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Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.

Several case reports and small series have indicated that tardive dystonia is responsive to globus pallidus deep brain stimulation. Whether different subtypes or distributions of tardive dystonia are associated with different outcomes remains unknown.We assessed the outcomes and temporal profile of improvement of eight tardive dystonia patients who underwent globus pallidus deep brain stimulation over the past six years through record review. Due to the retrospective nature of this study, it was not blinded or placebo controlled.Consistent with previous studies, deep brain stimulation improved the overall the Burke-Fahn-Marsden motor scores by 85.1 ± 13.5%. The distributions with best responses in descending order were upper face, lower face, larynx/pharynx, limbs, trunk, and neck. Patients with prominent cervical dystonia demonstrated improvement in the Toronto Western Spasmodic Torticollis Rating Scale but improvements took several months. In four patients the effects of deep brain stimulation on improvement in Burke Fahn Marsden score was rapid, while in four cases there was partial rapid response of neck and trunk dystonia followed by was gradual resolution of residual symptoms over 48 months.Our retrospective analysis shows excellent resolution of tardive dystonia after globus pallidus deep brain stimulation. We found instantaneous response, except with neck and trunk dystonia where partial recovery was followed by further resolution at slower rate. Such outcome is encouraging for using deep brain stimulation in treatment of tardive dystonia.

Clower, William T. and Garrett E. Alexander. Movement sequence-related activity reflecting numerical order of components in supplementary and presupplementary motor areas. J. Neurophysiol. 80: 1562–1566, 1998. The supplementary motor area (SMA) and presupplementary motor areas (pre-SMA) have been implicated in movement sequencing, and neurons in SMA have been shown to encode what might be termed the relational order among sequence components (e.g., movement X followed by movement Y). To determine whether other aspects of movement sequencing might also be encoded by SMA or pre-SMA neurons, we analyzed task-related activity recorded from both areas in conjunction with a sequencing task that dissociated the numerical order of components (e.g., movement X as the 2nd component, irrespective of which movements precede or follow X). Sequences were constructed from eight component movements, each characterized by three spatial variables (origin, direction, and endpoint). Task-related activity recorded from 56 SMA and 63 pre-SMA neurons was categorized according to both the epoch (delay, reaction time, and movement time) and the spatial variable or component movement with which it was associated. All but one instance of task-related activity was selective for one of the spatial variables (SV-selective) rather than for any of the component movements themselves. Of 110 instances of SV-selective activity in SMA, 43 (39%) showed significant effects of numerical order. The corresponding incidence in pre-SMA, 82 (71%) of 116, was substantially higher ( P < 0.00001). No effects of numerical order were evident among the hand paths, movement times, or electromyographic activity associated with task performance. We concluded that neurons in SMA and pre-SMA may encode the numerical order of components, at least for sequences that are distinguished mainly by that aspect of component ordering.

VISUALLY guided reaching requires complex neural transformations to link visual and proprioceptive inputs with appropriate motor outputs1,2. Despite the complexity of these transformations, hand–eye coordination in humans is remarkably flexible, as demonstrated by the ease with which reaching can be adapted to distortions in visual feedback. If subjects attempt to reach to visual targets while wearing displacing prisms, they initially misreach in the direction of visual displacement. Given feedback about their reaching errors, however, they quickly adapt to the visual distortion. This is shown by the gradual resumption of accurate reaching while the prisms remain in place, and by the immediate onset of reaching errors in the opposite direction after the prisms have been removed3. Despite an abundance of psy-chophysical data on adaptation to prisms, the functional localization of this form of sensorimotor adaptation is uncertain. Here we use positron emission tomography (PET) to localize changes in regional cerebral blood flow (rCBF) in subjects who performed a prism-adaptation task as well as a task that controlled for the sensory, motor and cognitive conditions of the adaptation experiment. Difference images that reflected the net effects of the adaptation process showed selective activation of posterior parietal cortex contralateral to the reaching limb.

