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THE ROLE OF THE THALAMUS AND BASAL GANGLIA IN HUMAN COGNITION
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J. Neurolinguistics, Vol. 10, No. 4, pp. 255±265, 1997 # 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0911-6044/97 $17.00 + 0.00 S0911-6044(97)00020-1
THE ROLE OF THE THALAMUS AND BASAL GANGLIA IN HUMAN COGNITION SALVATORE AGLIOTI* *Dipartimento di Scienze Neurologiche e della Visione, Sezione di Fisiologia Umana, Universita di Verona, Strada le Grazie, 8, I-37134, Verona, Italy AbstractÐCerebral lesions involving the thalamus or the basal ganglia can impair cognitive functions (e.g. language, memory, or attention) that were previously believed to be linked almost exclusively to cortical structures. These impairments are mostly evident when, in addition to nuclear lesions, there is an involvement of the subcortical white matter that includes bundles of ®bres for cortico-cortical and cortico-subcortical connections. Based on this result, it has been hypothesized that cognitive de®cits after subcortical lesions are due entirely to remote eects on select cortical targets. Thus, the notion of subcortical cognition has been questioned. However, since cortical lesions can have remote eects on their subcortical targets, the notion of cortical cognition can be challenged as well. The present article deals with the concept of subcortical cognition and reviews lesion studies hinting at a role for thalamus and basal ganglia in complex human behaviour. A proposal is made that the notion of large neural networks with both cortical and subcortical nodes may give a plausible interpretation of cognitive de®cits. # 1997 Elsevier Science Ltd. All rights reserved
INTRODUCTION
The cerebral cortex has been traditionally considered as the neural basis of human cognition. Comparatively recent studies have suggested a possible ``cognitive'' role of subcortical structures such as the thalamus, basal ganglia and cerebellum that were classically considered as linked mainly to sensory±motor functions. Extensive anatomic and physiological analyses of the neural circuitry of these structures suggest that they are well equipped to play a crucial role in motor, cognitive and complex behavioural functions [1±3]. For example, recent anatomical evidence has shown that basal ganglia and cerebellum not only send projections to the premotor and motor areas, but are also connected, via the thalamus, to higher order cortical areas [4, 5]. Moreover, a number of clinical reports have related subcortical lesions to complex cognitive and behavioural functions. It has been suggested, however, that the cognitive de®cits following subcortical lesions can be explained almost entirely as a hypofunction of disconnected cortical areas [6]. This hypothesis is based on two lines of evidence. Firstly, there is evidence to suggest that subcortical lesions aect cognitive functions mainly if concomitant with lesions to the paraventricular white matter [6±10]. Secondly, regional cerebral blood ¯ow studies have documented both cortical [11, 12] and cerebellar [11] areas of hypoperfusion in patients with subcortical stroke. Moreover, a transient ipsilateral hypoperfusion in the thalamus and cerebral cortex after a pontine infarct has Address for correspondence. Telephone: +39 45 8098134; Facsimile: +39 45 580881; Email: [email protected]. 255
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been reported [13]. This evidence, however, does not necessarily exclude the possibilty that subcortical nuclear structures play a crucial role in cognition. It is nothing but a truism that subcortical structures do not work in isolation and that a symptom related to their lesion may ensue from a disconnection of these structures from their cortical targets. This may turn out to be true also for cortical lesions since there are few, if any, complex operations in the brain not linked to large neuronal networks. Since the term subcortical has a morphological meaning, the lack of evidence for cortical lesions is sucient to credit the use of the term ``subcortical'' without any ambiguity. A major issue is to examine whether or not the type of neuronal processing that takes place in subcortical structures has to do with a mere transmission of information from and to the cortex. Were this the case, only a minor cognitive role for subcortical structures could be hypothesized. However, there are reasons to believe that neuronal processing in subcortical structures, such as the thalamus and basal ganglia, shows high levels of complexity [3, 14]. While there is evidence for cognitive and behavioural de®cits following lesions to thalamus and basal ganglia, the involvement of the human cerebellum in cognitive non-motor functions has been reported only very recently [15±17]. Moreover, authoritative students of cerebellar functions have cast doubts on such involvement [18]. Thus, this issue is at present much too controversial and will not be addressed in the present article. The present contribution is, instead, focused on the cognitive impairments consequent to focal damage of the thalamus and basal ganglia in humans. It is noteworthy, however, that subcortical lesions often involve the white matter deep to the cortex and adjacent the lateral ventricles. Therefore, the role of the peri- and paraventricular white matter in subcortical cognition should not be ignored [6]. Degenerative lesions involving subcortical structures (e.g. Parkinson's disease as a model of basal ganglia dysfunction or Korsako's syndrome as a model of thalamic dysfunction) are very complex and may not be an optimal model for relating a given symptom to its neural basis. Thus, degenerative lesions will be considered only marginally. Since other articles in this special issue concern the relationships between subcortical lesions and language, mainly non-linguistic areas of human cognition will be discussed in the following. By the same token, impairments in higher-order motor control (praxis) closely related to language are not considered (see [19] for review). SUBCORTICAL LESIONS AND COGNITION
There is clinical evidence to suggest that subcortical structures may be crucial for complex behaviours (e.g. bulimia or hypersexuality after basal ganglia lesions, [20, 21]). However, given the purpose of this contribution, such evidence will be considered only if closely related to cognition. THALAMUS
Anatomic and physiological circuitry Both the ventral and dorsal thalamus have a fairly complex anatomic and functional architecture [22, 23]. The ventral thalamus mainly consists of the thalamic reticular nucleus that receives aerent ®bres from the dorso-thalamo-cortical pathways and sends GABAergic inhibitory connections to the dorsal thalamus [23]. The thalamic
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reticular nucleus relies upon a variety of operational modes and is in a strategic position for modulating functional states such as alertness and sleep. The dorsal thalamus, i.e. the main mass from which cerebral cortex receives most of its subcortical aerents, consists of three main categories of nuclei, each related to a distinct set of functions [22]. The ®rst group, extrinsic or ``relay'' nuclei, have to do with primary sensory channels (ventro-posterior complex for somatosensation, lateral geniculate and medial geniculate nuclei for vision and audition, respectively), motor functions (ventralis anterior and ventralis lateralis that receive inputs from the basal ganglia), limbic inputs (anterior groups: anterodorsal, anteromedial, that are heavily connected to the limbic circuits). These structures transfer to the telencephalon information from pre-thalamic structures including sensory receptors, spinal cord, brainstem, cerebellum, basal ganglia, limbic system. The second nuclear group, referred to as intrinsic nuclei (mediodorsal, laterodorsal, lateroposterior and pulvinar), is the recipient of intrathalamic input and projects to association areas. The third group includes: (i) midline and anterior intralaminar nuclei that receive from multiple lower sources (brainstem, spinal cord, cerebellum) and send eerents to the rhinencephalon and basal ganglia; and (ii) posterior intralaminar nuclei that are believed to terminate densely on the basal ganglia and only sparsely on somatosensory, motor and premotor cortices [23]. From a functional point of view, two distinct types of thalamic nuclei are proposed [14]. ``First order nuclei'' receive primary aerent ®bres from ascending pathways and provide main paths to the cerebral cortex for information about what the external world is doing or the subcortical parts of the brain are doing. These nuclei receive cortico-thalamic aerents from pyramidal cells in cortical layer 6, which also send branches to the thalamic reticular nucleus and appear to have a modulatory function. ``Higher order nuclei'' receive most or all of their ``primary aerents'' from pyramidal cells in cortical layer 5 and also receive modulatory aerents from layer 6. It has been proposed that these nuclei are largely concerned with transmitting information about the output of one cortical area to another cortical area and that they are likely to play a key role in corticocortical communication and higher cortical functions [14]. To sum up, anatomic and physiological data suggest that the thalamus not only transfers information to the cortex but also has modulatory functions achieved through the capability of thalamic neurons to alternate electrophysiological properties from synchronized to desynchronized modes. Moreover, the great complexity of the thalamo-cortical and cortico-thalamic connections and the capability of thalamic neurons to combine, balance and discriminate, temporally and spatially pre-thalamic messages, is likely to give the thalamus integrative properties [24]. Thalamic networks tune the information appropriate for cortical processing preparing it for the complex operations performed at cortical level; these nets are an essential prerequisite for cortical mechanisms of arousal, perception and cognition. Lesion studies in humans Behavioural and cognitive de®cits following lesions con®ned to thalamic structures have been repeatedly reported. In a recent radiological-clinical study Chung et al. [25] attempted to relate neurocognitive de®cits and site and extent of lesions in a large sample of patients who had suered from thalamic stroke. The study reported that cognitive de®cits were most frequently in global and posterolateral lesions. In all cases
