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). Interneurons and neuromodulators Interneurons in the striatum are considered to be importan t to basal ganglia function. Interneurons constitute about 5% of all stri- atal neurons in rodents, but may account for a larger proportion of striatal cells in primates. Most intern euron classes are GABAergic (53 \200\22356). An important group of neurons within this cate gory is the parvalbumin-positive \200\230fast-spiking \200\231 interneurons, which receive cortical input and provide signifi cant GABAergic inhibition to neurons around them, inclu ding striatal output neurons (57). Non-GABAergic interneuron classes also exist, most notab ly the cholinergic interneurons. As discussed below, these neurons are active during reward learning and are strongly driven by thalam- ostriatal inputs. Interactions between cerebellum and basal ganglia For many years, researchers have seen the basal ganglia \200\223 thalamocortical and cerebello-thalamocortical systems as anatom- ic ally and functionally distinct systems. In recent years, this view has soft ened considerab ly, with the demonstration of anatomical connections between the two systems. A bisynaptic pathway link- ing the deep cerebellar nuclei to the striatum via the centrolateral nucleus of the thalamus was fi rst demonstrated in mice (88), and later in primates (89). A connect ion between the STN and the cer- ebellar cortex was documented more recently (90). Th ere i s also evidence that the striatum receives inputs from portions of the ventral thalamus tha t are related to the cerebellum (discussed in ref. 67). Of course, further interactions bet ween the cerebellar and basal ganglia circuits occur at the cortical level. Th e functional sig- nifi cance of the cortical and subcortical interplay between the two systems is not c lear, but there is evidence from studies in rodent models and in patients that disturbances of these interactions may be relevant in the expression of some movement disorders, such a s tremor and dystonia. Another important feature of basal ganglia function is that the activity of basal ganglia c ells is subject to modulation by neu- romodulators. Of these, the functions of dopamine are strongly emphasized in all of the proposed functions of the basal gan- glia. Dopamine is r eleased at both striatal and extrastriatal basal ganglia locations from terminals of the ni grostriatal projection (emanating from the SNc) and from projections from the ventral tegme ntal area (VTA). Judging by studies in dopamine-depleted animals and parkinsonian patients, the steady-state levels of dopamine strongly infl uence the overall activity and activity patterns in the basal ganglia. In addition, the studies by Schultz and other authors (58) h ave implicated the phasic release of dopamine, together with changes in acetylcholine level s (59), in regulating the strength of corticostriatal synapses, a function that may be high ly important in the context of reward-based learning (see below). Dopaminergic inputs to th e striatum may also have trophic functions, helping to maintain the morphol- ogy of dendrit ic spines. Consistent with this, it has been shown in (dopamine-depleted) patients with Par kinson \200\231s disease, and in rodent and monkey models of parkinsonism, that there is a substantial reduction in the size of dendritic trees, and other changes in dendritic spine morphology, in the parkinsonian state (60 \200\22366). Basal ganglia functions Th e rapidly advancing knowledge of basal ganglia anatomy, as well as clinical observations in people with basal ganglia diseases, has resulted in the formula tion of concrete hypotheses about their involvement in movement-related functions. In contr ast, despite solid anatomical evidence that large portions of the basal ganglia belong to n on-motor circuits, little is known about the role that these structures play in non-motor f unctions. Th erefore most of the following descriptions of basal ganglia functions focus on their possible motor functions, followed by only a very brief discussion of non-motor func tions. Oxford Textbook of Movement Disorders 24 Inhibition of thalamocortical activities Several of the major hypotheses regarding the func tion of the basal ganglia are built around the notion that the output from the basal gangli a inhibits thalamocortical activities, and therefore funda- mentally serves to limit cortic al activation (and movement). Th is concept makes sense from an anatomical point of view bu t, like any other hypothesis regarding the functions of these structures, the view that suc h inhibition is essential must be weighed against the fact that near-complete lesions of th e basal ganglia output nuclei in animals and in patients with movement disorders have relat ively few detrimental eff ects on behavior (see below). Th is discrepancy can be interprete d either as evidence in favor of a view that the eff ects of basal ganglia on cortical func tions are subtle, and there- fore that their absence is hard to detect, or that the basal g anglia have eff ects on thalamocortical activity which are at least partially redundant, so that they can be compensated for. Th e latter view is also supported by the observation th at altered fi ring rates and pat- terns in basal ganglia output, as have been documented in move- ment disorders such as Parkinson \200\231s disease (see review in ref. 91) and dysto nia (e.g. 92), are seemingly far more disruptive to behav- iour than the complete absence o f basal ganglia output following therapeutic or experimental lesioning. by lateral inhibition of striatal output neurons through fast-spiking GABAergic interneuron s (53, 57, 96, 97). Both the scaling and action selection (focusing) hypotheses are complicated by the fact tha t the fi ring activity of basal ganglia neu- rons in relation to limb movement is too slow to allow for meaning- ful scaling or focusing. Even the fastest route by which the cerebral cortex would have access to the basal ganglia (i.e. the corticosub- thalamic pathway (32)) would be active only aft er cortical selec- tion of motor programs has occurred. According ly, phasic changes in neuronal activity in the STN and GPi in relation to the onset of limb movement occur relatively late with respect to ongoing movements, oft en aft er the start of EMG activity of related muscles (14, 93, 98 \200\223100). Additional uncertainty with re gard to the scaling and focusing hypotheses arises from the fact that the input to the stri atum does not appear to refl ect \200\230motor programs \200\231 in a recogniz- able manne r. Taken together, these fi ndings make it unlikely that functions like scaling and focusin g are primarily mediated by the basal ganglia. More likely, these functions rely heavily on cortical processing, even if the basal ganglia are also involved. Response inhibition Th e inhibition of ongoing motor programs is important under behavioral situations that require \200\230set \200\231-shift ing, or stop-signal inhibition. Under these conditions, ongoing movements or motor programs are inhibited or terminated in respon se to external cues (101, 102). It has been suspected for many years that the basal gan- gl ia are part of a network that serves this inhibitory function (34, 103), and that dysfuncti on in this network may be important in the pathophysiology of a variety of disorders includ ing, in particu- lar, attention defi cit hyperactivity disorder (ADHD) (104 \200\223109). I maging and other studies have suggested that the response inhibi- tion network includes not only the basal ganglia, but also several frontal and prefrontal regions (particularly the right inferior pre- frontal cortex and the pre-supplementary motor area (pre-SMA)) (105, 11 0). Involvement of the basal ganglia in the response inhibi- tory network is supported by t he observation that lesions in the basal ganglia produce defi cits in response inhibition ( as measured with stop-signal reaction time tasks) that are similar in extent to those produ ced by prefrontal cortical damage (111). Action selection and scaling of movement Th e interplay between direct and indirect basal g anglia pathways is central to several specifi c hypotheses regarding the motor func- tions of the basal ganglia, based on the notion that activation of the direct and indirect pathwa ys have opposing eff ects on basal ganglia output. Specifi cally, it is thought that the di rect pathway suppresses basal ganglia output by monosynaptic GABAergic inhibition, which ma y lead to disinhibition of thalamic and cortical activities, and, potentially, to facilitat ion of movement. In contrast, activation of striatal source neurons of the indirect pathway is expected to result in inhibition of GPe cells, which would lead to disinhibition of STN neurons, and thus increased drive of the basal ganglia output nuclei GPi and SNr. Increase d basal ganglia output would eventually lead to greater inhibition of thalamocortical proje ctions, and to a reduc- tion of movement. One hypothesis that makes use of this opposition between the direct and indirect pathways i s the \200\230scaling \200\231 hypothesis. Th is states that the direct and indirect pathw ays interact to regulate the ampli- tude or speed of movement. In this model, activation of the direct pathway facilitates movement by disinhibition of thalamocortical neurons. Th e facilitated movement is then terminated (or its ampli- tude is limited) by the inhibitory a ctions of the indirect pathway, leading to increased basal ganglia output. Evidence for suc h a role of the basal ganglia comes from studies of the activity of pallidal neurons in mon keys trained to perform movements with diff er- ent amplitudes (93). Another hypothesis is that the basal ganglia contribute to an \200\230action selection \200\231 mechanism by whi ch activation of the direct pathway facilitates intended movements or motor programs, while unintended movements are suppressed by acti- vation of the indirect and hyperdirect pathwa ys, perhaps acting in a center-surround fashion (e.g. 22, 32, 94, 95). Th is \200\230focus ing \200\231 hypothesis relies on the possibility that direct- and indirect-pathway neurons in the striatum receive information about intended and unintended movements, respectively, or that the opposing activa- tion patterns of the direct and indirect pathways are produce d by specifi c inhibitory eff ects in the striatum \200\224for instance, mediated Th e STN may have a particularly prominent role in this inhibi- tory network, as it is anat omically positioned to drive inhibitory pallidal and nigral output, which may then act to i nhibit thalamo- cortical transmission (32, 34, 94, 112 \200\223117). Consistent with such a role, studies