Predicting sensory events. The role of the cerebellum in motor learning.

There is growing evidence that the cerebellum is involved in the implicit learning of movement sequences. On the serial reaction time (RT) task patients with cerebellar lesions fail to demonstrate normal decreases in RT and we have shown a similar effect in monkeys with bilateral cerebellar lesions. However, it is not clear if this impairment is unique to sequence learning or whether the cerebellum is also involved in the learning of discrete responses to predictable visual targets. We investigated this possibility in another group of monkeys with bilateral lesions of the cerebellum centred on the lateral nuclei. Three animals were pre-operatively trained to make rapid manual responses to a single target appearing on a touch-sensitive VDU screen. In one condition, a target could appear at any of three possible locations (spatially unpredictable). In a second condition the target always appeared in the same place (spatially predictable). A third condition was similar to the second except that the onset of the target was temporally predictable whereas in the previous conditions this parameter was randomized. Following the lesions, the RT savings earned on the conditions in which the cues were predictable were abolished. This was despite a lack of significant increase in movement times. The results imply that the animals were either failing to predict the spatial location or time of presentation of the target, or that they were unable to use their prediction to improve their reaction times. The function of the cerebellum in motor sequence learning may therefore be part of a more general operation in learning to prepare responses to predictable sensory events.

The cerebellum and cognition: cerebellar lesions impair sequence learning but not conditional visuomotor learning in monkeys.

Claims that the cerebellum contributes to cognitive processing in humans have arisen from both functional neuroimaging and patient studies. These claims challenge traditional theories of cerebellar function that ascribe motor functions to this structure. We trained monkeys to perform both a visuomotor conditional associative learning task and a visually guided sequence task, and studied the effects of bilateral excitotoxic lesions in the lateral cerebellar nuclei. In the first experiment three operated monkeys showed a small impairment in post-operative retention of a visuomotor associative task (A) but were then not impaired in learning a new task (B). However, the impairment on A could have been due to a problem in making the movements themselves. In a second experiment we therefore gave the three control animals a further pre-operative retest on both A and B and then tested after surgery on retention of both tasks. Though again the animals showed motor problems on task A, they reached criterion, and at this stage could clearly make both movements satisfactorily. The critical test was then retention of task B, and they were not impaired. In the final experiment (serial reaction time task) the monkeys response times on a repeating visuomotor sequence were compared with those for a pseudo-random control sequence. After bilateral nuclei lesions they were slow to execute the pre-operatively learned sequence but were still faster on this than on the control task. However, when they were then given a new repeating sequence to learn, they never performed the sequence as quickly as they had on retention of the first sequence. We conclude that the cerebellum is not essential for the learning or recall of stimulus-response associations but that it is crucially involved in the process by which motor sequences become automatic with extended practice.

The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys.

Anatomical studies in non-human primates have shown that the cerebellum has prominent connections with the dorsal, but not the ventral, visual pathways of the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited in support of the view that the cerebellum may be involved in cognitive functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore trained on a classic test of working memory, the spatial delayed alternation (SDA) task, and also on a visual concurrent discrimination (VCD) task. Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in three of the animals. When retested after surgery the lesioned animals were as quick to relearn both tasks as the remaining unoperated animals. However, when the response times (RT) for each task were directly compared, on the SDA task the monkeys with cerebellar lesions were relatively slow to decide where to respond. We argue that on the SDA task animals can prepare their responses between trials whereas this is not possible on the VCD task, and that the cerebellar lesions may disrupt this response preparation. We subsequently made bilateral lesions in the DPFC of the control animals and retested them on the SDA task. These monkeys failed to relearn the task. The results show that, unlike the dorsal prefrontal cortex, the cerebellum is not essential for working memory or the executive processes that are necessary for correct performance, though it may contribute to the preparation of responses.

The striatum and self-paced movements.

Monkeys (Macacca fascicularis) were tested for their ability to perform learned, self-initiated arm movements for reward, both before and after receiving bilateral putamen lesions. The rate at which they made the movements was significantly reduced postoperatively, but their performance on a visually cued control task was normal. It is argued that the impairment was not a consequence of poor motor control or motivation, but that it reflected a reduced capacity to recall learned movements in the absence of external cues. The results complement similar findings for monkeys with supplementary motor cortex (SMA) lesions; the putamen is interconnected with the SMA in a cortico-striatal-thalamocortical loop.

The left hemisphere and the selection of learned actions.

