Imaging the premotor areas.

Recent imaging studies of motor function provide new insights into the organization of the premotor areas of the frontal lobe. The pre-supplementary motor area and the rostral portion of the dorsal premotor cortex, the 'pre-PMd', are, in many respects, more like prefrontal areas than motor areas. Recent data also suggest the existence of separate functional divisions in the rostral cingulate zone.

Direction of action is represented in the ventral premotor cortex.

The ventral premotor area (PMv) is a major source of input to the primary motor cortex (M1). To examine the potential hierarchical processing between these motor areas, we recorded the activity of PMv neurons in a monkey trained to perform wrist movements in different directions with the wrist in three different postures. The task dissociated three major variables of wrist movement: muscle activity, direction of joint movement and direction of movement in space. Many PMv neurons were directionally tuned. Nearly all of these neurons (61/65, 94%) were 'extrinsic-like'; they seemed to encode the direction of movement in space independent of forearm posture. These results are strikingly different from results from M1 of the same animal, and suggest that intracortical processing between PMv and M1 may contribute to a sensorimotor transformation between extrinsic and intrinsic coordinate frames.

The inferior parietal lobule is the target of output from the superior colliculus, hippocampus, and cerebellum.

The inferior parietal lobule (IPL) is a functionally and anatomically heterogeneous region that is concerned with multiple aspects of sensory processing and sensorimotor integration. Although considerable information is available about the corticocortical connections to the IPL, much less is known about the origin and importance of subcortical inputs to this cortical region. To examine this issue, we used retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 (HSV1) to identify the second-order neurons in subcortical nuclei that project to the IPL. Four monkeys (Cebus apella) received injections of HSV1 into three different subregions of the IPL. Injections into a portion of the lateral intraparietal area labeled second-order neurons primarily in the superficial (visual) layers of the superior colliculus. Injections of HSV1 into a portion of area 7a labeled many second-order neurons in the CA1 region of the hippocampus. In contrast, virus injections within a portion of area 7b labeled second-order neurons in posterior regions of the dentate nucleus of the cerebellum. These observations have some important functional implications. The IPL is known to be involved in oculomotor and attentional mechanisms, the establishment of maps of extrapersonal space, and the adaptive recalibration of eye-hand coordination. Our findings suggest that these functions are subserved by distinct subcortical systems from the superior colliculus, hippocampus, and cerebellum. Furthermore, the finding that each system appears to target a separate subregion of the IPL provides an anatomical substrate for understanding the functional heterogeneity of the IPL.

Novel proteoglycan epitope expressed in functionally discrete patterns in primate cortical and subcortical regions.

The molecular diversity of neuronal subpopulations was examined with a new monoclonal antibody, 8B3, that recognizes a condroitin sulfate proteoglycan expressed in anatomically discrete domains of central nervous system regions. In the neocortex, interneurons display 8B3 immunoreactivity in a rostrocaudal gradient, with a distinctive staining pattern that distinguishes known cytoarchitectonic and functional boundaries. The distribution pattern of 8B3 immunoreactivity in subcortical structures is very restricted. In the striatum, 8B3 stains spiny stellate neurons clearly defining a compartment that may correspond to the matrix. Gradients of immunoreactivity are detected in the putamen, globus pallidus, and deep cerebellar nuclei, where the most dense areas of 8B3 immunoreactivity corresponds to zones of polysynaptic projections to association prefrontal cortex. In contrast, the sensorimotor domains express lower levels of immunoreactivity. Only the projection neurons of the ventrolateral nucleus and the GABAergic neurons of the reticular nucleus express significant 8B3 immunoreactivity in the thalamus. In the spinal cord, 8B3 immunoreactivity is primarily associated with a subpopulation of motor neurons in the ventral horn and neurons in Clarke's nucleus. The complex distribution pattern reflects novel aspects of the functional organization of cortical and subcortical systems in the CNS of the primate brain and represents a potentially useful tool to assess subpopulations of neurons and brain areas as putative targets in human disease.

Cerebellar projections to the prefrontal cortex of the primate.

The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.

Rabies as a transneuronal tracer of circuits in the central nervous system.