of the eff ects of STN lesions in rats showed clear impairments of response inhibition in situations of behavioral confl ict (118 \200\223120). Th e STN has also been shown to play a role in inhibiting automatic eye movements when switching to voluntary eye movements (121). Similar evidence is available with regard to a basal ganglia role in inhib iting limb movements (but see ref. 122). Areas of the basal ganglia other than the STN may also be involved in response inhibition functions. For instance, lesions of the rodent stri atum increase stop-signal reaction times (123, 124), and imaging and other studies have led to speculation that func- tional disturbances of associative portions of the striatum may play a role in the development of features of ADHD (e.g. 108, 125), which may be considered the result of failure of response inhibition. Additional evidence for a role of the basal ganglia in response inhibition comes from studi es of deep brain stimulation (DBS) and other functional neurosurgical interventions, which are frequently CHAPTER 4 Functional Aspects of the Basal Ganglia 25 performed as treatment in patients with advanced movement dis- orders. STN-DBS treatment in patients with Parkinson \200\231s disease has been shown to interfere with response inhibi tion functions, as measured in cognitive and motor tasks (126 \200\223132). Most studies ha ve shown STN-DBS to be related to impaired response inhibition, resulting, for instance, in a higher number of commission errors in Go \200\223No Go tasks (131), but improvements in response inhibition have also been described (133). More recent research suggests that the eff ects of STN-DBS on response inhibition functions may, in fact, be specifi c to the loca tion stimulated: stimulation of the dor- sal (motor) portion of the STN was found to infl u ence response inhibition in a Go \200\223No Go task less than stimulation of the ventral (n on-motor) portion of the nucleus (134). is based on the observation that the dopamine loss in Parkinson \200\231s disease aff ects the putamen (associated with habitual behaviors) more than the caudate nucleus (more closel y associated with goal-directed behaviors). Another clinical entity, obsessive com- pulsive disorder, has also been interpreted as a disorder of the procedural learning function of t he basal ganglia (170). However, as in the experimental animal studies mentioned above, it cannot be said with certainty whether the learning impairments in these disorders are speci fi c to the basal ganglia, as patients with disorders like Parkinson \200\231s or Huntingto n \200\231s diseases almost always also have substantial pathology outside the basal gangli a which may contrib- ute to the defi cits (171 \200\223177). Reward learning Th e basal ganglia were fi rst identifi ed as having a specifi c role in re ward learning in studies of the response properties of dopamin- ergic neurons in the SNc. T h ese neurons tend to fi re in relation to (positive) prediction errors in rewarded tasks ( 178 \200\223184). Th is model was later extended into an \200\230actor \200\223critique \200\231 model in which the dopamine signal to the striatum would serve as the \200\230cri tique \200\231 of the actions of the medium spiny neurons in a particular behav- ioural con text, always acting to maximize the amount of reward to the animal. Other movement-related functions Procedural learning One of the most active lines of resear ch into basal ganglia functions addresses its role in procedural learning, i.e. the implici t acquisition of motor sequences and habits (e.g. 135 \200\223139). Large-scale regional sh ift s of basal ganglia activity have been observed when animals learn new tasks. Th e \200 \230associative \200\231 caudate nucleus appears to be involved in early phases of learning , while the \200\230motor \200\231 putamen is more prominently engaged when animals execut e previously learned movement sequences (140 \200\223149). Studies in rodents have shown th at the activities of individual striatal neurons or neuron groups also change during learni ng. In many neurons, neuronal spiking activities gradually shift to emphasize the beginning and end of movement sequences (150 \200\223152), which is interpreted as evi- dence for sh ift s in the encoded information in these cells. However, it is unclear whether the shift s in the involvement of basal ganglia regions, or in the fi ring patterns of individual cell s, originate in the basal ganglia, or whether they occur fi rst in the cerebral cortex or t halamus, and are then only secondarily refl ected at the basal gan- glia level. Th us, it i s perhaps more appropriate to see these changes as properties of the corticobasal ganglia \200\223thalamocortical circuits rather than as properties of the basal ganglia per se (for discussion, see ref. 153). Th is broader view is also supported by experiments comparing s equence learning in normal monkeys and monkeys in which the internal pallidum was inactivat ed. Th ese experiments failed to reveal any specifi c impairments of motor sequence learn- ing in the lesioned animals (154, 155). Dopamine release from terminals of the nigrostriatal projection in reward-driven learning s ituations appears to be closely coordi- nated with the activity of cholinergic interneurons in the striatum, which are thought to signal salience, driven by their