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lesions involved more than one nucleus and no conclusion about the cognitive role of single thalamus subsections can be drawn at present. Thalamus and memory The thalamus has long been known as a part of the mesiotemporal memory network and thus linked to explicit memory only. Recently, however, Bentivoglio et al. [1] assumed that the ventral anterior and the intralaminar thalamic nuclei, given their heavy connections with the striatum (see below), may play a role in implicit learning and memory (e.g. in acquisition of habits). This hypothesis has no experimental proof at present, but it may lead to future research and discoveries. Much more information on the relationships between the thalamus and explicit memory is available. In short, patients with bilateral mesial diencephalic lesions have extensive diculty in learning and retaining new information (both verbal and non verbal); unilateral thalamic lesions have shown that hemispheric specialisation extends to diencephalic structures [26]. This information, however, mainly comes from the study of Korsako's patients, where multiple thalamic and extrathalamic systems may be damaged. Isolate lesions of thalamic nuclei are dicult to place even under controlled experimental lesions and they are uncommon after spontaneous lesions in humans. A recent analysis of memory de®cits following focal thalamic lesions reports that dysfunctions of the medial thalamus (particular the dorsomedial nucleus) are likely to cause diencephalic amnesia [1]. Clinical evidence for a de®nite memory function of the anterior and laterodorsal thalamic nuclei is not clear-cut. Diencephalic amnesia is mostly severe after lesions extending to mammillary bodies and mammillo-thalamic tracts [26]. In view of this, it has been suggested that diencephalic amnesia is the pathological expression of a thalamic±mesiotemporal disconnection [27]. In any case, amnesic symptoms of diencephalic patients do not resemble either qualitatively or quantitatively the memory de®ciencies of patients with basal ganglia lesions [26]. Thalamus and visuo-spatial functions including attention Animal research and studies of functional anatomy in neurologically intact subjects suggest that the pulvinar has a crucial role in attentional processing [28, 29]. Lesion studies in humans indicate that after acute thalamic lesions, particularly after bilateral damage, patients may be initially comatose [26]. In early stages of recovery, alertness and attention can be severely impaired with ¯uctuations from moment to moment [26]. An attentional role for the dorsomedial nucleus has been postulated on the basis of its massive reciprocal connections with the prefrontal lobe. On the other hand, patients with a clear left-sided neglect, following thalamic lesions involving the dorsomedial nucleus, have been described [25, 26, 30]. Thalamus and psychiatric symptoms Confabulation, perseveration and reduplication symptoms may occur even years after the lesion. Patients with thalamic lesions may have diculties in arranging data in logical sequences and in other planning abilities. These patients are also highly susceptible to interference phenomena. Manic delirium and a frontal lobe-like syndrome have been reported in patients with paramedian infarction of the right thalamus [30]. Major personality and mood changes have also been reported. Thalamic patients have been described as apathetic, akinetic, withdrawn, abulic, unconcerned, euphoric, oc-
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casionally irritable and lacking spontaneity. Several aspects of these behavioural changes appear to be related to the lesional site: a lesion to dorsomedial±frontal connections seems to induce euphoria and lack of insight while the interruption of the anterior±cingulate projections is more likely to induce withdrawn behaviour and akinesia [26]. It has been suggested that some of the symptoms in acute schizophrenic patients may result from de®cits in the sensory ®ltering process at the level of the thalamus [31]. MRI analyses of structural alterations in the brain of patients with schizophrenia show speci®c regional abnormalities in the thalamus and adjacent white matter [31]. In keeping with this result are functional anatomy studies showing thalamic dysfunctions in schizophrenic patients. Buchsbaum et al. [32], for example, reported that patients with schizophrenia showed a diminished metabolic rate in the right posterior thalamus and the left anterior thalamus compared to control subjects. Moreover, schizophrenics presented a reduction of the size of the left anterior thalamus. In another recent PET study, Andreasen et al. [33] showed the activation of a prefronto-thalamo-cerebellar network when normal subjects recall complex narrative material. This same network resulted dysfunctional in schizophrenic patients. It may be relevant that the midline thalamic nuclei seem to be a site of action of antipsychotic drugs [34]. An abnormality in the thalamus and related circuitry may explain the diverse symptoms of schizophrenia parsimoniously because they could result from a defect in ®ltering or gating sensory input, which is one of the primary functions of the thalamus in the human brain [31]. BASAL GANGLIA
Anatomic and physiological circuitry The basal ganglia consist of ®ve interconnected subcortical grey masses, lateral to the thalamus, located at the inferior part of each cerebral hemisphere. The main mass consists of the caudate nucleus and putamen that share a telencephalic origin and together are called neostriatum. These nuclei, fused anteriorly, are composed of very similar cellular types and are the recipient structures of the basal ganglia. Neurochemical analyses showed that the neostriatum is organized in modules or patches that have some analogies with cortical columns. Striosomal patches, containing enkephalins and substance P, are embedded in a larger compartment called striatal matrix that contains acetylcholine and somatostatine. The striatum striosoma/matrix patchwork is better developed in caudate than in putamen and it may re¯ect a new addition in terms of evolution. Connectivity studies suggest that in spite of their intimate links, the putamen seems to be concerned primarily with motor control while the caudate seems to be involved in more complex functions [2]. The globus pallidus, derived from the diencephalon, is divided into external and internal segments. The substantia nigra is localized in the mesencephalon and consists of a pars compacta (dorsal, composed of dopaminergic neurons containing neuromelanin) and a pars reticulata (ventral, cytologically similar to the pallidum). The subthalamic nucleus is located below the thalamus at its junction with midbrain). Structure and connectivity of the basal ganglia The striatum receives a topographically organized glutaminergic input from the entire cortex; while the neocortical±striatal inputs go to the matrix (that in turn
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projects to the pallidum, substantia nigra and pars reticulata), allocortical±striatal inputs go to the striosomes (that project to the substantia nigra, pars compacta and thus in¯uence the dopaminergic pathway). The other input source to the striatum comes from the polisensory intralaminar thalamic nuclei. This thalamo-striatal input has some topography, the centromedian nucleus (that receives input from the motor cortex) mainly abutting the putamen and the centralis lateralis nucleus mainly abutting the caudate (thanks to this pathway the striatum receives sensory and higher-order information). The striatum sends its main output ®bres by means of pathways reaching, topographically, the internal pallidus and the substantia nigra, the pars reticulata that in turn projects to the ventro-lateral, ventral anterior, mediodorsal thalamic nuclei. The internal pallidus also projects to the centromedian thalamic nucleus. These strio-internal pallidal and strio-nigral pathways, called direct, are mediated by GABA and substance P and exert an inhibitory control on the thalamus. Through these thalamic connections, the basal ganglia appear to be inextricably linked to a high number of cortical areas. The striatum also sends output ®bres to the external pallidus that is reciprocally connected to the subthalamic nucleus (that in turn sends a glutamatergic input to the internal pallidus). Thus, the strio-externo-pallidal pathway, mediated by GABA and enkephalins, does not have direct connections with the thalamus and is called indirect. The arrangement of cortico-striatal±thalamo-cortical connections along multiple channels suggests a possibly parallel information processing in these structures. This novel notion has changed radically the classical view that basal ganglia simply integrate inputs from the entire cerebral cortex and deliver these signals via the ventrolateral thalamus to the motor cortex. Thus, in addition to the ``motor loop'' (mainly through the putamen) at least four additional complex circuits working in parallel with the motor circuit have been described [2]. These complex circuits in¯uence, mainly through the caudate, associative areas such as prefrontal lobes and appear to mediate higher-order functions such as spatial memory or complex behavioural choices [2]. Thus, at least some sectors of the basal ganglia are part of a highly dynamic system involved in adaptive control of action in the motor, planning and cognitive domains [3]. Lesion studies in humans Degenerative diseases (e.g. Parkinson's disease) may give clues to the normal functions of the basal ganglia. Dubois and Pillon [35], for example, reported that patients with Parkinson's disease have shown speci®c impairments, even in the early stages of the disease, which include de®cits of behavioural regulation in sorting or planning tasks, defective use of memory stores and impaired manipulation of internal representation of visuospatial stimuli. It may not be super¯uous to mention again that this disease involves multiple systems and therefore may not represent an optimal model for understanding basal ganglia functioning. The study of selective lesions may be a more useful approach although it should be kept in mind that, like the thalamus, spontaneous lesions of the basal ganglia typically involve more than one nucleus. However, thanks to the sophisticated imaging techniques currently available, it is possible to try and relate cognitive behaviour to select basal ganglia lesions. Thus, the best picture of
