholinergic stri- atal in terneurons (67, 70), the responses of striatal neurons to these inputs are not simply a ref l ection of the thalamic (glutamatergic) inputs, but also are strongly shaped by the intra- striatal circuitry, resulting in very complex response patterns (71, 72). In addition to fe eding back basal ganglia output to the striatum, neurons in the CM also respond to salient stimuli in the environment, and may help to regulate reward-related activities (particularl y those of the cholinergic neurons in the striatum) by favoring attention to relevant envir onmental stimuli (59, 73 \200\22377). Th e CM/Pf also sends projections to the STN (78 \200 \22387), but the functions of these connec- tions are not known. Th e origin(s) of the corticosubthalamic pathway are also not clear. It appears that this p athway is separate from the cortico- striatal pathway (41), and data in cats and rodents su ggest that it may arise as axon collaterals of other corticofugal systems, such as the cort icospinal tract (42 \200\22344), but this has not been confi rmed in primates. Basal ganglia outputs project to the thalamus in a topographi- cally specifi c manner. In p rimates, movement-related output from the basal ganglia, mostly emanating from GPi, reaches the vent- rolateral nucleus of the thalamus (VL), while non-motor output of the basal gang lia, emanating from the SNr, reaches the ventral anterior nucleus (VA). Th e basal ganglia \200\223thalamocortical circuits are then at least partially closed by projections from the VL and VA nuclei to motor and non-motor areas, respectively, of the frontal cortex. Additional basal ganglia output projections are directed at the brainstem, including promin ent reciprocal connections to the pedunculopontine nucleus (PPN) (see discussion in ref. 45 ) and other brainstem areas, which may then give rise to descending pro- jections, as well as reciprocal projections between the SNr/STN and the superior colliculus, known to be invo lved in the regulation of saccades and orienting movements (9, 46 \200\22352).