The motor circuitry of the basal ganglia is organized in parallel with basal ganglia circuits involved in oculomotor, associative, and limbic functions. These circuits comprise reentrant pathways that originate in various neocortical domains and pass through the basal ganglia before returning, by way of the thalamus, to select portions of the frontal lobe. Recent progress in characterizing the anatomy and physiology of these pathways has provided new insights into the pathophysiology of basal ganglia-related movement disorders and enhanced our understanding of the normal role of the basal ganglia in movement control and adaptive motor behavior.

Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.

Studies of single-cell discharge in the basal ganglia of behaving primates have revealed: characteristic patterns of spontaneous discharge in the striatum, external (GPe) and internal (GPi) globus pallidus, pars reticulata and pars compacta of the substantia nigra, and the subthalamic nucleus (STN); phasic changes in neural discharge in relation to movements of specific body parts (e.g. leg, arm, neck, face); short-latency (sensory) neural responses to passive joint rotation; a somatotopic organization of movement-related neurons in GPe, GPi, and STN; a clustering of functionally similar neurons in the putamen and globus pallidus; greater representation of the proximal than of the distal portion of the limb; changes in neural activity in reaction-time tasks, suggesting a greater role of the basal ganglia in the execution than in the initiation of movement in this paradigm; a clear relation of neuronal activity to direction, amplitude (?velocity) of movement, and force; a preferential relation of neural activity to the direction of movement, rather than to the pattern of muscular activity. Some of these findings suggest that the basal ganglia may play a role in the control of movement parameters rather than (or independent of) the pattern of muscular activity. Loss of basal ganglia output related to amplitude may account for the bradykinesia in Parkinson's disease. The presence of somatotopic organization in the putamen and globus pallidus, together with known topographic striopallidal connections, suggests that segregated, parallel cortico-subcortical loops subserve 'motor' and 'complex' functions.

Concepts of basal ganglia organization have changed markedly over the past decade, due to significant advances in our understanding of the anatomy, physiology and pharmacology of these structures. Independent evidence from each of these fields has reinforced a growing perception that the functional architecture of the basal ganglia is essentially parallel in nature, regardless of the perspective from which these structures are viewed. This represents a significant departure from earlier concepts of basal ganglia organization, which generally emphasized the serial aspects of their connectivity. Current evidence suggests that the basal ganglia are organized into several structurally and functionally distinct 'circuits' that link cortex, basal ganglia and thalamus, with each circuit focused on a different portion of the frontal lobe. In this review, Garrett Alexander and Michael Crutcher, using the basal ganglia 'motor' circuit as the principal example, discuss recent evidence indicating that a parallel functional architecture may also be characteristic of the organization within each individual circuit.

