Functional models of movement disorders of basal ganglia origin and effects of functional neurosurgery]

The rate model regarding the development of movement disorders of basal ganglia origin suggests that hyperkinetic and hypokinetic disorders occur as a result of changes in the firing rates in the GPi and SNr, which in turn suppress thalamocortical output. Dopamine depletion in Parkinson's disease increases basal ganglia output, then decreases thalamocortical output, leading to bradykinesia. This model, however, cannot explain a lack of deterioration of parkinsonian signs following thalamic coagulation surgery. Instead of the rate model, the beta oscillation hypothesis has been proposed, explaining that synchronized oscillation in the beta frequency in the basal ganglia disturbs initiation of voluntary movement. We observed that effective high-frequency STN stimulation in parkinsonian monkeys was associated with increase in the firing rate and the pattern shift from irregular burst firing to regular high-frequency firing in the projecting sites. High-frequency neural activation by deep brain stimulation is supposed to cancel lower frequency oscillation including beta oscillation, leading to improvement of bradykinesia. Our observation supports the significance of the neural activity pattern, rather than the tonic activity level, in the development of movement disorders. The rate model cannot explain the improvement of ballismus and chorea by pallidotomy because pallidotomy increases the disinhibition of the thalamocortical projection, which should increase the movements. We observed repetitive bursts or pauses of neuronal firing of the globus pallidus synchronized to ballistic movements in patients with hemiballism or chorea, suggesting that phasic neuronal driving in the basal ganglia is important as their pathophysiology.     

Primate models of movement disorders of basal ganglia origin.

Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorders (of which Parkinson's disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntington's disease and hemiballismus) at the other. Both extremes of this movement disorder spectrum can be accounted for by postulating specific disturbances within the basal ganglia-thalamocortical 'motor' circuit. In this paper, Mahlon DeLong describes the changes in neuronal activity in the motor circuit in animal models of hypo- and hyperkinetic disorders.     

Functional imaging for disorders of basal ganglia]

The nigrostriatal dopaminergic function and regional glucose metabolism were evaluated in patients suffering from various disorders of basal ganglia by using positron emission tomography with 18F-dopa and 18F-FDG, respectively. The 18F-dopa uptake in the striatum (the caudate head and the putamen) decreased in patients with Parkinson's disease but was relatively unaffected in the caudate. The cerebral glucose metabolism was normal in patients with Parkinson's disease. The 18F-dopa uptake in the striatum also decreased in cases of multiple system atrophy and progressive supranuclear palsy, but there was no difference in the uptake between the caudate and the putamen. The glucose metabolism decreased in the cerebral cortices and the striatum: this finding was also different from those of Parkinson's disease. A normal 18F-dopa uptake with a markedly decreased striatal glucose metabolism was observed in cases of Huntington's disease. The 18F-dopa uptake increased and the glucose metabolism was normal in cases of idiopathic dystonia. Various patterns of 18F-dopa uptake and glucose metabolism were thus observed in the various disorders of basal ganglia. These results suggest that the measurements of the 18F-dopa uptake and glucose metabolism would be useful for evaluating the function of the basal ganglia in various disorders of basal ganglia.     

The functional anatomy of basal ganglia disorders

Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.     

Paradoxes of functional neurosurgery: Clues from basal ganglia recordings

Deep brain stimulation (DBS) can be remarkably effective in treating movement disorders such as Parkinson's disease, dystonia, and essential tremor. Yet these effects remain essentially unexplained, even paradoxical. Equally challenging is the fact that DBS of motor targets in the basal ganglia appears to reverse abnormalities of movement without any obvious deleterious effects on remaining aspects of movement. Here, we explore the extent to which the noisy signal hypothesis might help solve some of these apparent paradoxes. Essentially the hypothesis, first tentatively advanced by Marsden and Obeso (1994), suggests that disease leads to a pattern of basal ganglia activity that disrupts local and distant function and that surgery acts to suppress or override this noisy signal. Critical to the success this theory is that different disease phenotypes are associated with different patterns of noisy signal, and we survey the evidence to support this contention, with specific emphasis on different types of pathological synchronization. However, just as DBS may suppress or override noisy signals in the basal ganglia, it must equally antagonize any remaining physiological functioning in these key motor structures. We argue that the latter effect of DBS becomes manifest when baseline motor performance is relatively preserved, i.e., when pathological activity is limited. Under these circumstances, the deleterious effects of DBS are no longer obscured by its therapeutic actions in suppressing noisy signals. Whether true, oversimplified or simply incorrect, the noisy signal hypothesis has served to focus attention on the detailed character of basal ganglia discharge and its variation with disease and therapy. © 2007 Movement Disorder Society     