The ability of selected neurotropic viruses to move transneuronally in the central nervous system makes them particularly well suited for use as tracers in experimental neuroanatomy. Recently, techniques have been developed for using rabies virus as a transneuronal tracer. Several features of rabies infection make the virus particularly useful for this purpose. We examined transneuronal transport of rabies in the central nervous system of primates after intracortical and intramuscular injections. Rabies was transported in a time-dependent manner to infect synaptically-connected chains of neurons. Transport occurred exclusively in the retrograde direction. At the survival times we used, rabies infection was restricted to neurons and did not cause cell lysis. There are several methodological and safety issues that must be considered when designing studies that use rabies as a transneuronal tracer. When appropriate protocols and laboratory practices have been established, transneuronal transport of rabies can be a safe and efficient tool for revealing the organization of multi-synaptic circuits in the central nervous system.

A functional magnetic resonance imaging study of the role of left posterior superior temporal gyrus in speech production: implications for the explanation of conduction aphasia.

Conduction aphasia, characterized by good auditory comprehension and fluent but disordered speech production, is classically viewed as a disconnection syndrome. We review recent evidence which suggests that at least one form of conduction aphasia results from damage to cortical fields in the left posterior superior temporal gyrus which participate not only in speech perception, but also in phonemic aspects of speech production. As a test of this hypothesis, we carried out a 4T functional magnetic resonance imaging study in which subjects named visually presented objects sub-vocally. Group-based analyses showed that a majority of participants showed activation in two regions on the dorsal portion of the left posterior superior temporal gyrus.

Basal ganglia output and cognition: evidence from anatomical, behavioral, and clinical studies.

The traditional view that the basal ganglia are simply involved in the control of movement has been challenged in recent years. Three lines of evidence indicate that the basal ganglia also are involved in nonmotor operations. First, the results of anatomical studies clearly indicate that the basal ganglia participate in multiple circuits or 'loops' with cognitive areas of the cerebral cortex. Second, the activity of neurons within selected portions of the basal ganglia is more related to cognitive or sensory operations than to motor functions. Finally, in some instances basal ganglia lesions cause primarily cognitive or sensory disturbances without gross motor impairments. In this report, we briefly review some of these data and present a new anatomical framework for understanding the basal ganglia contributions to nonmotor function.

Basal ganglia and cerebellar loops: motor and cognitive circuits.

The traditional view that the basal ganglia and cerebellum are simply involved in the control of movement has been challenged in recent years. One of the pivotal reasons for this reappraisal has been new information about basal ganglia and cerebellar connections with the cerebral cortex. In essence, recent anatomical studies have revealed that these connections are organized into discrete circuits or 'loops'. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia and cerebellum. The properties of neurons within the basal ganglia or cerebellar components of these circuits resembles the properties of neurons within the cortical areas subserved by these loops. For example, neuronal activity within basal ganglia and cerebellar loops with motor areas of the cerebral cortex is highly correlated with parameters of movement, while neuronal activity within basal ganglia and cerebellar loops with areas of the prefrontal cortex is more related to aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Studies of basal ganglia and cerebellar pathology support this conclusion. Damage to the basal ganglia or cerebellar components of circuits with motor areas of cortex leads to motor symptoms, whereas damage of the subcortical components of circuits with non-motor areas of cortex causes higher-order deficits. In this report, we review some of the new anatomical, physiological and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex.

Muscle and movement representations in the primary motor cortex.

What aspects of movement are represented in the primary motor cortex (M1): relatively low-level parameters like muscle force, or more abstract parameters like handpath? To examine this issue, the activity of neurons in M1 was recorded in a monkey trained to perform a task that dissociates three major variables of wrist movement: muscle activity, direction of movement at the wrist joint, and direction of movement in space. A substantial group of neurons in M1 (28 out of 88) displayed changes in activity that were muscle-like. Unexpectedly, an even larger group of neurons in M1 (44 out of 88) displayed changes in activity that were related to the direction of wrist movement in space independent of the pattern of muscle activity that generated the movement. Thus, both "muscles" and "movements" appear to be strongly represented in M1.

The organization of cerebellar and basal ganglia outputs to primary motor cortex as revealed by retrograde transneuronal transport of herpes simplex virus type 1.

We used retrograde transneuronal transport of herpes simplex virus type 1 to map the origin of cerebellar and basal ganglia "projections" to leg, arm, and face areas of the primary motor cortex (M1). Four to five days after virus injections into M1, we observed many densely labeled neurons in localized regions of the output nuclei of the cerebellum and basal ganglia. The largest numbers of these neurons were found in portions of the dentate nucleus and the internal segment of the globus pallidus (GPi). Smaller numbers of labeled neurons were found in portions of the interpositus nucleus and the substantia nigra pars reticulata. The distribution of neuronal labeling varied with the cortical injection site. For example, within the dentate, neurons labeled from leg M1 were located rostrally, those from face M1 caudally, and those from arm M1 at intermediate levels. In each instance, labeled neurons were confined to approximately the dorsal third of the nucleus. Within GPi, neurons labeled from leg M1 were located in dorsal and medial regions, those from face M1 in ventral and lateral regions, and those from arm M1 in intermediate regions. These results demonstrate that M1 is the target of somatotopically organized outputs from both the cerebellum and basal ganglia. Surprisingly, the projections to M1 originate from only 30% of the volume of the dentate and <15% of GPi. Thus, the majority of the outputs from the cerebellum and basal ganglia are directed to cortical areas other than M1.

