Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems

Disconnection syndromes were originally conceptualized as a disruption of communication between different cerebral cortical areas. Two developments mandate a re-evaluation of this notion. First, we present a synopsis of our anatomical studies in monkey elucidating principles of organization of cerebral cortex. Efferent fibers emanate from every cortical area, and are directed with topographic precision via association fibers to ipsilateral cortical areas, commissural fibers to contralateral cerebral regions, striatal fibers to basal ganglia, and projection subcortical bundles to thalamus, brainstem and/or pontocerebellar system. We note that cortical areas can be defined by their patterns of subcortical and cortical connections. Second, we consider motor, cognitive and neuropsychiatric disorders in patients with lesions restricted to basal ganglia, thalamus, or cerebellum, and recognize that these lesions mimic deficits resulting from cortical lesions, with qualitative differences between the manifestations of lesions in functionally related areas of cortical and subcortical nodes. We consider these findings on the basis of anatomical observations from tract tracing studies in monkey, viewing them as disconnection syndromes reflecting loss of the contribution of subcortical nodes to the distributed neural circuits. We introduce a new theoretical framework for the distributed neural circuits, based on general, and specific, principles of anatomical organization, and on the architecture of the nodes that comprise these systems. We propose that neural architecture determines function, i.e., each architectonically distinct cortical and subcortical area contributes a unique transform, or computation, to information processing; anatomically precise and segregated connections between nodes define behavior; and association fiber tracts that link cerebral cortical areas with each other enable the cross-modal integration required for evolved complex behaviors. This model enables the formulation and testing of future hypotheses in investigations using evolving magnetic resonance imaging techniques in humans, and in clinical studies in patients with cortical and subcortical lesions.     

Functional MRI assessment of orofacial articulators: neural correlates of lip, jaw, larynx, and tongue movements

Compared with complex coordinated orofacial actions, few neuroimaging studies have attempted to determine the shared and distinct neural substrates of supralaryngeal and laryngeal articulatory movements when performed independently. To determine cortical and subcortical regions associated with supralaryngeal motor control, participants produced lip, tongue and jaw movements while undergoing functional magnetic resonance imaging (fMRI). For laryngeal motor activity, participants produced the steady-state/i/vowel. A sparse temporal sampling acquisition method was used to minimize movement-related artifacts. Three main findings were observed. First, the four tasks activated a set of largely overlapping, common brain areas: the sensorimotor and premotor cortices, the right inferior frontal gyrus, the supplementary motor area, the left parietal operculum and the adjacent inferior parietal lobule, the basal ganglia and the cerebellum. Second, differences between tasks were restricted to the bilateral auditory cortices and to the left ventrolateral sensorimotor cortex, with greater signal intensity for vowel vocalization. Finally, a dorso-ventral somatotopic organization of lip, jaw, vocalic/laryngeal, and tongue movements was observed within the primary motor and somatosensory cortices using individual region-of-interest (ROI) analyses. These results provide evidence for a core neural network involved in laryngeal and supralaryngeal motor control and further refine the sensorimotor somatotopic organization of orofacial articulators.     

Functional anatomy of thalamus and basal ganglia

THALAMUS: The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts (the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus). The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) project to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the "correct" input, while at the same time suppressing irrelevant information. Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the thalamic functions affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion can develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterised by contralateral anaesthesia (or hypaesthesia), contralateral weakness, ataxia and, often, persistent spontaneous pain. BASAL GANGLIA: Basal ganglia form a major centre in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). Basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well. The striatum (caudate nucleus, putamen and nucleus accumbens) receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas (prefrontal, premotor and supplementary motor areas) which are concerned with motor planning. These circuits: (i) have an important regulatory influence on cortex, providing information for both automatic and voluntary motor responses to the pyramidal system; (ii) play a role in predicting future events, reinforcing wanted behaviour and suppressing unwanted behaviour, and (iii) are involved in shifting attentional sets and in both high-order processes of movement initiation and spatial working memory. Basal ganglia-thalamo-cortical circuits maintain somatotopic organisation of movement-related neurons throughout the circuit. These circuits reveal functional subdivisions of the oculomotor, prefrontal and cingulate circuits, which play an important role in attention, learning and potentiating behaviour-guiding rules. Involvement of the basal ganglia is related to involuntary and stereotyped movements or paucity of movements without involvement of voluntary motor functions, as in Parkinson's disease, Wilson's disease, progressive supranuclear palsy or Huntington's disease. The symptoms differ with the location of the lesion. The commonest disturbances in basal ganglia lesions are abulia (apathy with loss of initiative and of spontaneous thought and emotional responses) and dystonia, which become manifest as behavioural and motor disturbances, respectively.     

Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways

The striatum, the primary site of degeneration in Huntington's disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. Diffusion Tensor Imaging (DTI) tractography was used to identify connections between the striatum and seven major cortical regions in 12 HD patients and 14 matched controls. The striatum of both groups was parcellated into subregions based on connectivity with the cerebral cortex. Volumetric and DTI microstructural measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) were obtained within each subregion and compared statistically between groups. Tractography demonstrated the topographic organization of cortical connections in the striatum of both controls and HD patients. In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD.     

Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury

The plasticity of sensorimotor systems in mammals underlies the capacity for motor learning as well as the ability to relearn following injury. Spinal cord injury, which both deprives afferent input and interrupts efferent output, results in a disruption of cortical somatotopy. While changes in corticospinal axons proximal to the lesion are proposed to support the reorganization of cortical motor maps after spinal cord injury, intracortical horizontal connections are also likely to be critical substrates for rehabilitation-mediated recovery. Intrinsic connections have been shown to dictate the reorganization of cortical maps that occurs in response to skilled motor learning as well as after peripheral injury. Cortical networks incorporate changes in motor and sensory circuits at subcortical or spinal levels to induce map remodeling in the neocortex. This review focuses on the reorganization of cortical networks observed after injury and posits a role of intracortical circuits in recovery.     

Mapping the basal ganglia: fMRI evidence for somatotopic representation of face, hand, and foot

OBJECTIVE: To noninvasively investigate the somatotopy of the basal ganglia in humans. METHODS: Functional MRI, 1.5-T, was performed on six normal right-handed volunteers during simple acoustically paced motor tasks involving the right hand, foot, and face. RESULTS: In a single-subject analysis, statistical parametric maps showed overlapping activation extending along the anteroposterior extent of the left lentiform nucleus (LLN) for the hand, foot, and face representations. Within the LLN, the centers of gravity of each body part, reflecting both the extent and gradient of activation, were all located in the retrocommissural portion of the putamen. Their spatial relationship followed a similar pattern across subjects-face was medial to toes and fingers, toes were dorsal and rostral to fingers. CONCLUSIONS: The somatotopic organization of hand, face, and foot representation in the human lentiform nucleus suggests a triangular pattern, rather than the linear pattern seen in primate studies. The overlap observed between the distinct body parts differs from the cortical sensorimotor representation, indicating a different organizational concept of the basal ganglia.     

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.     

Somatotopy in the Human Motor Cortex Hand Area. A High-Resolution Functional MRI Study

Fine-scale somatotopic encoding in brain areas devoted to sensorimotor processing has recently been questioned by functional neuroimaging studies which suggested its absence within the hand area of the human primary motor cortex. We re-examined this issue by addressing somatotopy both in terms of functional segregation and of cortical response preference using oxygenation-sensitive magnetic resonance imaging at high spatial resolution. In a first step, spatial representations of self-paced isolated finger movements were mapped by using motor rest as a control state. A subsequent experimental design studied the predominance of individual finger movements by using contrasting finger movements as the control task. While the first approach confirmed previous reports of extensive overlap in spatial representations, the second approach revealed foci of differential activation which displayed an orderly mediolateral progression in accordance with the classical cortical motor homunculus. We conclude that somatotopy within the hand area of the primary motor cortex does not present as qualitative functional segregation but as quantitative predominance of certain movement or digit representation embedded in an overall joint hand area.     

Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology

Summary. Catatonia was originally described as a psychomotor syndrome in the 19^th century by Kahlbaum including motor, affective and behavioral symptoms. Later, at the beginning of the 20th century, catatonia was rather considered as the motoric manifestation of schizophrenia. Accordingly, neuropathological research focused predominantly on those neuroanatomical substrates, i.e. the basal ganglia being primarily involved in the generation of movements. Even though some authors observed minor alterations in the basal ganglia, consistent findings in these subcortical structures could not be obtained. Since neuroleptics can induce catatonic-like symptoms i.e. neuroleptic malignant syndrome (NMS), there has been a recent re-emergence in clinical and scientific interest in catatonia. However, exact psychopathological and pathophysiological characterization of both NMS and catatonia remains unclear. Clinically, catatonia and NMS show more or less similar motor symptoms i.e. akinesia. These may be accounted for by dysregulation in cortical-subcortical circuits between motor/premotor cortex and basal ganglia i.e. the so-called “motor loop”. While in NMS the “motor loop” may be dysregulated by neuroleptic blockade of subcortical striatal D-2 receptors one may rather assume cortical gaba-ergic alteration in catatonia. The premotor/motor cortex and consecutively the “motor loop” may be dysregulated by gaba-ergic abnormalities in orbitofrontal cortex. Gaba-ergic cortical dysfunction may account for affective and behavioural abnormalities in catatonia which cannot be observed as such in NMS. Consequently, one may characterize catatonia as a cortical “psychomotor syndrome” while NMS may rather be regarded as subcortical “motor syndrome”. Received January 10, 2002; accepted May 15, 2002 Published online July 26, 2002 Author's address: G. Northoff, MD, PhD, PhD, Harvard University, Beth Israel Deaconnes Medical Center, Department of Behavioral Neurology, Kirstein Building KS 454, 330 Brookline Avenue, 02215 Boston, Ma, USA, e-mail: gnorthof@caregroup.harvard.edu     

Functional anatomy of the basal ganglia: Limbic aspects

IntroductionThe basal ganglia (BG) have been implicated in different processes that control action such as the control of movement parameters but also in processing cognitive and emotional information from the environment. Here, we review existing anatomical data on the interaction between the BG and the limbic system that support implication of the BG in limbic functions.State of the artThe BG form a system that is fairly different from the limbic system, but have strong ties, both anatomical and functional, to the latter. Different models have been proposed. In the parallel model, five segregated circuits from the frontal cortex are individualized and terminate in different regions of the BG and thalamus, before projecting back to their cortical area of origin. Based on the extrafrontal cortical projections, another model has been proposed. It subdivides the cortico-striatal projection into three functional territories: limbic, associative and sensorimotor. In a third spiral model, propagation is possible between limbic information processed by the most medial striatal neurons to motor information processed by the most lateral neurons.PerspectivesThree main levels of interaction between the BG system and the limbic system are considered. (1) The BG receive direct afferences from several structures associated with the limbic system. Limbic cortical areas project to the striatum, of which the internal architecture is particularly complex, with significant cross-species differences: a compartmental striosome/matrix subdivision described mainly in primates, and a core/shell topographic subdivision of the nucleus accumbens more sharply marked in rodents. (2) Projections from the amygdala form a patchy dorso-ventral progressive gradient in the nucleus accumbens and ventral caudate. (3) Both shell and striosomes receive limbic information from cortical and subcortical limbic structures and project to the dopaminergic neurons of the substantia nigra pars compacta, which in turn modulates their activity. (4) There is a significant overlap between the ventral portions of the BG, nucleus accumbens and ventral pallidum, and the ventral subcortical structures of the limbic system, extended amygdala and nucleus basalis.ConclusionImportant interactions exist between the limbic system and the BG system but questions remain about the role that this information plays in the functional organisation of this system. Is limbic information processed separately in the BG, or is it integrated to motor and cognitive information? Do pathological conditions such as obsessive-compulsive disorders or Tourette syndrome result from abnormal afferent limbic input to the BG or abnormal processing within the BG?     