Pathophysiology of the basal ganglia and movement disorders: from animal models to human clinical applications

Electrophysiological studies in control and MPTP treated primates have played a major role in our understanding of the physiology of the basal ganglia and the pathophysiology of Parkinson's disease (PD). Early models emphasized discharge rate and viewed the basal ganglia as a network of boxes (nuclei) connected by excitatory or inhibitory connections. More recent studies view the basal ganglia as neural networks with weak and non-linear interactions in and between the different nuclei. Microelectrode electrophysiological recording enables the high resolution-both in the temporal domain (spike) and the spatial domain (neuron)-required for the in vivo investigation of neuronal networks of the basal ganglia. MPTP treated primates exhibit the full pathological and clinical spectrum of human Parkinsonism and therefore their electrophysiological study has promoted better understanding of the normal state, the dopamine-depleted state, and finally the testing of potential therapeutic interventions for PD. Here, we review the main insights learned from microelectrode physiological studies of MPTP monkeys over the last 20 years since the introduction of this animal model.     

Sensory-motor disintegration in the basal ganglia disorders]

Basal ganglia lie between the cerebral cortex and the thalamus, and have dense fiber connections between them. These connections form 4-5 distinct loops to allow parallel processing of information. Among them, the most intensively studied is the motor loop, which comprises 2 distinct direct and indirect pathways. The direct pathway disinhibits the powerful inhibition of Gpi/SNr upon the thalamic VL nuclei with a net result of facilitatory influence upon the motor cortex. By contrast, the indirect pathway exerts an inhibitory effect. Overall this dual system provides a center-surround mechanism to focus its effect on selected cortical neurons. The functional role of the loop in motor control has not been precisely understood. Several lines of evidence have recently been presented to support the view that this mechanism is used to focus the output to a specific group of muscles required for performing a specific task. Recent observations in dystonia and Parkinsonism suggest that this operation is made possible through opening the sensory channel for the expected sensory feed-back afferents during movement. Thus one of the important functions of basal ganglia seems to be the gating of sensory input for motor control.     

Targeting the caudal intralaminar nuclei for functional neurosurgery of movement disorders

The caudal intralaminar nuclei, in particular the Centrum-Medianum Parafascicularis (CM-Pf) nucleus complex, are involved in various functions, particularly in pain processing and in motor control, through their projections to the subthalamic nucleus and their afferents from the pallidum internus (GPi) (or entopeduncular nucleus in the rat). The nociceptive inputs received by the CM-Pf are modulated by the somato-sensory thalamus. The lateral habenula (HbL) receives noxious inputs and has an inhibitory influence on the nigral dopaminergic neurons. CM-Pf and the HbL share comparable response characteristics to noxious inputs and might play comparable, and perhaps complementary, roles in conveying the nociceptive information to the basal ganglia system, thereby modulating motor responses, such as freezing and dyskinesias. The interaction between CM-Pf, HbL, GPi, STN and SNC might provide a new template for high frequency stimulation strategies in the treatment of movement disorders.     

Stereotactic neurosurgery for movement disorders

Stereotactic neurosurgery for the treatment of movement disorders focuses primarily on the treatment of Parkinson's disease (PD), essential tremor (ET), and dystonia. The surgical targets in use are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for PD, GPi for dystonia, and ventralis intermedius (Vim) nucleus of the thalamus for ET. Following target selection, procedures include the generation of lesions or the placement of deep brain stimulating electrodes in the selected target. Additionally, transplantation has been used in the treatment of PD. The indications, outcomes, and risks of the various procedures are reviewed.     

Neuropsychology for movement disorders neurosurgery

The neuropsychologist plays a crucial role in three phases of the neurosurgical treatment of movement disorder patients, namely screening, outcome evaluation and research. In screening patients, the differential diagnosis of dementia, impact of depression or other psychiatric conditions, and the influence of disease and medication-induced symptoms on cognitive performance must be determined. Postoperatively, systematic evaluations elucidate the cognitive costs or benefits of the procedure. The neuropsychologist is then able to provide feedback and counselling to the professional staff, patient and family to inform management strategies. Neuropsychologists also study alteration of cognitive processing due to lesions or stimulation, which, in tandem with functional imaging, shed light on plasticity in cortical and subcortical processing.     