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the role of basal ganglia in subcortical cognition may come from the combination of information provided by both degenerative and lesion studies. Basal ganglia and memory Implicit or non cognitive memory includes not only the formation of speci®c stimulus-response connections but also complex memory processes such as visuomotor skills and rule or category learning. Patients with neostriatal dysfunction appear impaired in tasks belonging in these categories [36]. Knowlton et al. [37] reported that non-demented Parkinson's patients were unable to learn a probabilistic classi®cation task in spite of a preserved memory of the learning episode. By contrast, amnesic patients with ``hippocampal'' or ``diencephalic'' lesions could learn the task but had no memory of the learning episode. Clinical investigations also suggest that patients with basal ganglia lesions have problems with the activation of overlearned programs or routine procedures (e.g. writing, signing their name, typewriting). Patients with lesions to the caudate appear impaired in mirror reading and serial reaction time tasks, while patients with lesions to the putamen show de®cits in the rotor pursuit task [20]. The exact implication of this result is at present unclear. There are some suggestions that basal ganglia lesions, particularly when involving the caudate, aect tasks that rely upon explicit memory. A de®cit in memory retrieval has been reported. This impairment, however, seems to be related to a diculty in activating ecient retrieval strategies. Indeed, in patients with lesions to the caudate encoding and recognition processes are intact, despite a poor free recall [20]. Thus, the caudate is unlikely to have a autonomous key role in explicit memory. It can instead be part of a strio-pallido-cortical network for activation of conscious recall strategies. Basal ganglia and psychiatric symptoms Behavioural changes in patients with focal lesions to the basal ganglia are not uncommon. Patients may show psychic akinesia: they appear apathetic, unconcerned and their aective state is ¯attened. Such blank inactivity can be reversed by external stimulation. This behavioural pattern has been observed after lesions to the globus pallidus, caudate and lesions to the thalamus thus suggesting that the strio-pallidal thalamic complex may be part of a neural network related to behavioural activation [20]. In an extensive review on the behavioural and motor consequences of focal lesions to the basal ganglia, Bhatia and Marsden [7] reported that behavioural disturbances (mainly abulia) are rare after putaminal lesions, but prominent after lesions to the caudate nucleus. This evidence supports the involvement of the caudate in behavioural and cognitive functions. A true psychotic episode has been reported in a woman (she showed excessive fussiness about germs and heard voices) with lesions to the caudate nucleus [38]. Basal ganglia and obsessive±compulsive disorders (OCD) Focal lesions to the basal ganglia may induce stereotyped activities (e.g. repetition of mandatory sentences, coprolalia, repetitive movements of the ®ngers) and compulsions [20]. Functional anatomy studies suggest that in patients with OCD (where perseverative series of actions aict patients) there is an abnormal function in the anterior striatum as well as in the frontal and anterior cingulate areas of the cortex [39, 40]. Laplane et al. [41] reported that patients with lesions bilaterally involving the
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putamen and the globus pallidus, presented with a dysfunctional activation pattern (on PET imaging) of the prefrontal cortex, perchance as a result of the subcortical lesions. The main features were inertia and loss of drive in spite of preserved intellectual functions. Berthier et al. [42] investigated behavioural, cognitive and neuroimaging characteristics of patients with idiopathic OCD or with OCD consequent to focal brain lesions. The two groups had a comparable clinical phenomenology and pro®le of neuropsychological de®cits (de®cits of attention, intellectual function, memory, word retrieval and motor and executive functions). Neuroimaging in the acquired OCD group disclosed a variety of lesions involving the cerebral cortex (frontal, temporal, or cingulate regions), the basal ganglia, or both. Thus, structural damage to speci®c frontal±limbic±subcortical circuits may play an important role in the pathogenesis of acquired OCD. In contrast to the above studies, Aylward et al. [43] examined, with a standard MRI technique, volumes of the caudate nucleus and putamen in patients with adult-onset OCD and evaluated the function of the caudate nucleus by a quantitative, meta-analytic review of normalized data from functional neuroimaging studies in OCD patients. Patients did not demonstrate evidence for structural abnormalities of basal ganglia. No support for a relative caudate metabolic or perfusion dysfunction was found in the literature (although increased function in the frontal cerebral cortex was identi®ed). Thus, these authors deny that evidence for the involvement of basal ganglia in OCD is ®rmly established. Basal ganglia and schizophrenia Morphological abnormalities of caudate, putamen and globus pallidus in schizophrenic patients have been reported [44] and neurochemical changes in the left basal ganglia [45] hinted at the possible relationship between basal ganglia and schizophrenia perchance related to striato-limbic [46] or fronto-striatal connections. It has also been reported that, despite some similarities, the cognitive performance of patients with subcortical dysfunctions diered from that of schizophrenic patients: slowed thinking or impaired motor function, which are considered hallmarks of subcortical grey matter disease, were absent in schizophrenic patients who, in turn, showed poor performance on tests of executive function [47]. Thus, schizophrenic symptoms seem to be at least partially related to a pre-frontal dysfunction. Basal ganglia and frontal lobe like syndromes In spite of a global intellectual eciency within normal limits, patients with focal or degenerative lesions of basal ganglia often present with a dysexecutive syndrome that may result from a fundamental de®cit concerning allocation of attentional resources, temporal organisation of behaviour, elaboration of internal strategies [20]. Similar de®cits have been reported as a consequence of frontal lobe lesions, thus supporting anatomical evidence in favour of the relevance of the strio-frontal system for complex behaviours. A recent study suggests a dierent role for frontal lobe and striatum in behavioural adaptation. The frontal lobe would control the elaboration of new acts in association with inhibition of previously established ones, while the striatum would maintain new programmes until the action has been accomplished [5].
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DISCUSSION
There is compelling evidence suggesting that lesions involving the thalamus or the basal ganglia may induce dramatic changes in cognitive and behavioural domains [1, 3, 20]. However, there is some controversy on whether or not these eects are actually due to the subcortical lesion or to remote eects on the cerebral cortex. The often concomitant lesions to the subcortical white matter typically worsen the de®cit because they interrupt long range, cortico-cortical and cortico-subcortical connections. This may explain the multifarious symptoms following subcortical lesions. In any case, the notion of subcortical neuropsychological syndromes does not imply at all the absence of remote eects on the function of cortical structures. On the other hand, remote eects on distant cortical and subcortical regions are observable as a consequence of select cortical areas. Does this mean that we cannot use the term cortical for these lesions? A purely morphological acceptation of terms such as cortical or subcortical is not misleading. Complex cognitive and behavioural functions, however, are likely to be subserved by cortico-subcortical neural networks. In line with this hypothesis is the recent suggestion of a functional continuity or complementarity between subcortical structures and association areas of the cortex [35]. Indeed, both similarities and dierences in cognitive de®cits deriving from subcortical and cortical lesions are reported. For example, the frontal-lobe like syndrome following basal ganglia lesion is similar but not identical to the true frontal lobe syndrome. Although there is abulia in both cases, patients with basal ganglia lesions do not present the typical markers of prefrontal syndrome such as puerile, facetious, or irresponsible behaviour, lack of foresight, inability to delay grati®cation and similar [7]. By the same token, psychiatric disturbances following basal ganglia lesions are not identical to the correspondent idiopathic syndrome; basal ganglia patients with psychiatric-like symptoms for example, do lack sadness and anxiety typical of neuropsychiatric diseases [20]. In conclusion, the thalamus and basal ganglia do not seem to be loci of mere retransmission of the cortical signals. They appear, instead, to be involved in higher order cognitive and behavioural functions. Crucial to the de®nition of subcortical cognition is, however, the exact knowledge of the type of neuronal processing that takes place in subcortical and cortical neurons. Although we still lack details on this, the complexity of subcortical nuclei seem to suggest their active role in complex behaviours. Until we learn more about functional peculiarities and informational ¯ows in subcortical structures no de®nite conclusion can be drawn. AcknowledgementsÐThis chapter has been prepared with the ®nancial help of the Consiglio Nazionale delle Ricerche and the Ministero della Ricerca Scienti®ca e Tecnologica, Italy.
REFERENCES 1. Bentivoglio, M., Aggleton, J. and Mishkin, M. The Thalamus and Memory Formation. In Handbook on Thalamus, M. Steriade, E.G. Jones, D.A. McCormick (Editors). Elsevier, Oxford, 1997, pp. 689±720. 2. Alexander, G. E., DeLong, R. M. and Strick, P. L., Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 1986, 9, 357±381. 3. Graybiel, A. M., Building action repertoires: memory and learning functions of the basal ganglia. Current Opinion in Neurobiology 1995, 5, 733±741. 4. Middleton, F. A. and Strick, P. L., Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994, 266, 458±461.