Step-tracking movements of the wrist. IV. Muscle activity associated with movements in different directions.

We examined the patterns of muscle activity associated with multiple directions of step-tracking movements of the wrist in humans and monkeys. Human subjects made wrist movements to 12 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. Wrist muscles displayed two patterns of electromyographic (EMG) modulation as movement direction changed: amplitude graded and temporally shifted. The amplitude-graded pattern was characterized by modulation of the quantity of muscle activity that occurred during two distinct time periods, an agonist burst interval that began before movement onset and an antagonist burst interval that began just after movement onset. The timing of muscle activity over the two intervals showed little variation with changes in movement direction. For some directions of movement, EMG activity was present over both time intervals, resulting in "double bursts." Modulation of activity during the agonist burst interval was particularly systematic and was well fit by a cosine function. In contrast, the temporally shifted pattern was characterized by a gradual change in the timing of a single burst of muscle activity. The burst occurred at a time intermediate between the agonist and antagonist burst intervals. The temporally shifted pattern was seen less frequently than the amplitude-graded pattern and was present only in selected wrist muscles for specific directions of movement. Monkeys made wrist movements to 8-16 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. These movements were performed more slowly than those of human subjects. The wrist muscles of the monkeys we examined displayed the amplitude-graded pattern of activity but not the temporally shifted pattern. Stimulation of individual wrist muscles in monkeys resulted in wrist movements that were markedly curved, particularly for the wrist extensors. These results indicate that step-tracking movements of the wrist are generated mainly by using the amplitude-graded pattern to modulate muscle activity. We propose that this pattern reflects a central process that decomposes an intended movement into an agonist, "propulsive" component and an antagonist, "braking" component. Separate bursts of muscle activity then are generated to control each component. On the other hand, we argue that the temporally shifted pattern may function to reduce the amount of movement curvature associated with the activation of wrist muscles.

The cerebellum: an overview.

Life has been compared to a beautiful tapestry, woven in intricate design of many threads and colors. By means of physics, chemistry, physiology, anatomy, embryology and genetics we unravel this texture, separate its constituent threads and colors, but lose the pattern as a whole. These analytical sciences have enormously increased our knowledge of life's constituent elements and processes, but the pattern of the tapestry is usually neglected or ignored.

Common principles underlying the control of rapid, single degree-of-freedom movements at different joints.

Studies of rapid, single degree-of-freedom movements have shown different changes in electromyographic patterns for movement tasks that appear very similar (e.g., movements over different ranges of distance). However, it is not clear whether these differences are a result of joint-specific control schemes or whether they are instead due to the limited range of task parameters studied relative to the mechanical constraints of each joint (e.g., short compared with long movements relative to the range of motion of a particular joint). In this study, we measured and compared the kinematic trajectories and electromyograms recorded during various movement tasks at the wrist, elbow, and ankle. Subjects performed movements over a wide range of distances "as fast as possible," "at a comfortable speed," and against two inertial loads (at the elbow only), and they performed movements over a fixed distance at three different speeds at the wrist and ankle. For fast movements we show that, in spite of some joint-specific differences, the basic pattern of electromyographic (EMG) modulation is similar at all three joints; for example, the agonist EMG burst transitions from a fixed duration to an increasing duration with increasing movement distance at all three joints. Moreover, the distance at which this transition occurs in one joint relative to the distance at which this transition occurs in the other two joints is consistent across subjects. The transition occurs at the shortest distance at the ankle and the longest distance at the wrist. In general we suggest that the data are consistent with a single set of control rules applied at all three joints, with the biomechanical constraints at each joint accounting for the differences in the EMG and kinematic patterns observed across joints.

Motor areas on the medial wall of the hemisphere.