Oscillations in the basal ganglia under normal conditions and in movement disorders.

A substantial body of work within the last decade has demonstrated that there is a variety of oscillatory phenomena that occur in the basal ganglia and in associated regions of the thalamus and cortex. Most of the earlier studies focused on recordings in rodents and primates. More recently, significant advances have been made in this field of research through the analysis of basal ganglia field potentials recorded from implanted deep brain stimulation electrodes in the basal ganglia of human patients with Parkinson's disease and other disorders. It now appears that oscillatory activity may play a significant role in the pathogenesis of these diseases. The most significant finding is that in Parkinson's disease synchronized oscillatory activity in the 10- to 35-Hz band (often termed "beta-band") is prevalent in the basal ganglia-thalamocortical circuits, and that such activity can be reduced by dopaminergic treatments. The entrainment of large portions of these circuits may disrupt information processing in them and may lead to parkinsonian akinesia (and perhaps tremor). Although less firmly established than the role of oscillations in movement disorders, oscillatory activities at higher frequencies may also be a component of normal basal ganglia physiology.     

The basal ganglia and the initiation of movement

The positive and negative signs of basal ganglia disease provide strong clinical evidence that the basal ganglia and allied nuclei participate in the neural mechanisms underlying volitional activity. This chapter reviews the range of neural subsystems in the basal ganglia that may contribute to these functions and their relationships with the dopamine-containing cell groups of the substantia nigra.     

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.     

The enigma of the basal ganglia and movement

Ever since Kinnier Wilson⁸ discovered in 1912 that lesions of the basal ganglia cause abnormal involuntary movements (dyskinesias) in the disease that now bears his name, hepatolenticular degeneration, it has been accepted that the basalganglia are connected with movement, although it is not known how. What exactly is their function? In this review C. D. Marsden examines some recent hypotheses.     

Surgical complications of functional neurosurgery treating movement disorders: results with anatomical localisation

Thalamic and pallidal lesions can alleviate movement disorders, but to achieve this safely and efficaciously requires accurate target localization. We report the surgical complications encountered using an anatomical localization technique to create 121 thalamic and pallidal lesions in 79 consecutive patients over a 3 year period. There was no perioperative mortality, although there was one late death indirectly related to surgery. The risk of haemorrhage was 3.3% per lesion made. Anatomical localization offers a relatively safe way of identifying targets for functional neurosurgery, with complication rates which compare favourably with the published literature.     

Functional movement disorders

Functional movement disorders (FMD) represent a complex and disabling entity characterized by a broad range of clinical symptoms not explained by a classical neurological disease. In 2013, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) added a clinical criterion based on incongruence and inconsistency, supported by recent literature highlighting the role of “positive clinical signs”. These clinical signs allow a “rule-in” procedure in making a diagnosis of FMD so that the diagnosis is no longer a “rule-out” or “by default” diagnosis made after exclusion of other neurological conditions. This review summarizes current evidence on common clinical features and highlights bedside signs in FMD, such as tremor, dystonia, myoclonus and parkinsonism. Tics, chorea and hemiballism are also briefly discussed.     

Physiological localisation in functional neurosurgery for movement disorders: a simple approach.

Controversy exists between anatomical methods and single cell recording as the preferred approach in target localisation in functional neurosurgery for movement disorders. The controversy centres on accuracy as compared to practicality. We describe a mapping technique of semi-microstimulation utilising threshold measurements which has been used in 66 procedures in 50 subjects. We compared the accuracy of anatomical localisation with the final chosen target using the above technique. We also compared the benefit, the side effects and the surgical complication rate with published data on single cell recording and anatomical localisation. The mean difference in 3-dimensional space between the anatomical target and the physiological target was 6.85 mm (P < 0.0001). A good response was obtained in 80% of procedures. Mortality was 1.5%. The surgical complication rate was 1.5%. Mild side effects, serious side effects, transient side effects and permanent side effects were evident in 4.5%, 10.6%, 6.1% and 9.1% of procedures. These figures compared better than anatomical studies and similar to single cell recording studies. It is concluded that this approach provides both accuracy and simplicity and is recommended as a compromise to the currently available methods.