Shen, Liming and Garrett E. Alexander. Preferential representation of instructed target location versus limb trajectory in dorsal premotor area. J. Neurophysiol. 77: 1195–1212, 1997. The dorsal premotor area (PMd) of monkeys has been implicated in processes relating to movement preparation and movement selection. In the present study, we sought to determine whether PMd neurons that are activated during a delayed reaching task have directional responses that reflect either the target (i.e., the goal) of an intended movement or the physical properties of the movement itself. Two macaque monkeys were trained to perform a visually instructed, delayed reaching task with indirect visual feedback. The subjects and methods were identical to those described in the preceding paper. In the behavioral task, each subject moved a two-dimensional joystick with the right forelimb to align a cursor with targets presented on a video display. The paradigm dissociated the direction of forelimb movement from the spatial location of the target. This was accomplished by varying the spatial mappings between joystick and cursor. A variable delay separated the visual stimulus that instructed the target location (IS) from the visual stimulus that triggered the instructed movement (TS). Task-related activity was recorded from a total of 181 PMd neurons. The focus of this study was on directionally tuned neuronal responses that included 1) stimulus-related activity (phasic, following IS); 2) set-related activity (tonic, between IS and TS); and 3) movement-related activity (phasic, following TS). Of the entire sample of PMd neurons with directionally tuned activity, 114 were tested with two joystick/cursor mappings, permitting dissociation of directional responses that depended on limb trajectory from those that depended on target location. Task-related neuronal activity was classified as target-dependent if it covaried exclusively with target location across both conditions, and as limb-dependent if it covaried exclusively with limb trajectory. Directional activity that changed significantly across rotation conditions was classified as complex. Approximately one half of the sample of PMd neurons showed stimulus-related activity that was directionally tuned (56%, 64 of 114). Nearly all of the directionally classifiable stimulus-related activity was target dependent (94%, 44 of 47 responses), and none was limb dependent. A small proportion was classified as complex (6%, 3 of 47 responses). More than two thirds of the PMd neurons showed set-related activity that was directionally tuned (69%, 79 of 114). Among cells with set-related activity that was directionally classifiable, there were ∼9 times as many target-dependent responses (76%, 48 of 63) as there were limb-dependent responses (8%, 5 of 63), with the remainder being complex (16%, 10 of 63). Approximately three quarters of the sample of PMd neurons showed early movement-related activity (before movement onset) that was directionally tuned (78%, 89 of 114). Among those cells whose early movement-related activity was directionally classifiable, there were >3 times as many target-dependent responses (51%, 34 of 66) as limb-dependent responses (14%, 9 of 66), with the remainder being complex (35%, 23 of 66). Approximately two thirds of the sample showed late movement-related responses (after movement onset) that were directionally tuned (68%, 78 of 114). Among those cells whose late movement-related activity was directionally classifiable, there were comparable numbers of target-dependent (25%, 15 of 61) and limb-dependent responses (28%, 17 of 61), with the remainder being complex (47%, 29 of 61). These results indicate a preferential representation of target location rather than limb trajectory among PMd neurons. Over the extended interval from IS to motor response, there was a gradual decline in the frequency of target-dependent activity and corresponding increases in the frequencies of both limb-dependent and complex activity. These findings suggest that PMd neurons may participate in mediating the sensory-to-motor transformation required by the delayed reaching task. Comparison of the responses of PMd neurons with those of motor cortex neurons recorded in the same experimental subjects indicates that PMd may play a preferential role in sensory or context-dependent processing related to task performance, whereas motor cortex may be more involved in processing related to the purely motor aspects of task performance.

Shen, Liming and Garrett E. Alexander. Neural correlates of a spatial sensory-to-motor transformation in primary motor cortex. J. Neurophysiol. 77: 1171–1194, 1997. Primary motor cortex (MC) has been strongly implicated in motor processing, but there have been relatively few attempts to determine whether MC may also play a role in either sensory or context-dependent processing. In the present study, neuronal activity in MC was characterized in relation to the planning and execution of visually instructed limb movements whose trajectories were dissociated from their spatial targets. This design permitted the dissociation of neuronal activity related to motor processing from activity related to sensory or context-dependent processing. Two macaque monkeys were trained to perform a visually instructed, delayed reaching paradigm with indirect visual feedback. Subjects used the right forelimb to capture targets presented on a video display by moving a two-dimensional joystick whose position was reflected by a cursor. The target to be captured on each trial was indicated by a visual instruction stimulus (IS), which was separated from a movement-triggering stimulus (TS) by a variable delay. The direction of forelimb movement was dissociated from the location of the target by varying the spatial mappings between joystick and cursor across two conditions, unrotated (0° offset between cursor and limb direction) and rotated (90° offset). Task-related activity was recorded from a total of 180 MC neurons. The focus of this study was on directionally tuned neuronal activity that included phasic, stimulus-related activity following the IS; tonic, set-related activity between IS and TS; and phasic, movement-related activity following the TS. Of the entire sample of MC neurons with directionally tuned activity, 119 cells were tested under both rotation conditions, permitting dissociation of directional responses that depended on target location from those that depended on limb trajectory. Task-related neuronal activity was classified as target dependent if it covaried exclusively with target location across both conditions, and as limb dependent if it covaried exclusively with limb trajectory. Directional activity that did not fulfill the criteria for either target or limb dependence, because of changes across rotation conditions, was classified as complex. Approximately one quarter of MC neurons showed weak, but consistent, stimulus-related activity that was directionally tuned (24%, 29 of 119). Nearly all of the directionally classifiable stimulus-related activity was target dependent (94%, 15 of 16 responses), with the exception of a single limb-dependent response (6%, 1 of 16). A majority of MC neurons showed set-related activity that was directionally tuned (61%, 72 of 119). Of the directionally classifiable set-related activity, there were comparable numbers of target-dependent (37%, 16 of 43) and limb-dependent responses (35%, 15 of 43), with the remainder being complex (27%, 12 of 43). Movement-related activity following the TS was considered to be early or late, depending on whether it preceded or followed the onset of movement. The large majority of MC neurons showed early movement-related activity that was directionally tuned (86%, 102 of 119): among those whose neurons early activity was directionally classifiable, there were only one third as many target-dependent responses (14%, 11 of 79) as limb-dependent responses (43%, 34 of 79), with the remainder being complex (43%, 34 of 79). There was also a large majority of MC neurons that showed late movement-related activity that was directionally tuned (84%, 100 of 119): among those whose late activity was directionally classifiable, there were only one ninth as many target-dependent responses (5%, 4 of 88) as there were limb-dependent responses (41%, 36 of 88), with the remainder being complex (55%, 48 of 88). The instructed delay task employed in this study required a sensory-to-motor transformation through which the instructed target location was associated with a limb movement of the appropriate direction. Over the extended interval between IS and motor response, we observed a gradual decline in the frequency of target-dependent activity and gradual increases in the respective frequencies of both limb-dependent and complex activity. This suggests that MC neurons may play a role in mediating the spatial sensory-to-motor transformation required by the task. The substantial proportions of target-dependent activity observed in this study reinforce the growing evidence that at least some MC neurons do play a role in either sensory or context-dependent processing of spatial information relevant to specific motor tasks.