inputs from the int ralaminar thalamic nuclei (59, 74 \200\22377, 185 \200\223190). It was shown that the arriv al of reward information in the striatum triggers a pause in the fi ring of these \200\230 tonically active \200\231 cholinergic interneu- rons which coincides with an increase in do paminergic signaling (59, 186, 191, 192). Together with other intrastriatal mechanisms, spe cifi cally the endocannabinoid and adenosinergic systems (e.g. 193 \200\223198), dopamine r elease infl uences the synaptic strength of specifi c corticostriatal synapses that may be relevant to maximize behaviors that will produce reward. In addition to the positive error prediction signals mentioned above, recent studies have s uggested that negative prediction error signals may reach the basal ganglia from the latera l habenula. Th ese signals infl uence SNc neuron activity, and thus may further modu- late dopamine release in the striatum (199 \200\223204). Th e concept that the basal ganglia are involved in reward learn- ing has obvious clinical relevance. For instance, disorders of habit formation (such as addiction) have been linked to altered dopamin- ergic signaling in the striatum (136, 138, 147, 169), and disorders tha t are characterized by altered dopaminergic transmission, such as Parkinson \200\231s disea se, may be associated with changes in reward learning (205, 206). Th e learning of action sequences has also been extensively stud- ied in the avian equivale nt of the basal ganglia \200\223thalamocortical cir- cuitry, the so-called anterior forebra in pathway (AFP) (156). During a critical developmental period, young songbirds learn by im itating adult birds to produce the species-specifi c sounds they will use for communication and courtship. Interruption in the AFP, specifi cally in area X, homologous to the striatu m and pallidum in mammals, interferes with the acquisition of songs during the critical per iod, or with the maintenance of learned songs thereaft er (157 \200\223160). Control of bimanual movements Because parkinsonian patients have signifi cant problems with the performance of bimanual movements, especially anti-phase move- ments (207, 208), many studies have been designed to examine the role of the basal ganglia in these movements, usi ng functional MRI (fMRI) and other functional tests. For example, it was shown that DBS of the STN reduces the impact of motivation on the perform- ance of bimanual movements (209), and that changes in the activa- tion patterns of the STN and GP may be involved in, or be r efl ective of, age-related declines in the performance of bimanual switching Clinical support for the notion that the basal ganglia are essential to procedural learning comes from studies that have shown that pro- cedural learning is disturbed in patients wit h basal ganglia patholo- gies (such as Parkinson \200\231s or Huntington \200\231s diseases ), as opposed to the loss of explicit memory functions by patients with hippocampal patholo gies (such as amnestic patients with Alzheimer \200\231s disease) (161 \200\223168). Specif i c disturbances in the control of habitual behav- iours, but not goal-directed behaviors, were recently postulated to occur in patients with Parkinson \200\231s disease (169). Th is hypothesis Oxford Textbook of Movement Disorders 26 tasks (210). In a task involving temporally uncoupled bimanual fi nger movements, fMRI show ed increased activation within right pre-motor and dorsolateral prefrontal, bilateral infer ior parietal, basal ganglia, and cerebellar areas, identifying the basal ganglia as part of a larger bimanual movement circuitry (211) that is disturbed in Parkinson \200\231s diseas e (208). As with the role of the basal ganglia in learning, the basal ganglia are rarely se en to be active alone in tests of bimanual movements, so their function is very diffi cult to sepa- rate from that of associated cortical areas. possibility has been examined in several diff erent contexts, includ- ing action selection, the scaling of movement, the inhibition of behaviors under confl ict situations, or the te rmination of motor programs that are already underway. A second major modulatory role of th ese structures arises from the fact that connections within the basal ganglia (and specifi cally in the striatum) are subject to considerable plasticity, allowing them to be \200 \230tuned \200\231 to the actions of the modulatory network to permit behavioral responses that are likely to be rewarded, while suppressing others that would interfere, or to bundle sequences of movement into larger units. Basal ganglia inactivation has relatively few eff ects on behavior, but disturbances of basal ganglia processing such as those seen in Parki nson \200\231s dis- ease (reviewed in ref. 91) or dystonia result in major behavioral impai rments, ranging from motor abnormalities such as akinesia (poverty of movement), bradykines ia (slowness of movement), or involuntary movements, to obsessive \200\223compulsive sympto ms or behavioral disinhibition. Non-motor functions Th ere is increasing discussion of the role of limbic portions of the b asal ganglia in the control of motivation and mood, in addition to their role in cognition (as discussed earlier under response inhi- bition). Th ere is also evidence that the basal ganglia and associ- ated areas of the thalamus, particularly the CM \200\223Pf