The basal ganglia: a neural network with more than motor function

The basal ganglia is a group of subcortical nuclei involved in motor control, cognition, and emotion. Basal ganglia disorders are manifested by abnormal movement and a number of neuropsychiatric disorders. Basal ganglia nuclei are organized into sensorimotor, associative, and limbic territories based on their connectivity and function. The caudate nucleus, putamen, and subthalamic nucleus comprise the input nuclei of the basal ganglia. The internal segment of globus pallidus and substantia nigra reticulata are the output nuclei. The input and output nuclei are interconnected by direct and indirect pathways. The cerebral cortex, basal ganglia, and thalamus communicate with each other via closed (segregated) parallel as well as open (split) loops. Recent anatomic, functional, and clinical data have necessitated modifications in the classical models of local connectivity between input and output nuclei of the basal ganglia as well as in the corticobasal ganglia-thalamus-cortical loops.     

Predicting auditory feedback control of speech production from subregional shape of subcortical structures

Although a growing body of research has focused on the cortical sensorimotor mechanisms that support auditory feedback control of speech production, much less is known about the subcortical contributions to this control process. This study examined whether subregional anatomy of subcortical structures assessed by statistical shape analysis is associated with vocal compensations and cortical event‐related potentials in response to pitch feedback errors. The results revealed significant negative correlations between the magnitudes of vocal compensations and subregional shape of the right thalamus, between the latencies of vocal compensations and subregional shape of the left caudate and pallidum, and between the latencies of cortical N1 responses and subregional shape of the left putamen. These associations indicate that smaller local volumes of the basal ganglia and thalamus are predictive of slower and larger neurobehavioral responses to vocal pitch errors. Furthermore, increased local volumes of the left hippocampus and right amygdala were predictive of larger vocal compensations, suggesting that there is an interplay between the memory‐related subcortical structures and auditory‐vocal integration. These results, for the first time, provide evidence for differential associations of subregional morphology of the basal ganglia, thalamus, hippocampus, and amygdala with neurobehavioral processing of vocal pitch errors, suggesting that subregional shape measures of subcortical structures can predict behavioral outcome of auditory‐vocal integration and associated neural features. Hum Brain Mapp 39:459–471, 2018. © 2017 Wiley Periodicals, Inc.     

Breakdown of the affective‐cognitive network in functional dystonia

Previous studies suggested that brain regions subtending affective‐cognitive processes can be implicated in the pathophysiology of functional dystonia (FD). In this study, the role of the affective‐cognitive network was explored in two phenotypes of FD: fixed (FixFD) and mobile dystonia (MobFD). We hypothesized that each of these phenotypes would show peculiar functional connectivity (FC) alterations in line with their divergent disease clinical expressions. Resting state fMRI (RS‐fMRI) was obtained in 40 FD patients (12 FixFD; 28 MobFD) and 43 controls (14 young FixFD‐age‐matched [yHC]; 29 old MobFD‐age‐matched [oHC]). FC of brain regions of interest, known to be involved in affective‐cognitive processes, and independent component analysis of RS‐fMRI data to explore brain networks were employed. Compared to HC, all FD patients showed reduced FC between the majority of affective‐cognitive seeds of interest and the fronto‐subcortical and limbic circuits; enhanced FC between the right affective‐cognitive part of the cerebellum and the bilateral associative parietal cortex; enhanced FC of the bilateral amygdala with the subcortical and posterior cortical brain regions; and altered FC between the left medial dorsal nucleus and the sensorimotor and associative brain regions (enhanced in MobFD and reduced in FixFD). Compared with yHC and MobFD patients, FixFD patients had an extensive pattern of reduced FC within the cerebellar network, and between the majority of affective‐cognitive seeds of interest and the sensorimotor and high‐order function (“cognitive”) areas with a unique involvement of dorsal anterior cingulate cortex connectivity. Brain FC within the affective‐cognitive network is altered in FD and presented specific features associated with each FD phenotype, suggesting an interaction between brain connectivity and clinical expression of the disease.     