Prevailing engineering-inspired theories of motor control based on sequential/algorithmic or motor-programming models are difficult to reconcile with what is known about the anatomy and physiology of the motor areas. This is partly because of certain problems with the theories themselves and partly because of features of the cortical and basal ganglionic motor circuits that seem ill-suited for most engineering analyses of motor control. Recent developments in computational neuroscience offer more realistic, that is, connectionist, models of motor processing. The distributed, highly parallel, and nonalgorithmic processes in these models are inherently self-organizing and hence more plausible biologically than their more traditional algorithmic or motor-programming counterparts. The newer models also have the potential to explain some of the unique features of natural, brain-based motor behavior and to avoid some of the computational dilemmas associated with engineering approaches.

1. To examine the functional organization of the primate "motor" thalamus, neuronal activity was studied systematically in awake behaving monkeys throughout the nucleus ventralis lateralis, pars oralis (VLo), nucleus ventralis posterior lateralis, pars oralis (VPLo), ventralis lateralis, pars caudalis (VLc), and portions of ventralis anterior (VA) and Area X. In addition, portions of the sensory nucleus ventralis posterior lateralis, pars caudalis (VPLc) were explored. Isolated neurons were examined for their responses to somatosensory examination and active movement (n = 919) and for their response to torque-induced joint displacements (n = 375). A total of 684 neurons was determined histologically to lie within specific subnuclei of the motor (n = 574) or sensory (n = 110) thalamus. 2. The sensorimotor response properties of neurons in the thalamic subnuclei showed clear differences in their response to somatosensory examination. In order of decreasing frequency, the percent of neurons responding to passive somatosensory examination in each subnucleus were as follows: VPLc, 96% (106/110), VPLo, 93% (252/270), VLc, 77% (43/56), VLo, 37% (59/155), Area X, 22% (12/53), and VA, 12% (5/40). Conversely, neurons that responded only to active movement were most frequent in VLo, 44% (68/155), VA, 45% (18/40), and Area X, 40% (21/53) and relatively infrequent in VLc 11% (6/56) and VPLo, 3% (7/270). In VPLc, no neurons were found that responded only to active movement (0/110). 3. A well-defined somatotopic organization was found in VLo, VPLo, and VPLc and was suggested strongly for VLc. Individual body regions were represented in a series of lamellae, organized in a partial onion skin-like arrangement with the leg represented in the outermost lamella, and the trunk, arm, and orofacial regions represented in successively deeper lamellae. In general the body representations, although present for each subnucleus thoroughly examined, i.e., VLo, VPLo, and VPLc, also were contiguous across subnuclei. Based on the available data, a clear somatotopic picture could not be discerned for Area X or VA. 4. Responses to torque application were more common in neurons in VPLo (77%; 60/78) and VLc (73%; 16/22) than in VLo (44%; 12/27). Mean latencies were shortest for neurons in VPLo (25 +/- 14 ms; mean +/- SD) and the bordering (shell) region of VPLc (22 +/- 15 ms) and were approximately twice as long in VLc (51 +/- 23 ms) and VLo (47 +/- 21 ms).(ABSTRACT TRUNCATED AT 400 WORDS)