264
S. Aglioti
5. Partiot, A., Verin, M., Pillon, B., Teixeiraferreira, C., Agid, Y. and Dubois, B., Delayed response tasks in basal ganglia lesions in manÐfurther evidence for a striato-frontal cooperation in behavioural adaptation. Neuropsychologia 1996, 34, 709±721. 6. Alexander, M.P. Clinical-anatomical correlations of aphasia following predominantly subcortical lesions. In Handbook of Neuropsychology, vol. 2, F. Boller and J. Grafman (Editors). Elsevier, Amsterdam, 1989. 7. Bhatia, K. P. and Marsden, C. M., The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 1994, 117, 859±876. 8. Corbett, A., Bennet, H. and Kos, S., Cognitive dysfunction following subcortical infarction. Archives of Neurology 1994, 51, 999±1007. 9. Mega, M. S. and Alexander, M. P., Subcortical aphasia: the core pro®le of capsulostriatal infarction. Neurology 1994, 44, 1824±1829. 10. D'Esposito, M. and Alexander, M. P., Subcortical aphasia: distinct pro®les following left putaminal hemorrhage. Neurology 1995, 45, 38±41. 11. Weiller, C., Willmes, K., Reiche, W., Thron, A., Isensee, C. and Buell, U., The case of aphasia or neglect after striatocapsular infarction. Brain 1993, 116, 1509±1525. 12. Perani, D., Di Piero, V., Lucignani, G., Gilardi, M.C., Pantano, P. and Rossetti, C. et al.,, Remote eects of subcortical cerebrovascular lesions: A SPECT cerebral perfusion study. Journal Cerebral Blood Flow Metabolism 1988, 8, 560±567. 13. Kuroda, S., Houkin, K., Abe, H. and Mitsumori, K., Transient ipsilateral blood ¯ow reduction in the thalamus and cerebral cortex after pontine infarction. Neuroradiology 1996, 38, 239±242. 14. Guillery, R. W., Anatomical evidence concerning the role of the thalamus in corticocortical communication. Journal of Anatomy 1995, 187, 583±592. 15. Fietz, J., Petersen, S. E., Cheney, M. K. and Reichle, M. E., Impaired non-motor learning and error detection associated with cerebellar damage. Brain 1992, 115, 155±178. 16. Fietz, J., Cerebellar contributions to cognition. Neuron 1996, 16, 13±15. 17. Allen, G., Buxton, R. B., Wong, E. C. and Courchesne, E., Attentional activation of the cerebellum independent of motor involvement. Science 1997, 275, 1940±1943. 18. Glickstein, M., Motor skills but not cognitive tasks. Trends in Neuroscience 1993, 16, 450±451. 19. Pramstaller, P. P. and Marsden, C. D., The basal ganglia and apraxia. Brain 1996, 119, 319±340. 20. Dubois, B., Defontaines, B., Deweer, B., Malapani, C. and Pillon B. Cognitive and behavioral changes in patients with focal lesions of the basal ganglia. In Advances in Neurology, vol. 65, W.J. Weiner and A.E. Lang (Editors), Raven Press, New York, 1995. 21. Libman, R. B. and Wirkowski, E. J., Hypersexuality and strokeÐa role for the basal ganglia. Cerebrovascular Diseases 1996, 6, 111±113. 22. Macchi, G., Bentivoglio, M., Minciacchi, D. and Molinari, M., Trends in the anatomical organization and functional signi®cance of the mammalian thalamus. Italian Journal of Neurolological Sciences 1996, 17, 105±129. 23. Sherman, S. M. and Guillery, R. W., Functional organization of thalamocortical relays. Journal of Neurophysiology 1996, 76, 1367±1395. 24. Adams, N. C., Lozsadi, D. A. and Guillery, R. W., Complexities in the thalamocortical and corticothalamic pathways. European Journal of Neuroscience 1997, 9, 204±209. 25. Chung, C., Caplan, L. R., Han, W., Pessin, M. S., Lee, K. and Kim, J., Thalamic haemorrhage. Brain 1996, 119, 1873±1886. 26. Butters, N. and Stuss, D. Diencephalic amnesia. In Handbook of Neuropsychology, vol. 3, F. Boller and J. Grafman (Editors), Elsevier, Amsterdam, 1989. 27. Cramon, D., v Hebel, N. and Schuri, U., A contribution to the anatomical basis of thalamic amnesia. Brain 1985, 108, 993±1008. 28. Robinson, L. and Petersen, S., Pulvinar and visual salience. Trends in Neurosciences 1992, 15, 127±132. 29. Laberge, D. and Buchsbaum, M. S., Positron emission tomographic measurements of pulvinar activity during an attention task. The Journal of Neuroscience 1990, 10, 613±619. 30. Bougasslovsky, J., Regli, F. and Uske, A., Thalamic infarcts: clinical syndromes, etiology and prognosis. Neurology 1988, 38, 837±848. 31. Andreasen, N. C., Arndt, S., Swayze, V., Cizadlo, T., Flaum, M. and O'Leary, D. et al., Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994, 266, 294±298. 32. Buchsbaum, M. S., Someya, T., Teng, C. Y., Abel, L., Chin, S. and Naja®, A. et al., PET and MRI of the thallamus in never-medicated patients with schizophrenia. American Journal of Psychiatry 1996, 53, 191±199. 33. Andreasen, N. C., O'Leary, D. S., Cizadlo, T., Arndt, S., Rezai, K. and Boles Ponto, L. L. et al., Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefron-
Subcortical cognition
34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
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tal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the U.S.A. 1996, 93, 9985±9990. Cohen, B. M. and Wan, W. H., The thalamus as a site of action of antipsychotic drugs. American Journal of Psychiatry 1996, 153, 104±106. Dubois, B. and Pillon, B., Cognitive de®cits in Parkinson's disease. Journal of Neurology 1997, 244, 2± 8. Saint Cyr, J. A., Taylor, A. E. and Lang, A. E., Procedural learning and neostriatal dysfunction in man. Brain 1988, 111, 941±959. Knowlton, B. J., Mangels, J. A. and Squire, L. R., A neostriatal habit learning system in humans. Science 1996, 273, 1399±1402. Mendez, M. F., Adams, N. L. and Lewandowsli, K. S., Neurobehavioral changes associated with caudate lesions. Neurology 1989, 39, 349±354. Swedo, S. E., Schapiro, M. B., Grady, C. L., Cheslow, D. L., Leonard, H. L. and Kumar, A. et al., Cerebral glucose metabolism in childhood-onset obsessive±compulsive disorder. Archives of General Psychiatry 1989, 46, 518±523. Baxter, L. R. Jr, Schwartz, J. M., Bergman, K. S., Szuba, M. P., Guze, B. H. and Mazziotta, J. C. et al., Caudate glucose metabolic rate changes with both drug and behavioral therapy of obsessive±compulsive disorder. Archives of General Psychiatry 1992, 49, 681±689. Laplane, D., Levasseur, M., Pillon, B., Dubois, B., Baulac, M. and Mazoyer, B. et al.,Obsessive±compulsive and other behavioural changes with bilateral basal ganglia lesions. Brain 1989, 112, 699±725. Berthier, M. L., Kulisevsky, J., Gironell, A. and Heras, J. A., Obsessive±compulsive disorder associated with brain lesionsÐclinical phenomenology, cognitive function and anatomic correlates. Neurology 1996, 47, 353±361. Aylward, E. H., Harris, G. J., Hoehnsaric, R., Barta, P. E., Machlin, S. R. and Pearlson, G. D., Normal caudate nucleus in obsessive±compulsive disorder assessed by quantitative neuroimaging. Archives of General Psychiatry 1996, 53, 577±584. Hokama, H., Shenton, M. E., Nestor, P. G., Kikinis, R., Levitt, J. J. and Metcalf, D. et al., Caudate, putamen and globus pallidus volume in schizophreniaÐa quantitative MRI study. Psychiatry Research Neuroimaging 1995, 61, 209±229. Shioiri, T., Hamakawa, H., Kato, T., Murashita, J., Fujii, K. and Inubushi, T. et al., Proton magnetic resonance spectroscpy of the basal ganglia in patients with Schizophrenia-A preliminary report. Schizophrenia Research 1996, 22, 19±26. Gray, J. A., A general model of the limbic system and basal ganglia: Application to schizophrenia and obsessive±compulsive disorder. Revue Neurologique 1994, 150, 605±613. Hanes, K. R., Andrewes, D. G., Pantelis, C. and Chiu, E., Subcortical dysfunction in schizophreniaÐa comparison with Parkinson's disease and Huntington's disease. Schizophrenia Research 1996, 19, 121± 128.