Parkinson's disease patients show reduced cortical‐subcortical sensorimotor connectivity

Reduced dopamine input to cortical and subcortical brain structures, particularly those in the sensorimotor network, is a hallmark of Parkinson's disease (PD). The extent to which dopamine dysfunction affects connectivity within this and other brain networks remains to be investigated. The purpose of this study was to measure anatomical and functional connectivity in groups of PD patients and controls to determine whether connectivity deficits within the cortico–basal ganglia thalamocortical system could be attributed to PD, particularly in sensorimotor connections. A neuroimaging paradigm involving diffusion‐weighted magnetic resonance imaging (MRI) and resting‐state functional MRI was implemented in a large cohort of PD patients and control subjects. Probabilistic tractography and functional correlation analyses were performed to map connections between brain structures and to derive indices of connectivity that were then used to compare groups. Anatomical connectivity deficits were demonstrated in PD patients, specifically for sensorimotor connections. Functional deficits were also found in some of the same connections. In addition, functional connectivity was found to increase in associative and limbic connections in PD patients compared with controls. This study lends support to findings regarding the dysfunction of the sensorimotor circuit in PD. As deficits in anatomical and functional connectivity within this circuit were in some cases concordant in PD patients, a possible link between brain structure and function is suggested. Increases in functional connectivity in other cortico–basal ganglia thalamocortical circuits may be indicative of compensatory effects in response to system deficits elsewhere. © 2012 Movement Disorder Society     

Parietofrontal circuits in goal-oriented behaviour

Parietal and frontal cortical areas play important roles in the control of goal-oriented behaviour. This review examines how signal processing in the parietal and frontal eye fields is involved in coding and storing space, directing attention and processing the sensorimotor transformation for saccades. After a survey of the functional specialization of these areas in monkeys, we discuss homologous regions in the human brain in terms of topographic organization, storage capacity, target selection, spatial remapping, reference frame transformations and effector specificity. The overall picture suggests that bottom-up sensory, top-down cognitive signals and efferent motor signals are integrated in dynamic sensorimotor maps as part of a functionally flexible parietofrontal network. Neuronal synchronization in these maps may be instrumental in amplifying behaviourally relevant representations and setting up a functional pathway to route information in this parietofrontal circuit.     

Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson's disease

Parkinson's disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and synchronized dynamics of subcortical areas in Parkinson's disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN) and electroencephalograms (EEGs) from the scalp in parkinsonian patients, and analysed the correlation between the time courses of the spike–LFP synchronization and inter‐electrode EEG synchronization. We found the (non‐invasively obtained) time course of the synchrony strength between EEG electrodes and the (invasively obtained) time course of the synchrony between spiking units and LFP in STN to be weakly, but significantly, correlated with each other. This correlation is largest for the bilateral motor EEG synchronization, followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinson's disease: not only may synchronization be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially a more global functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way, causing correlations between changes in synchrony strength in the two regions.     

Temporal dynamics of cortical and subcortical responses to apomorphine in Parkinson disease: an H2(15)O PET study

H2(15)O positron emission tomography (PET) was used to study the temporal course of central nervous system (CNS) responses to apomorphine in patients with idiopathic Parkinson disease (PD). Agonist-induced changes in regional cerebral blood flow (rCBF) were evaluated within corticostriatal-thalamocortical circuits as well as in regions that extend beyond the standard pathophysiological model for PD. Compared with controls, rCBF was increased in PD patients in subcortical regions including the basal ganglia and cerebellum and both increased and decreased in prefrontal, parietal, sensorimotor, and paralimbic cortical areas. Apomorphine reversed many of these effects and had widespread effects throughout the brain. We evaluated the effects of apomorphine as they changed over time, comparing rCBF before the motor response and at later times when the motor response was maximal. Apomorphine's effects on functional connectivity also changed over time; activity in the ventrolateral thalamus was coupled with that in the SMA and cerebellum at the time of maximum motor response, but not at 45 seconds. Apomorphine affected rCBF in regions commonly considered part of the pathophysiological model of PD (eg, basal ganglia, thalamus, SMA), and other effects were seen in regions outside of the model (eg, cerebellum and superior parietal lobule). Results are discussed in light of this model.     