Publisher Summary The control of goal-directed limb movements requires that the target or goal of each movement be translated quickly and efficiently into an appropriate set of muscle activation patterns that will carry the limb along the required trajectory. The control of goal-directed limb movements in three-dimensional space represents an enormously complex challenge to the motor system. Theorists have embraced the concept of the motor program in an attempt to account for the remarkable speed and flexibility of skilled motor behaviors. However, fundamental issues regarding the origin and nature of motor programs have yet to be addressed in detail. This chapter focuses on the parallel distributed processing (PDP) models of motor control, which represent an exciting new approach to the study of the neural substrates of motor behavior. Such models provide detailed and testable hypotheses concerning the neural basis for the complex and highly adaptive motor behavior of primates. Recent neurophysiological investigations of the motor system in awake, behaving primates have shown that each of three interconnected motor areas contains neural representations of several different levels of motor processing. The concept of parallel distributed motor processing represents an important theoretical advance in the study of the neural control of movement. PDP approaches to neural modeling will very likely provide the first detailed, testable, and neurobiologically relevant models of motor processing in primates.

The central theme of the "segregated circuits" hypothesis is that structural convergence and functional integration occurs within, rather than between, each of the identified circuits. Admittedly, the anatomical evidence upon which this scheme is based remains incomplete. The hypothesis continues to be predicated largely on comparisons of anterograde and retrograde labeling studies carried out in different sets of animals. Only in the case of the "motor" circuit has evidence for the continuity of the loop been demonstrated directly in individual subjects; for the other circuits, such continuity is inferred from comparisons of data on different components of each circuit obtained in separate experiments. Because of the marked compression of pathways leading from cortex through basal ganglia to thalamus, comparisons of projection topography across experimental subjects may be hazardous. Definitive tests of the hypothesis of maintained segregation await additional double- and multiple-label tract-tracing experiments wherein the continuity of one circuit, or the segregation of adjacent circuits, can be examined directly in individual subjects. It is worthy of note, however, that the few studies to date that have employed this methodology have generated results consistent with the segregated circuits hypothesis. Moreover, single cell recordings in behaving animals have shown striking preservation of functional specificity at the level of individual neurons throughout the "motor" and "oculomotor" circuits. It is difficult to imagine how such functional specificity could be maintained in the absence of strict topographic specificity within the sequential projections that comprise these two circuits. This is not to say, however, that we expect the internal structure of functional channels (e.g., the "arm" channel within the "motor" circuit) to have cable-like, point-to-point topography. When the grain of analysis is sufficiently fine, anatomical studies have shown repeatedly that the terminal fields of internuclear projections (e.g., to striatum, pallidum, nigra, thalamus, etc.) often appear patchy and highly divergent, suggesting that neighboring groups of projection cells tend to influence interdigitating clusters of postsynaptic neurons. While more intricate and complex than simple point-to-point topography, however, this type arrangement should also be capable of maintaining functional specificity. As discussed briefly above, it is not yet clear to what extent the inputs to the "motor" circuit from the different precentral motor fields (e.g., MC, SMA, APA) are integrated in their passage through the circuit. It now appears that at the level of the putamen such inputs remain segregated.(ABSTRACT TRUNCATED AT 400 WORDS)