J. Neurolinguistics, Vol. 10, No. 4, pp. 255±265, 1997 # 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0911-6044/97 $17.00 + 0.00 S0911-6044(97)00020-1
THE ROLE OF THE THALAMUS AND BASAL GANGLIA IN HUMAN COGNITION SALVATORE AGLIOTI* *Dipartimento di Scienze Neurologiche e della Visione, Sezione di Fisiologia Umana, Universita di Verona, Strada le Grazie, 8, I-37134, Verona, Italy AbstractÐCerebral lesions involving the thalamus or the basal ganglia can impair cognitive functions (e.g. language, memory, or attention) that were previously believed to be linked almost exclusively to cortical structures. These impairments are mostly evident when, in addition to nuclear lesions, there is an involvement of the subcortical white matter that includes bundles of ®bres for cortico-cortical and cortico-subcortical connections. Based on this result, it has been hypothesized that cognitive de®cits after subcortical lesions are due entirely to remote eects on select cortical targets. Thus, the notion of subcortical cognition has been questioned. However, since cortical lesions can have remote eects on their subcortical targets, the notion of cortical cognition can be challenged as well. The present article deals with the concept of subcortical cognition and reviews lesion studies hinting at a role for thalamus and basal ganglia in complex human behaviour. A proposal is made that the notion of large neural networks with both cortical and subcortical nodes may give a plausible interpretation of cognitive de®cits. # 1997 Elsevier Science Ltd. All rights reserved
INTRODUCTION
The cerebral cortex has been traditionally considered as the neural basis of human cognition. Comparatively recent studies have suggested a possible ``cognitive'' role of subcortical structures such as the thalamus, basal ganglia and cerebellum that were classically considered as linked mainly to sensory±motor functions. Extensive anatomic and physiological analyses of the neural circuitry of these structures suggest that they are well equipped to play a crucial role in motor, cognitive and complex behavioural functions [1±3]. For example, recent anatomical evidence has shown that basal ganglia and cerebellum not only send projections to the premotor and motor areas, but are also connected, via the thalamus, to higher order cortical areas [4, 5]. Moreover, a number of clinical reports have related subcortical lesions to complex cognitive and behavioural functions. It has been suggested, however, that the cognitive de®cits following subcortical lesions can be explained almost entirely as a hypofunction of disconnected cortical areas [6]. This hypothesis is based on two lines of evidence. Firstly, there is evidence to suggest that subcortical lesions aect cognitive functions mainly if concomitant with lesions to the paraventricular white matter [6±10]. Secondly, regional cerebral blood ¯ow studies have documented both cortical [11, 12] and cerebellar [11] areas of hypoperfusion in patients with subcortical stroke. Moreover, a transient ipsilateral hypoperfusion in the thalamus and cerebral cortex after a pontine infarct has Address for correspondence. Telephone: +39 45 8098134; Facsimile: +39 45 580881; Email: [email protected]. 255
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been reported [13]. This evidence, however, does not necessarily exclude the possibilty that subcortical nuclear structures play a crucial role in cognition. It is nothing but a truism that subcortical structures do not work in isolation and that a symptom related to their lesion may ensue from a disconnection of these structures from their cortical targets. This may turn out to be true also for cortical lesions since there are few, if any, complex operations in the brain not linked to large neuronal networks. Since the term subcortical has a morphological meaning, the lack of evidence for cortical lesions is sucient to credit the use of the term ``subcortical'' without any ambiguity. A major issue is to examine whether or not the type of neuronal processing that takes place in subcortical structures has to do with a mere transmission of information from and to the cortex. Were this the case, only a minor cognitive role for subcortical structures could be hypothesized. However, there are reasons to believe that neuronal processing in subcortical structures, such as the thalamus and basal ganglia, shows high levels of complexity [3, 14]. While there is evidence for cognitive and behavioural de®cits following lesions to thalamus and basal ganglia, the involvement of the human cerebellum in cognitive non-motor functions has been reported only very recently [15±17]. Moreover, authoritative students of cerebellar functions have cast doubts on such involvement [18]. Thus, this issue is at present much too controversial and will not be addressed in the present article. The present contribution is, instead, focused on the cognitive impairments consequent to focal damage of the thalamus and basal ganglia in humans. It is noteworthy, however, that subcortical lesions often involve the white matter deep to the cortex and adjacent the lateral ventricles. Therefore, the role of the peri- and paraventricular white matter in subcortical cognition should not be ignored [6]. Degenerative lesions involving subcortical structures (e.g. Parkinson's disease as a model of basal ganglia dysfunction or Korsako's syndrome as a model of thalamic dysfunction) are very complex and may not be an optimal model for relating a given symptom to its neural basis. Thus, degenerative lesions will be considered only marginally. Since other articles in this special issue concern the relationships between subcortical lesions and language, mainly non-linguistic areas of human cognition will be discussed in the following. By the same token, impairments in higher-order motor control (praxis) closely related to language are not considered (see [19] for review). SUBCORTICAL LESIONS AND COGNITION
There is clinical evidence to suggest that subcortical structures may be crucial for complex behaviours (e.g. bulimia or hypersexuality after basal ganglia lesions, [20, 21]). However, given the purpose of this contribution, such evidence will be considered only if closely related to cognition. THALAMUS
Anatomic and physiological circuitry Both the ventral and dorsal thalamus have a fairly complex anatomic and functional architecture [22, 23]. The ventral thalamus mainly consists of the thalamic reticular nucleus that receives aerent ®bres from the dorso-thalamo-cortical pathways and sends GABAergic inhibitory connections to the dorsal thalamus [23]. The thalamic
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reticular nucleus relies upon a variety of operational modes and is in a strategic position for modulating functional states such as alertness and sleep. The dorsal thalamus, i.e. the main mass from which cerebral cortex receives most of its subcortical aerents, consists of three main categories of nuclei, each related to a distinct set of functions [22]. The ®rst group, extrinsic or ``relay'' nuclei, have to do with primary sensory channels (ventro-posterior complex for somatosensation, lateral geniculate and medial geniculate nuclei for vision and audition, respectively), motor functions (ventralis anterior and ventralis lateralis that receive inputs from the basal ganglia), limbic inputs (anterior groups: anterodorsal, anteromedial, that are heavily connected to the limbic circuits). These structures transfer to the telencephalon information from pre-thalamic structures including sensory receptors, spinal cord, brainstem, cerebellum, basal ganglia, limbic system. The second nuclear group, referred to as intrinsic nuclei (mediodorsal, laterodorsal, lateroposterior and pulvinar), is the recipient of intrathalamic input and projects to association areas. The third group includes: (i) midline and anterior intralaminar nuclei that receive from multiple lower sources (brainstem, spinal cord, cerebellum) and send eerents to the rhinencephalon and basal ganglia; and (ii) posterior intralaminar nuclei that are believed to terminate densely on the basal ganglia and only sparsely on somatosensory, motor and premotor cortices [23]. From a functional point of view, two distinct types of thalamic nuclei are proposed [14]. ``First order nuclei'' receive primary aerent ®bres from ascending pathways and provide main paths to the cerebral cortex for information about what the external world is doing or the subcortical parts of the brain are doing. These nuclei receive cortico-thalamic aerents from pyramidal cells in cortical layer 6, which also send branches to the thalamic reticular nucleus and appear to have a modulatory function. ``Higher order nuclei'' receive most or all of their ``primary aerents'' from pyramidal cells in cortical layer 5 and also receive modulatory aerents from layer 6. It has been proposed that these nuclei are largely concerned with transmitting information about the output of one cortical area to another cortical area and that they are likely to play a key role in corticocortical communication and higher cortical functions [14]. To sum up, anatomic and physiological data suggest that the thalamus not only transfers information to the cortex but also has modulatory functions achieved through the capability of thalamic neurons to alternate electrophysiological properties from synchronized to desynchronized modes. Moreover, the great complexity of the thalamo-cortical and cortico-thalamic connections and the capability of thalamic neurons to combine, balance and discriminate, temporally and spatially pre-thalamic messages, is likely to give the thalamus integrative properties [24]. Thalamic networks tune the information appropriate for cortical processing preparing it for the complex operations performed at cortical level; these nets are an essential prerequisite for cortical mechanisms of arousal, perception and cognition. Lesion studies in humans Behavioural and cognitive de®cits following lesions con®ned to thalamic structures have been repeatedly reported. In a recent radiological-clinical study Chung et al. [25] attempted to relate neurocognitive de®cits and site and extent of lesions in a large sample of patients who had suered from thalamic stroke. The study reported that cognitive de®cits were most frequently in global and posterolateral lesions. In all cases