The primary motor cortex (M1) receives input from four premotor areas on the medial wall of the hemisphere: the supplementary motor area (SMA) and three cingulate motor areas located on the banks of the cingulate sulcus (CMAr, CMAd and CMAv). All four premotor areas have maps of the body containing distinct proximal and distal representations of the arm. Surprisingly, the size of the distal representation is comparable to or larger than the size of the proximal representation in each area. Thus, contrary to some previous hypotheses, the anatomical substrate exists for the premotor areas on the medial wall to be involved in the control of distal, as well as proximal arm movements. Each of the premotor areas on the medial wall also has substantial direct projections to the spinal cord. Corticospinal axons from these premotor areas terminate in the intermediate zone of the spinal cord. Some corticospinal axons from SMA, CMAd, and CMAv terminate around motoneurons. In this respect, these motor areas are like M1 and appear to have direct connections with spinal motoneurons, particularly those innervating muscles of the fingers and wrist. These results suggest that the premotor areas on the medial wall are an important source of descending commands for the generation and control of movement. In recent experiments we examined the pattern of functional activation in the premotor areas on the medial wall during the performance of sequences of pointing movements. The patterns of activation were then compared with the body maps revealed by our anatomical studies. Overall, our initial results indicate that the attributes of motor control are unequally represented across the premotor areas. For example, one of the areas on the medial wall, the CMAd, was strongly and selectively activated during the performance of highly practised, remembered sequences of movement. Further insights into the function of the premotor areas are likely to come from examining their participation in a broad range of behavioural paradigms. These initial results support our hypothesis that each premotor area makes some unique contribution to the planning, initiation and/or execution of movement.

Cerebellar output: motor and cognitive channels.

The input to the cerebellum has long been known to originate from widespread regions of the cerebral cortex including the frontal, parietal and temporal lobes. The output of the cerebellum, however, was thought to project mainly to the primary motor cortex. Recent anatomical observations have challenged this view. It is now apparent that cerebellar output goes to multiple cortical areas, including not only the primary motor cortex, but also areas of premotor and prefrontal cortex. In fact, there is growing evidence that each of the areas of cerebral cortex that project to the cerebellum is also the target of cerebellar output. The cerebellar output to individual cortical areas originates from distinct clusters of neurons in the deep nuclei which we have termed `output channels'. The individual output channels to the cortical areas we have examined display little or no overlap. Physiological recordings in awake trained primates indicate that neurons in different output channels appear to be involved in distinct aspects of behavior, and in both motor and cognitive functions. These observations indicate that the cerebellar influence on the cerebral cortex is more extensive than previously recognized.

Activation on the medial wall during remembered sequences of reaching movements in monkeys.

We used the 2-deoxyglucose (2DG) method to map activation in the motor areas on the medial wall of the hemisphere. One group of monkeys licked juice delivered at variable time intervals (LICK task). For these animals, the motor areas on the medial wall displayed restricted activation. 2DG uptake was limited largely to the face representation of the supplementary motor area (SMA). Additional labeling was present more rostrally in the banks of the cingulate sulcus. A second group of animals performed remembered sequences of reaching movements (REM task) for juice rewards. Activation related to licking also was present in this group. In addition, separate, discrete activations were found on the superior frontal gyrus and in the cingulate sulcus during the REM task. The most intense and extensive 2DG labeling was located in the dorsal bank of the cingulate sulcus, coincident with the dorsal cingulate motor area (CMAd). Weaker activations were present in the arm area of the SMA and in the pre-SMA. There was no significant 2DG incorporation in the ventral bank of the cingulate sulcus where the ventral cingulate motor area is located. Our findings suggest that the CMAd is involved more than any other medial area in the preparation for and/or execution of highly practiced, remembered sequences of movements. Overall, our results indicate that the attributes of motor control are not represented equally across the motor areas on the medial wall.

Cerebellar output channels.

The cerebellum has long been regarded as involved in the control of movement, in part through its connections with the cerebral cortex. These connections were thought to combine inputs from widespread regions of the cerebral cortex and "funnel" them into the motor system at the level of the primary motor cortex. Retrograde transneuronal transport of herpes simplex virus type I has recently been used to identify areas of the cerebral cortex that are "directly" influenced by the output of the cerebellum. Results suggest that cerebellar output projects via the thalamus to multiple cortical areas, including premotor and prefrontal cortex, as well as the primary motor cortex. In addition, the projections to different cortical areas appear to originate from distinct regions of the deep cerebellar nuclei. These observations have led to the proposal that cerebellar output is composed of a number of separate "output channels." Evidence from functional imaging studies in humans and single neuron recording studies in monkeys suggests that individual output channels are concerned with different aspects of motor or cognitive behavior.