Congenic mice of the MRL/Mp strain spontaneously develop an autoimmune connective tissue disease that shares immunological and histopathological features with systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome. The autoimmune disorder in these mice is accelerated markedly by the recessive gene lpr. By 6 months of age, MRL/Mp-lpr/lpr mice developed prominent mononuclear cell infiltrates restricted to the choroid plexus and meninges, whereas congeneric MRL/Mp- +/+ mice (which lack the lpr gene) showed delayed but widespread inflammatory infiltrates involving cerebral vessels and meninges, with sparing of the choroid plexus. These distinctive patterns of cerebral inflammation, which are comparable in many respects to those seen in human connective tissue disease, provide some of the first animal models of relevant central nervous system histopathological processes associated with underlying connective tissue disease.

The pathogenesis of central nervous system complications in primary Sjogren's syndrome (CNS-SS) is unknown. In order to determine whether patients with active CNS-SS have cerebrospinal fluid (CSF) abnormalities indicative of CNS inflammation, CSF analyses from 30 patients with active CNS-SS (SSA) were contrasted with those from 20 SS patients without CNS involvement (SSI) and 20 patients with systemic lupus erythematosus and active CNS disease (SLEA). Elevations of total protein concentration, IgG concentration, IgG to total protein ratio, and IgG index were observed in patients with SSA, but not in those with SSI. Agarose gel electrophoresis results were abnormal, with 1 or more bands, in 25 of 29 SSA patients (86%), but in only 3 of 18 SSI patients (17%). Similar, but less striking, CSF abnormalities were seen in a minority of SLEA patients. Fifteen SSA patients (50%) had transient, mild-to-moderate CSF pleocytosis, while only 1 SSI patient and 2 SLEA patients had similar findings. Cytologic findings were abnormal in 18 SSA patients (60%); these included atypical mononuclear cells, lymphoblastoid cells, and plasma cells. The presence of immuno-competent cells and evidence for the intrathecal synthesis of IgG within the CSF of SSA, but not SSI, patients provide diagnostic parameters which are indicative of active disease and which can be monitored serially during therapy.

A 37-year-old woman with primary Sjogren syndrome developed mixed cryoglobulinemia and systemic vasculitis. Subarachnoid hemorrhage occurred as a result of necrotizing anterior spinal arteritis. Although rarely seen in mixed cryoglobulinemia, central nervous system complications have recently been documented in Sjogren syndrome. The patient's serum contained antibodies to the Ro(SSA) cytoplasmic antigen, and these antibodies were concentrated in the cryoglobulin fraction. Anti-Ro(SSA) antibodies are associated with the occurrence of vasculitis in patients with Sjogren syndrome, which suggests that the spinal arteritis and subarachnoid hemorrhage in this patient may have been directly related to the underlying connective tissue disorder.

THE emergence of increasingly complex cognitive functions with age is widely assumed to reflect in part the maturation of connections within the central nervous system, but the neural bases of cognitive development have resisted identification. There is some evidence to indicate that the dorsolateral prefrontal association cortex in monkeys acquires its adult functional capacities over a protracted span of postnatal development1–3. Most of this evidence, however, has come from studies involving surgical ablation. The study of cerebral development in brain-damaged subjects is complicated by anterograde and retrograde degenerative changes, as well as by the possibility of compensatory neural reorganisation which could occur during the weeks or months between surgical ablation and assessment of behavioural performance4. It is now possible to study the functions of specific brain sites without producing permanent brain damage by localised cortical cooling, a method which allows reversible inactivation of restricted regions of cortex in otherwise normal animals. The latter are able to serve as their own controls before and after the episodes of cortical hypothermia5–7. This method has previously been used only in research on mature animals. In this study, local hypothermia was produced for the first time in the dorsolateral prefrontal cortex of young, developing rhesus monkeys during repeated assessment of their performance on a delayed-response task. Such performance in adult monkeys is known to be dependent on the integrity of that region8. Our findings provide direct evidence that part of the dorsolateral prefrontal association cortex does not become functionally mature until at least 34–36 month of age, that is, close to sexual maturity in this species.