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lesions involved more than one nucleus and no conclusion about the cognitive role of single thalamus subsections can be drawn at present. Thalamus and memory The thalamus has long been known as a part of the mesiotemporal memory network and thus linked to explicit memory only. Recently, however, Bentivoglio et al. [1] assumed that the ventral anterior and the intralaminar thalamic nuclei, given their heavy connections with the striatum (see below), may play a role in implicit learning and memory (e.g. in acquisition of habits). This hypothesis has no experimental proof at present, but it may lead to future research and discoveries. Much more information on the relationships between the thalamus and explicit memory is available. In short, patients with bilateral mesial diencephalic lesions have extensive diculty in learning and retaining new information (both verbal and non verbal); unilateral thalamic lesions have shown that hemispheric specialisation extends to diencephalic structures [26]. This information, however, mainly comes from the study of Korsako's patients, where multiple thalamic and extrathalamic systems may be damaged. Isolate lesions of thalamic nuclei are dicult to place even under controlled experimental lesions and they are uncommon after spontaneous lesions in humans. A recent analysis of memory de®cits following focal thalamic lesions reports that dysfunctions of the medial thalamus (particular the dorsomedial nucleus) are likely to cause diencephalic amnesia [1]. Clinical evidence for a de®nite memory function of the anterior and laterodorsal thalamic nuclei is not clear-cut. Diencephalic amnesia is mostly severe after lesions extending to mammillary bodies and mammillo-thalamic tracts [26]. In view of this, it has been suggested that diencephalic amnesia is the pathological expression of a thalamic±mesiotemporal disconnection [27]. In any case, amnesic symptoms of diencephalic patients do not resemble either qualitatively or quantitatively the memory de®ciencies of patients with basal ganglia lesions [26]. Thalamus and visuo-spatial functions including attention Animal research and studies of functional anatomy in neurologically intact subjects suggest that the pulvinar has a crucial role in attentional processing [28, 29]. Lesion studies in humans indicate that after acute thalamic lesions, particularly after bilateral damage, patients may be initially comatose [26]. In early stages of recovery, alertness and attention can be severely impaired with ¯uctuations from moment to moment [26]. An attentional role for the dorsomedial nucleus has been postulated on the basis of its massive reciprocal connections with the prefrontal lobe. On the other hand, patients with a clear left-sided neglect, following thalamic lesions involving the dorsomedial nucleus, have been described [25, 26, 30]. Thalamus and psychiatric symptoms Confabulation, perseveration and reduplication symptoms may occur even years after the lesion. Patients with thalamic lesions may have diculties in arranging data in logical sequences and in other planning abilities. These patients are also highly susceptible to interference phenomena. Manic delirium and a frontal lobe-like syndrome have been reported in patients with paramedian infarction of the right thalamus [30]. Major personality and mood changes have also been reported. Thalamic patients have been described as apathetic, akinetic, withdrawn, abulic, unconcerned, euphoric, oc-
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casionally irritable and lacking spontaneity. Several aspects of these behavioural changes appear to be related to the lesional site: a lesion to dorsomedial±frontal connections seems to induce euphoria and lack of insight while the interruption of the anterior±cingulate projections is more likely to induce withdrawn behaviour and akinesia [26]. It has been suggested that some of the symptoms in acute schizophrenic patients may result from de®cits in the sensory ®ltering process at the level of the thalamus [31]. MRI analyses of structural alterations in the brain of patients with schizophrenia show speci®c regional abnormalities in the thalamus and adjacent white matter [31]. In keeping with this result are functional anatomy studies showing thalamic dysfunctions in schizophrenic patients. Buchsbaum et al. [32], for example, reported that patients with schizophrenia showed a diminished metabolic rate in the right posterior thalamus and the left anterior thalamus compared to control subjects. Moreover, schizophrenics presented a reduction of the size of the left anterior thalamus. In another recent PET study, Andreasen et al. [33] showed the activation of a prefronto-thalamo-cerebellar network when normal subjects recall complex narrative material. This same network resulted dysfunctional in schizophrenic patients. It may be relevant that the midline thalamic nuclei seem to be a site of action of antipsychotic drugs [34]. An abnormality in the thalamus and related circuitry may explain the diverse symptoms of schizophrenia parsimoniously because they could result from a defect in ®ltering or gating sensory input, which is one of the primary functions of the thalamus in the human brain [31]. BASAL GANGLIA
Anatomic and physiological circuitry The basal ganglia consist of ®ve interconnected subcortical grey masses, lateral to the thalamus, located at the inferior part of each cerebral hemisphere. The main mass consists of the caudate nucleus and putamen that share a telencephalic origin and together are called neostriatum. These nuclei, fused anteriorly, are composed of very similar cellular types and are the recipient structures of the basal ganglia. Neurochemical analyses showed that the neostriatum is organized in modules or patches that have some analogies with cortical columns. Striosomal patches, containing enkephalins and substance P, are embedded in a larger compartment called striatal matrix that contains acetylcholine and somatostatine. The striatum striosoma/matrix patchwork is better developed in caudate than in putamen and it may re¯ect a new addition in terms of evolution. Connectivity studies suggest that in spite of their intimate links, the putamen seems to be concerned primarily with motor control while the caudate seems to be involved in more complex functions [2]. The globus pallidus, derived from the diencephalon, is divided into external and internal segments. The substantia nigra is localized in the mesencephalon and consists of a pars compacta (dorsal, composed of dopaminergic neurons containing neuromelanin) and a pars reticulata (ventral, cytologically similar to the pallidum). The subthalamic nucleus is located below the thalamus at its junction with midbrain). Structure and connectivity of the basal ganglia The striatum receives a topographically organized glutaminergic input from the entire cortex; while the neocortical±striatal inputs go to the matrix (that in turn
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projects to the pallidum, substantia nigra and pars reticulata), allocortical±striatal inputs go to the striosomes (that project to the substantia nigra, pars compacta and thus in¯uence the dopaminergic pathway). The other input source to the striatum comes from the polisensory intralaminar thalamic nuclei. This thalamo-striatal input has some topography, the centromedian nucleus (that receives input from the motor cortex) mainly abutting the putamen and the centralis lateralis nucleus mainly abutting the caudate (thanks to this pathway the striatum receives sensory and higher-order information). The striatum sends its main output ®bres by means of pathways reaching, topographically, the internal pallidus and the substantia nigra, the pars reticulata that in turn projects to the ventro-lateral, ventral anterior, mediodorsal thalamic nuclei. The internal pallidus also projects to the centromedian thalamic nucleus. These strio-internal pallidal and strio-nigral pathways, called direct, are mediated by GABA and substance P and exert an inhibitory control on the thalamus. Through these thalamic connections, the basal ganglia appear to be inextricably linked to a high number of cortical areas. The striatum also sends output ®bres to the external pallidus that is reciprocally connected to the subthalamic nucleus (that in turn sends a glutamatergic input to the internal pallidus). Thus, the strio-externo-pallidal pathway, mediated by GABA and enkephalins, does not have direct connections with the thalamus and is called indirect. The arrangement of cortico-striatal±thalamo-cortical connections along multiple channels suggests a possibly parallel information processing in these structures. This novel notion has changed radically the classical view that basal ganglia simply integrate inputs from the entire cerebral cortex and deliver these signals via the ventrolateral thalamus to the motor cortex. Thus, in addition to the ``motor loop'' (mainly through the putamen) at least four additional complex circuits working in parallel with the motor circuit have been described [2]. These complex circuits in¯uence, mainly through the caudate, associative areas such as prefrontal lobes and appear to mediate higher-order functions such as spatial memory or complex behavioural choices [2]. Thus, at least some sectors of the basal ganglia are part of a highly dynamic system involved in adaptive control of action in the motor, planning and cognitive domains [3]. Lesion studies in humans Degenerative diseases (e.g. Parkinson's disease) may give clues to the normal functions of the basal ganglia. Dubois and Pillon [35], for example, reported that patients with Parkinson's disease have shown speci®c impairments, even in the early stages of the disease, which include de®cits of behavioural regulation in sorting or planning tasks, defective use of memory stores and impaired manipulation of internal representation of visuospatial stimuli. It may not be super¯uous to mention again that this disease involves multiple systems and therefore may not represent an optimal model for understanding basal ganglia functioning. The study of selective lesions may be a more useful approach although it should be kept in mind that, like the thalamus, spontaneous lesions of the basal ganglia typically involve more than one nucleus. However, thanks to the sophisticated imaging techniques currently available, it is possible to try and relate cognitive behaviour to select basal ganglia lesions. Thus, the best picture of