complex, are involved in the regulation of pain-related behaviors, and poten- tially in the modulation of nociceptive information (212 \200\223214) and feeding behaviors (including responses to appetitive stimuli (215)). Like other basal ganglia areas, the STN may be involved in assoc iative and limbic functions, as demonstrated by DBS surgery which may result in mood and co gnition changes (216), and from animal studies in which STN interventions were shown to lea d to changes in motivation and attention (120, 217 \200\223221). As with the potential moto r functions of the basal ganglia, the non-motor func- tions of these structures cannot be c onsidered apart from cortical and thalamic functions. It is worthwhile pointing out here some aspects of our models of basal ganglia function tha t may need revision. For instance, the basic assumption that basal ganglia output generally acts to inhibit thalamocortical and brainstem operations should be re-evaluated. Many stud ies have shown that the interactions between GABAergic and glutamatergic systems may result in a variety of discharge patterns (for instance, oscillatory phenomena or rebound bursts) which are not fully explained by simple inhibitory interactions, and are not well integrat ed into current models of basal ganglia activities. It is also not clear to what extent the separation of neighboring \200\230channels \200 \231 within the basal ganglia is a by-product of the anatomical arrangement of these pathwa ys, and to what extent it is an actively maintained condition. Another potentially undue bi as is our almost exclusive focus on basal ganglia \200\223thalamocortical circuits. As men- tioned above, the basal ganglia have strong reciprocal interactions with brainstem areas s uch as the PPN, but little is known of the function(s) of these interactions. Conclusion Th e fact that the basal ganglia are very closely linked to the tha- lamocortica l operations in the form of modularly organized closed loops makes it virtually impossible to assign specifi c functions to these nuclei distinct from those of the other related brai n regions. Th e behavioral and other roles of these structures are inextrica- bly linked to anatomically associated areas of thalamus, cortex, and perhaps brainstem and cerebellum. A ll of these structures are simultaneously involved in behavioral control, and disease condi - tions in any of these brain areas will aff ect activity patterns in all of the related st ructures. Identifying the role of the basal ganglia is further complicated by the apparentl y substantial redundancy in these circuits, which accounts for the relative lack of functio nal def- icits observed in animals and patients with basal ganglia lesions. Finally, it is obvious that our views of basal ganglia functions are strongly biased by the fact that movements are easier to examine than cognition or emotion. Given the anatomy of the basal ganglia \200\223 thalamocortical system, it is likely that some of the modulatory func- tions of the basal ganglia functions described above for behavior also apply to non- motor domains, and there is growing recognition that the cognitive and emotional abnormalit ies in ADHD, obsessive \200\223 compulsive disorder, and other conditions involve the basal ganglia. Th e possibility that the basal ganglia may not only refl ect primary cortical ch anges but also play a more active role in cognition and emo- tion has become apparent from changes in these domains observed with DBS surgery and other functional surgical interventi ons. While such changes are currently most oft en seen as unwanted side eff ects of DBS tre atments for movement disorders, it may become possible to harness our understanding of non- motor functions in the future to treat conditions such as obsessive \200\223compulsive diso rder, ADHD, or even depression, with targeted neurosurgical interventions. However, a few generalizations can be made. One is that, although the basal ganglia are imp ortant for the planning and on-line control of movement, as proposed by the focusing, scali ng, and response inhibition models described above, it is probably too simple to conclude t hat this is their \200\230function \200\231, because lesions of the basal ganglia output n uclei have little or no eff ect on most movements in normal animals or humans (168). Indeed , patients undergoing pallidotomy, an obviously major interruption of the motor circuit, ha ve no perceived complaints or clearly observable disturbances of voluntary movement, and ex perimental inactivation of the palli- dum in monkeys results in slowing, but no obvious dis inhibitory phenomena (154, 155). Acknowledgements Th e preparation of this article was supported through grants from the NIH /NINDS (R01-NS054976, R01-NS071074 and P50-NS071669 (TW)), and by NIH/NCRR grant RR-000165 (Yerkes National Primate Center). Another general observation is that the basal ganglia appear to have a predominantly inhibi tory role in the modulation of behav- iour. By virtue of their tonic inhibitory output to t he thalamus, they may serve to limit cortical activation. As mentioned before, this CHAPTER 4 Functional Aspects of the Basal Ganglia 27 References 1. Alexander GE, DeLong MR, Strick PL . Parallel organization of func- tionally segregated circuits linking basal ganglia and cortex. 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