Publisher Summary This chapter primarily describes the role of the basal ganglia in the control of limb movements. Data from recent anatomical and behavioral/neurophysiological studies in primates is emphasized. The results of recent neurophysiologic studies in trained primates suggest that, basal ganglia output may play a role in scaling the amplitude of step movements by its effects on the magnitude of agonist EMG activity, but that it is not primarily involved in the initiation of limb movement in a reaction time task or in the selection of specific muscles. These studies are generally consistent with the available data on limb movements, in patients with Parkinson's disease. This consistency indicates major deficit in the control of movement amplitude in step-tracking tasks with little or no impairment of reaction time or disruption of the pattern of muscular activity. Evidence for a role of the basal ganglia in the preparation for movements has recently been determined. A role in other aspects of movement, such as motor programming and “complex” behavior, appears likely to be based on both anatomical and physiological data.

We studied eight patients who had primary Sjogren syndrome and central nervous system (CNS) disorders that were not attributable to other causes. Focal cerebral deficits were observed in five patients. Aseptic meningoencephalitis was seen in five patients, recurrent in one. Spinal cord manifestations in three patients took several forms: acute transverse myelitis, chronic progressive myelopathy, and spinal subarachnoid hemorrhage. Precipitating antibodies to the Ro(SSA) cytoplasmic antigen were detected in the sera of seven of eight patients. This may be relevant to the pathogenesis of CNS disease in Sjogren syndrome, because there is a strong correlation between vasculitis and the presence of anti-Ro(SSA) antibodies in this connective tissue disorder.

Central nervous system involvement has occurred in approximately 20% of patients with primary Sjögren's syndrome evaluated at our institution. Characteristically, the neurologic dysfunction is multifocal, involving both the brain and spinal cord, and is recurrent over time. We present the features of 20 patients with primary Sjögren's syndrome and central nervous system involvement whose neurologic findings, evoked potential abnormalities, and cerebrospinal fluid profiles (elevated IgG indices, oligoclonal bands on agarose gel electrophoresis, and mild pleocytosis with reactive lymphoid cells) closely resembled those of multiple sclerosis. In fact, multiple sclerosis was considered the most likely diagnosis in each of these patients before diagnosis of Sjögren's syndrome, and each patient met criteria for definite multiple sclerosis. The clinical effects of corticosteroid treatment during episodes of acute neurologic dysfunction appeared to be beneficial in these patients.

Although peripheral nervous system disease has been well documented in Sjogren's syndrome (SS), central nervous system (CNS) involvement is considered distinctly uncommon. Sixteen patients with primary SS and CNS disorders not attributable to other causes were the subjects of this study. Cerebral manifestations, both focal and diffuse, as well as spinal cord disease, were observed. Peripheral vasculitis occurred in 12 patients (75%), 83% of whom had anti-Ro(SSA) antibodies. The high proportion of patients with concomitant peripheral vasculitis, and the observed association with antibodies to the Ro(SSA) antigen system which, in other studies, has been linked to vasculitis in SS, suggest that an immune vasculopathy may play a role in the pathogenesis of the CNS disease of SS.

Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in our concepts of the structural and functional organization of these nuclei. From earlier data it had appeared that the basal ganglia served primarily to integrate diverse inputs from the entire cerebral cortex and to "funnel" these influences, via the ventrolateral thalamus, to the motor cortex (Allen & Tsukahara 1974, Evarts & Thach 1969, Kemp & Powell 1971). In particular, the basal

Monkeys with chronically implanted cryogenic probes over the surface of the dorsolateral prefrontal cortex were tested in a delayed response task. Performance of this task was reversibly impaired by bilateral cooling and also, to a lesser extent, by unilateral cooling of this cortical area. Cooling to subdural temperatures of 25–30°C was sufficient to produce deficits. These deficits are interpreted as caused by reversible inactivation of the cortex around the sulcus principalis, with the consequent disruption of short-term memory function.