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the role of basal ganglia in subcortical cognition may come from the combination of information provided by both degenerative and lesion studies. Basal ganglia and memory Implicit or non cognitive memory includes not only the formation of speci®c stimulus-response connections but also complex memory processes such as visuomotor skills and rule or category learning. Patients with neostriatal dysfunction appear impaired in tasks belonging in these categories [36]. Knowlton et al. [37] reported that non-demented Parkinson's patients were unable to learn a probabilistic classi®cation task in spite of a preserved memory of the learning episode. By contrast, amnesic patients with ``hippocampal'' or ``diencephalic'' lesions could learn the task but had no memory of the learning episode. Clinical investigations also suggest that patients with basal ganglia lesions have problems with the activation of overlearned programs or routine procedures (e.g. writing, signing their name, typewriting). Patients with lesions to the caudate appear impaired in mirror reading and serial reaction time tasks, while patients with lesions to the putamen show de®cits in the rotor pursuit task [20]. The exact implication of this result is at present unclear. There are some suggestions that basal ganglia lesions, particularly when involving the caudate, aect tasks that rely upon explicit memory. A de®cit in memory retrieval has been reported. This impairment, however, seems to be related to a diculty in activating ecient retrieval strategies. Indeed, in patients with lesions to the caudate encoding and recognition processes are intact, despite a poor free recall [20]. Thus, the caudate is unlikely to have a autonomous key role in explicit memory. It can instead be part of a strio-pallido-cortical network for activation of conscious recall strategies. Basal ganglia and psychiatric symptoms Behavioural changes in patients with focal lesions to the basal ganglia are not uncommon. Patients may show psychic akinesia: they appear apathetic, unconcerned and their aective state is ¯attened. Such blank inactivity can be reversed by external stimulation. This behavioural pattern has been observed after lesions to the globus pallidus, caudate and lesions to the thalamus thus suggesting that the strio-pallidal thalamic complex may be part of a neural network related to behavioural activation [20]. In an extensive review on the behavioural and motor consequences of focal lesions to the basal ganglia, Bhatia and Marsden [7] reported that behavioural disturbances (mainly abulia) are rare after putaminal lesions, but prominent after lesions to the caudate nucleus. This evidence supports the involvement of the caudate in behavioural and cognitive functions. A true psychotic episode has been reported in a woman (she showed excessive fussiness about germs and heard voices) with lesions to the caudate nucleus [38]. Basal ganglia and obsessive±compulsive disorders (OCD) Focal lesions to the basal ganglia may induce stereotyped activities (e.g. repetition of mandatory sentences, coprolalia, repetitive movements of the ®ngers) and compulsions [20]. Functional anatomy studies suggest that in patients with OCD (where perseverative series of actions aict patients) there is an abnormal function in the anterior striatum as well as in the frontal and anterior cingulate areas of the cortex [39, 40]. Laplane et al. [41] reported that patients with lesions bilaterally involving the
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putamen and the globus pallidus, presented with a dysfunctional activation pattern (on PET imaging) of the prefrontal cortex, perchance as a result of the subcortical lesions. The main features were inertia and loss of drive in spite of preserved intellectual functions. Berthier et al. [42] investigated behavioural, cognitive and neuroimaging characteristics of patients with idiopathic OCD or with OCD consequent to focal brain lesions. The two groups had a comparable clinical phenomenology and pro®le of neuropsychological de®cits (de®cits of attention, intellectual function, memory, word retrieval and motor and executive functions). Neuroimaging in the acquired OCD group disclosed a variety of lesions involving the cerebral cortex (frontal, temporal, or cingulate regions), the basal ganglia, or both. Thus, structural damage to speci®c frontal±limbic±subcortical circuits may play an important role in the pathogenesis of acquired OCD. In contrast to the above studies, Aylward et al. [43] examined, with a standard MRI technique, volumes of the caudate nucleus and putamen in patients with adult-onset OCD and evaluated the function of the caudate nucleus by a quantitative, meta-analytic review of normalized data from functional neuroimaging studies in OCD patients. Patients did not demonstrate evidence for structural abnormalities of basal ganglia. No support for a relative caudate metabolic or perfusion dysfunction was found in the literature (although increased function in the frontal cerebral cortex was identi®ed). Thus, these authors deny that evidence for the involvement of basal ganglia in OCD is ®rmly established. Basal ganglia and schizophrenia Morphological abnormalities of caudate, putamen and globus pallidus in schizophrenic patients have been reported [44] and neurochemical changes in the left basal ganglia [45] hinted at the possible relationship between basal ganglia and schizophrenia perchance related to striato-limbic [46] or fronto-striatal connections. It has also been reported that, despite some similarities, the cognitive performance of patients with subcortical dysfunctions diered from that of schizophrenic patients: slowed thinking or impaired motor function, which are considered hallmarks of subcortical grey matter disease, were absent in schizophrenic patients who, in turn, showed poor performance on tests of executive function [47]. Thus, schizophrenic symptoms seem to be at least partially related to a pre-frontal dysfunction. Basal ganglia and frontal lobe like syndromes In spite of a global intellectual eciency within normal limits, patients with focal or degenerative lesions of basal ganglia often present with a dysexecutive syndrome that may result from a fundamental de®cit concerning allocation of attentional resources, temporal organisation of behaviour, elaboration of internal strategies [20]. Similar de®cits have been reported as a consequence of frontal lobe lesions, thus supporting anatomical evidence in favour of the relevance of the strio-frontal system for complex behaviours. A recent study suggests a dierent role for frontal lobe and striatum in behavioural adaptation. The frontal lobe would control the elaboration of new acts in association with inhibition of previously established ones, while the striatum would maintain new programmes until the action has been accomplished [5].
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DISCUSSION
There is compelling evidence suggesting that lesions involving the thalamus or the basal ganglia may induce dramatic changes in cognitive and behavioural domains [1, 3, 20]. However, there is some controversy on whether or not these eects are actually due to the subcortical lesion or to remote eects on the cerebral cortex. The often concomitant lesions to the subcortical white matter typically worsen the de®cit because they interrupt long range, cortico-cortical and cortico-subcortical connections. This may explain the multifarious symptoms following subcortical lesions. In any case, the notion of subcortical neuropsychological syndromes does not imply at all the absence of remote eects on the function of cortical structures. On the other hand, remote eects on distant cortical and subcortical regions are observable as a consequence of select cortical areas. Does this mean that we cannot use the term cortical for these lesions? A purely morphological acceptation of terms such as cortical or subcortical is not misleading. Complex cognitive and behavioural functions, however, are likely to be subserved by cortico-subcortical neural networks. In line with this hypothesis is the recent suggestion of a functional continuity or complementarity between subcortical structures and association areas of the cortex [35]. Indeed, both similarities and dierences in cognitive de®cits deriving from subcortical and cortical lesions are reported. For example, the frontal-lobe like syndrome following basal ganglia lesion is similar but not identical to the true frontal lobe syndrome. Although there is abulia in both cases, patients with basal ganglia lesions do not present the typical markers of prefrontal syndrome such as puerile, facetious, or irresponsible behaviour, lack of foresight, inability to delay grati®cation and similar [7]. By the same token, psychiatric disturbances following basal ganglia lesions are not identical to the correspondent idiopathic syndrome; basal ganglia patients with psychiatric-like symptoms for example, do lack sadness and anxiety typical of neuropsychiatric diseases [20]. In conclusion, the thalamus and basal ganglia do not seem to be loci of mere retransmission of the cortical signals. They appear, instead, to be involved in higher order cognitive and behavioural functions. Crucial to the de®nition of subcortical cognition is, however, the exact knowledge of the type of neuronal processing that takes place in subcortical and cortical neurons. Although we still lack details on this, the complexity of subcortical nuclei seem to suggest their active role in complex behaviours. Until we learn more about functional peculiarities and informational ¯ows in subcortical structures no de®nite conclusion can be drawn. AcknowledgementsÐThis chapter has been prepared with the ®nancial help of the Consiglio Nazionale delle Ricerche and the Ministero della Ricerca Scienti®ca e Tecnologica, Italy.
REFERENCES 1. Bentivoglio, M., Aggleton, J. and Mishkin, M. The Thalamus and Memory Formation. In Handbook on Thalamus, M. Steriade, E.G. Jones, D.A. McCormick (Editors). Elsevier, Oxford, 1997, pp. 689±720. 2. Alexander, G. E., DeLong, R. M. and Strick, P. L., Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 1986, 9, 357±381. 3. Graybiel, A. M., Building action repertoires: memory and learning functions of the basal ganglia. Current Opinion in Neurobiology 1995, 5, 733±741. 4. Middleton, F. A. and Strick, P. L., Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994, 266, 458±461.