Frontal-striatal circuit functions: context, sequence, and consequence.

The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinson's disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms.     

Pathophysiology of Parkinson's disease

Parkinson's disease (PD) has classically been considered a disease of motor dysfunction, but it also includes psychiatric symptoms. To better understand the symptoms and signs that accompany PD, the interrelationships of deep brain structures and cortical areas involved with this neurodegenerative disease must be investigated.Current models of basal ganglia/cortical physiology attempt to integrate motor and nonmotor physiology and describe the pathophysiology attributable to PD. The cortical areas comprising basal ganglia/cortical loops include frontal structures involved in motor program as well as more prefrontal structures likely subserving non-motor functions such as cognition. The etiology of PD is not clear, but studies have implicated oxidative stress from exogenous stressors or endogenous neurotoxins. A large number of PD patients have been found to exhibit mitochondrial dysfunction. Lewy bodies are seen within dopaminergic and other neuronal populations affected in PD, and they stain positive for ubiquitin and alpha-synuclein. The small percentage of familial PD has often been found to coincide with dominantly inherited mutations in the gene for alpha-synuclein, or with the recessive gene mutation for parkin, which is involved in the ubiquitination pathway. Selected neuronal populations are affected in PD, and the neurodegeneration may include dopaminergic neurons outside the substantia nigra pars compacta, as well and non-dopaminergic neurons. The loss of these neuronal populations within the basal ganglia-frontal circuits can have a profound effect upon the motor and neurobehavioral symptoms in PD. L-dopa remains the most effective pharmacologic therapy for PD, however as the disease progresses, the drug loses its efficacy and troublesome sideeffects often occur. The renewal of surgical interventions for PD has increased the insight into the pathophysiology of PD,and surgical lesions have shown that motor and cognitive fronto-subcortical circuits are seemingly segregated in patients with PD. Investigation into these circuits helps provides models underlying motor and cognitive pathophysiology of PD.     

Functional reorganization of the brain in recovery from striatocapsular infarction in man.

We used positron emission tomography (PET) to study organizational changes in the functional anatomy of the brain in 10 patients following recovery from striatocapsular motor strokes. Comparisons of regional cerebral blood flow maps at rest between the patients and 10 normal subjects revealed significantly lower regional cerebral blood flow in the basal ganglia, thalamus, sensorimotor, insular, and dorsolateral prefrontal cortices, in the brainstem, and in the ipsilateral cerebellum in patients, contralateral to the side of the recovered hand. These deficits reflect the distribution of dysfunction caused by the ischemic lesion. Regional cerebral blood flow was significantly increased in the contralateral posterior cingulate and premotor cortices, and in the caudate nucleus ipsilateral to the recovered hand. During the performance of a motor task by the recovered hand, patients activated the contralateral cortical motor areas and ipsilateral cerebellum to the same extent as did normal subjects. However, activation was greater than in normal subjects in both insulae; in the inferior parietal (area 40), prefrontal and anterior cingulate cortices; in the ipsilateral premotor cortex and basal ganglia; and in the contralateral cerebellum. The pattern of cortical activation was also abnormal when the unaffected hand, contralateral to the hemiplegia, performed the task. We showed that bilateral activation of motor pathways and the recruitment of additional sensorimotor areas and of other specific cortical areas are associated with recovery from motor stroke due to striatocapsular infarction. Activation of anterior and posterior cingulate and prefrontal cortices suggests that selective attentional and intentional mechanisms may be important in the recovery process. Our findings suggest that there is considerable scope for functional plasticity in the adult human cerebral cortex.