Monkeys were trained to perform a delayed response (DR) task. A visual cue—placement of food under one of two test objects—was succeded by a delay of 18 sec, during which the test objects were concealed and out of reach. At the end of the delay, the objects were made accessible for choice and, if the choice was correct, for reward. Single unit activity was recorded from thalamic nuclei during DR performance. The parvo- and magnocelularis portions of the nucleus medialis dorsalis (MD) were principally explored. Units spontaneously exhibiting rhytmic firing were commonly observed, particularly in MD pars magnocellularis. According to temporal patterns of firing frequency changes during DR trials, 6 different types of units were distinguished. Approximately one-half of all the units sampled in MD, pars parvocellularis, showed sustained elevations of discharge during the delay. These findings are comparable to those made in a separate study of the prefrontal cortical area to which MD, pars parvocellularis, is connected. The firing changes correlated with the behavioral task are interpreted as manifestations of a functional involvement of MD, together with the prefrontal cortex, in DR performance. The possible nature of this involvement is discussed in relation to the available evidence from anatomical, electrophysiological and behavioral research.

The spike activity of single units of the thalamus was explored during hypothermia of dorsolateral prefrontal cortex in monkeys trained to perform a delayed response (DR) task. Lowering prefrontal temperature to 15–20 °C — measured subdurally — induced a profound and reversible deficit of DR performance and a concomitant alteration of firing in cells of the parvocellular portion of the nucleus medialis dorsalis (MDpc). Spontaneous firing frequency was diminished in most of the units affected, while a tendency to grouped, rhythmic discharge was generally accentuated. The normal firing patterns related to DR performance were modified by prefrontal cooling in 63% of the units examined in MDpc. Prefrontal cooling induced a disruption of the sustained elevations of discharge shown by certain types of units during the delay period of DR trials. Sustained activation was attenuated, abbreviated or converted into a paradoxical inhibition as a result of cooling. The effects of prefrontal cooling on behavior and on unit activity in medialis dorsalis are discussed in the context of what is known about input and output connections of the prefrontal cortex. It is apparent that cryogenic depression of this cortical region interferes with the normal neural processes that constitute the substrate of short-term memory function.

Nerve cells in the monkey's prefrontal cortex and nucleus medialis dorsalis of the thalamus show changes of firing frequency associated with the performance of a delayed response test. Most cells increase firing during the cue presentation period or at the beginning of the ensuing delay; spike discharge highler than that in intertrial periods is present in some cells throughout the delay. These changes are interpreted as suggestive evidence of a role of frontothalamic circuits in the attentive process involved in short-term memory

To the Editor.— We present the first reported case, to our knowledge, in which jacksonian somatosensory seizures were the sole manifestation of a contralateral chronic subdural hematoma. The somatosensory seizures resolved following evacuation of the hematoma. Report of a Case.— A previously well, 43-year-old, right-handed male welder began to note transient paresthesias of the left hand, arm, and face. With each episode, which lasted from 30 to 60 s, the symptoms would spread from the distal left phalanges to include serially the entire hand, arm, shoulder, face, and torso on that side. This temporal sequence never varied. Initially occurring once or twice daily, the episodes gradually increased in frequency to ten or more per day. The Coronal section from computed tomographic scan, showing right parietal subdural hematoma and its associated contrast-enhancing membrane (arrow). paresthesias were accompanied by a sensation of heaviness in the left arm, but frank weakness was denied

The clinical features and CSF characteristics of five patients with primary Sjögren's syndrome (SS) and associated aseptic meningoencephalitis (AME) are described. Episodes of AME were recurrent in four patients. Viral, fungal, and bacterial cultures were uniformly negative. Plasma cells were observed in the CSF but not in the blood of three patients. The CSF IgG:albumin index was elevated, suggesting intrathecal synthesis of IgG in each of the four patients tested; each patient had either one or two broad bands with the mobility of IgG on CSF agarose electrophoresis. These observations are consistent with current understanding of SS as a polyclonal gammopathy associated with the multifocal proliferation of B lymphocytes and plasma cells.

Carbamazepine in daily doses of 600 to 1200 mg controlled hemi facial spasm in three patients. In other reports, carbamazepine was effective in over half of the patients. Controlled trials are needed to established whether Carbamazepine is as effective as the surgical therapies currently in vogue.