264
S. Aglioti
5. Partiot, A., Verin, M., Pillon, B., Teixeiraferreira, C., Agid, Y. and Dubois, B., Delayed response tasks in basal ganglia lesions in manÐfurther evidence for a striato-frontal cooperation in behavioural adaptation. Neuropsychologia 1996, 34, 709±721. 6. Alexander, M.P. Clinical-anatomical correlations of aphasia following predominantly subcortical lesions. In Handbook of Neuropsychology, vol. 2, F. Boller and J. Grafman (Editors). Elsevier, Amsterdam, 1989. 7. Bhatia, K. P. and Marsden, C. M., The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 1994, 117, 859±876. 8. Corbett, A., Bennet, H. and Kos, S., Cognitive dysfunction following subcortical infarction. Archives of Neurology 1994, 51, 999±1007. 9. Mega, M. S. and Alexander, M. P., Subcortical aphasia: the core pro®le of capsulostriatal infarction. Neurology 1994, 44, 1824±1829. 10. D'Esposito, M. and Alexander, M. P., Subcortical aphasia: distinct pro®les following left putaminal hemorrhage. Neurology 1995, 45, 38±41. 11. Weiller, C., Willmes, K., Reiche, W., Thron, A., Isensee, C. and Buell, U., The case of aphasia or neglect after striatocapsular infarction. Brain 1993, 116, 1509±1525. 12. Perani, D., Di Piero, V., Lucignani, G., Gilardi, M.C., Pantano, P. and Rossetti, C. et al.,, Remote eects of subcortical cerebrovascular lesions: A SPECT cerebral perfusion study. Journal Cerebral Blood Flow Metabolism 1988, 8, 560±567. 13. Kuroda, S., Houkin, K., Abe, H. and Mitsumori, K., Transient ipsilateral blood ¯ow reduction in the thalamus and cerebral cortex after pontine infarction. Neuroradiology 1996, 38, 239±242. 14. Guillery, R. W., Anatomical evidence concerning the role of the thalamus in corticocortical communication. Journal of Anatomy 1995, 187, 583±592. 15. Fietz, J., Petersen, S. E., Cheney, M. K. and Reichle, M. E., Impaired non-motor learning and error detection associated with cerebellar damage. Brain 1992, 115, 155±178. 16. Fietz, J., Cerebellar contributions to cognition. Neuron 1996, 16, 13±15. 17. Allen, G., Buxton, R. B., Wong, E. C. and Courchesne, E., Attentional activation of the cerebellum independent of motor involvement. Science 1997, 275, 1940±1943. 18. Glickstein, M., Motor skills but not cognitive tasks. Trends in Neuroscience 1993, 16, 450±451. 19. Pramstaller, P. P. and Marsden, C. D., The basal ganglia and apraxia. Brain 1996, 119, 319±340. 20. Dubois, B., Defontaines, B., Deweer, B., Malapani, C. and Pillon B. Cognitive and behavioral changes in patients with focal lesions of the basal ganglia. In Advances in Neurology, vol. 65, W.J. Weiner and A.E. Lang (Editors), Raven Press, New York, 1995. 21. Libman, R. B. and Wirkowski, E. J., Hypersexuality and strokeÐa role for the basal ganglia. Cerebrovascular Diseases 1996, 6, 111±113. 22. Macchi, G., Bentivoglio, M., Minciacchi, D. and Molinari, M., Trends in the anatomical organization and functional signi®cance of the mammalian thalamus. Italian Journal of Neurolological Sciences 1996, 17, 105±129. 23. Sherman, S. M. and Guillery, R. W., Functional organization of thalamocortical relays. Journal of Neurophysiology 1996, 76, 1367±1395. 24. Adams, N. C., Lozsadi, D. A. and Guillery, R. W., Complexities in the thalamocortical and corticothalamic pathways. European Journal of Neuroscience 1997, 9, 204±209. 25. Chung, C., Caplan, L. R., Han, W., Pessin, M. S., Lee, K. and Kim, J., Thalamic haemorrhage. Brain 1996, 119, 1873±1886. 26. Butters, N. and Stuss, D. Diencephalic amnesia. In Handbook of Neuropsychology, vol. 3, F. Boller and J. Grafman (Editors), Elsevier, Amsterdam, 1989. 27. Cramon, D., v Hebel, N. and Schuri, U., A contribution to the anatomical basis of thalamic amnesia. Brain 1985, 108, 993±1008. 28. Robinson, L. and Petersen, S., Pulvinar and visual salience. Trends in Neurosciences 1992, 15, 127±132. 29. Laberge, D. and Buchsbaum, M. S., Positron emission tomographic measurements of pulvinar activity during an attention task. The Journal of Neuroscience 1990, 10, 613±619. 30. Bougasslovsky, J., Regli, F. and Uske, A., Thalamic infarcts: clinical syndromes, etiology and prognosis. Neurology 1988, 38, 837±848. 31. Andreasen, N. C., Arndt, S., Swayze, V., Cizadlo, T., Flaum, M. and O'Leary, D. et al., Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 1994, 266, 294±298. 32. Buchsbaum, M. S., Someya, T., Teng, C. Y., Abel, L., Chin, S. and Naja®, A. et al., PET and MRI of the thallamus in never-medicated patients with schizophrenia. American Journal of Psychiatry 1996, 53, 191±199. 33. Andreasen, N. C., O'Leary, D. S., Cizadlo, T., Arndt, S., Rezai, K. and Boles Ponto, L. L. et al., Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefron-
Subcortical cognition
34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
265
tal-thalamic-cerebellar circuitry. Proceedings of the National Academy of Sciences of the U.S.A. 1996, 93, 9985±9990. Cohen, B. M. and Wan, W. H., The thalamus as a site of action of antipsychotic drugs. American Journal of Psychiatry 1996, 153, 104±106. Dubois, B. and Pillon, B., Cognitive de®cits in Parkinson's disease. Journal of Neurology 1997, 244, 2± 8. Saint Cyr, J. A., Taylor, A. E. and Lang, A. E., Procedural learning and neostriatal dysfunction in man. Brain 1988, 111, 941±959. Knowlton, B. J., Mangels, J. A. and Squire, L. R., A neostriatal habit learning system in humans. Science 1996, 273, 1399±1402. Mendez, M. F., Adams, N. L. and Lewandowsli, K. S., Neurobehavioral changes associated with caudate lesions. Neurology 1989, 39, 349±354. Swedo, S. E., Schapiro, M. B., Grady, C. L., Cheslow, D. L., Leonard, H. L. and Kumar, A. et al., Cerebral glucose metabolism in childhood-onset obsessive±compulsive disorder. Archives of General Psychiatry 1989, 46, 518±523. Baxter, L. R. Jr, Schwartz, J. M., Bergman, K. S., Szuba, M. P., Guze, B. H. and Mazziotta, J. C. et al., Caudate glucose metabolic rate changes with both drug and behavioral therapy of obsessive±compulsive disorder. Archives of General Psychiatry 1992, 49, 681±689. Laplane, D., Levasseur, M., Pillon, B., Dubois, B., Baulac, M. and Mazoyer, B. et al.,Obsessive±compulsive and other behavioural changes with bilateral basal ganglia lesions. Brain 1989, 112, 699±725. Berthier, M. L., Kulisevsky, J., Gironell, A. and Heras, J. A., Obsessive±compulsive disorder associated with brain lesionsÐclinical phenomenology, cognitive function and anatomic correlates. Neurology 1996, 47, 353±361. Aylward, E. H., Harris, G. J., Hoehnsaric, R., Barta, P. E., Machlin, S. R. and Pearlson, G. D., Normal caudate nucleus in obsessive±compulsive disorder assessed by quantitative neuroimaging. Archives of General Psychiatry 1996, 53, 577±584. Hokama, H., Shenton, M. E., Nestor, P. G., Kikinis, R., Levitt, J. J. and Metcalf, D. et al., Caudate, putamen and globus pallidus volume in schizophreniaÐa quantitative MRI study. Psychiatry Research Neuroimaging 1995, 61, 209±229. Shioiri, T., Hamakawa, H., Kato, T., Murashita, J., Fujii, K. and Inubushi, T. et al., Proton magnetic resonance spectroscpy of the basal ganglia in patients with Schizophrenia-A preliminary report. Schizophrenia Research 1996, 22, 19±26. Gray, J. A., A general model of the limbic system and basal ganglia: Application to schizophrenia and obsessive±compulsive disorder. Revue Neurologique 1994, 150, 605±613. Hanes, K. R., Andrewes, D. G., Pantelis, C. and Chiu, E., Subcortical dysfunction in schizophreniaÐa comparison with Parkinson's disease and Huntington's disease. Schizophrenia Research 1996, 19, 121± 128.