The left hemisphere's dominance for movement is well known. The basis of its dominance is less clear. We have tested 16 left hemisphere (LH) patients, 17 right hemisphere (RH) patients and 12 neurologically normal controls on a battery of five tasks. The tasks were based on animal lesion and recording studies, and human imaging and magnetic stimulation studies that identified two distributed systems that are important for the selection of motor responses and object-oriented responses. The LH patients were impaired on three response selection tasks: learning to select between joystick movement responses instructed by visual cues; learning to select between analogous object-oriented responses instructed by visual cues; learning to select movements in a sequence. Although we replicated the finding that LH damage impairs sequencing, some of the impaired tasks had no sequencing element. We therefore argue that the LH deficits are best explained as an impairment of response selection. This was confirmed by showing that LH subjects were unimpaired on a more demanding task-object discrimination learning-which imposed a greater memory load but had no response selection element. Moreover, the LH deficits could not be attributed to disorganization of movement kinematics. The lesions of the impaired LH group were widespread but always included the distributed systems known to be important for response selection-the dorsolateral frontal and parietal cortices, striatum, thalamus and white matter fascicles.

The left parietal cortex and motor attention.

The posterior parietal cortex, particularly in the right hemisphere, is crucially important for covert orienting; lesions impair the ability to disengage the focus of covert orienting attention from one potential saccade target to another (Posner, M. I. et al., Journal of Neuroscience, 1984, 4, 1863-1874). We have developed a task where precues allow subjects to covertly prepare subsequent cued hand movements, as opposed to an orienting or eye movement. We refer to this process as motor attention to distinguish it from orienting attention. Nine subjects with lesions that included the left parietal cortex and nine subjects with lesions including the right parietal cortex were compared with control subjects on the task. The left hemisphere subjects showed the same ability as controls to engage attention to a movement when they were forewarned by a valid precue. The left hemisphere subjects, however, were impaired in their ability to disengage the focus of motor attention from one movement to another when the precue was incorrect. The results support the existence of two distinct attentional systems allied to the orienting and limb motor systems. Damage to either system causes analogous problems in disengaging from one orienting/movement target to another. The left parietal cortex, particularly the supramarginal gyrus, is associated with motor attention. All the left hemisphere subjects had ideomotor apraxia and had particular problems performing sequences of movements. We suggest that the well documented left hemisphere and apraxic impairment in movement sequencing is the consequence of a difficulty in shifting the focus of motor attention from one movement in a sequence to the next.

Ventral prefrontal cortex is not essential for working memory.

It is widely held that the prefrontal cortex is important for working memory. It has been suggested that the inferior convexity (IC) may play a special role in working memory for form and color (). We have therefore assessed the ability of monkeys with IC lesions to perform visual pattern association tasks and color-matching tasks, both with and without delay. In experiment 1, six monkeys were trained on a visual association task with delays of up to 2 sec. Conservative IC lesions that removed lateral area 47/12 in three animals had no effect on the task. Further experiments showed that these lesions had no effect on the postoperative new learning of a color-matching task with delays of up to 2 sec or versions of the visual association task involving delays of up to 8 sec. In experiment 2, larger lesions of both areas 47/12 and 45A were made in the three control animals. This lesion caused a profound deficit in the ability to relearn simultaneous color matching, but subsequent matching with delays of up to 8 sec was clearly unimpaired. We suggest that the IC may be more important for stimulus selection and attention as opposed to working memory.

Parietal cortex and movement. II. Spatial representation.

Lesions in the two divisions of parietal cortex, 5/7b/MIP and 7a/LIP, produce dissociable reaching deficits. Monkeys with 5/7b/MIP removals were tested on reaching in the dark under two different conditions. All the reaches made on any day were from the same starting position to the same target position in the control condition. In the "transfer" condition, all the reaches were made to the same target position but consecutive reaches were made from different starting positions. The target could be represented as a constant pattern of joint and muscle positions in the control condition. The transfer condition required a representation of the starting position of the hand and/or a representation of the target in terms of its position in space. Removal of areas 5, 7b and MIP produced only a very mild impairment in the control condition and a severe impairment in the transfer condition. This suggests that 5/7b/MIP does not represent the limb in simple sensory or motor coordinates but in terms of its spatial position.

Parietal cortex and movement. I. Movement selection and reaching.

Recording studies in the parietal cortex have demonstrated single-unit activity in relation to sensory stimulation and during movement. We have performed three experiments to assess the effect of selective parietal lesions on sensory motor transformations. Animals were trained on two reaching tasks: reaching in the light to visual targets and reaching in the dark to targets defined by arm position. The third task assessed non-standard, non-spatial stimulus response mapping; in the conditional motor task animals were trained to either pull or turn a joystick on presentation of either a red or a blue square. We made two different lesions in the parietal cortex in two groups of monkeys. Three animals received bilateral lesions of areas 5, 7b and MIP, which have direct connections with the premotor and motor cortices. The three other animals subsequently received bilateral lesions in areas 7a, 7ab and LIP. Both groups were still able to select between movements arbitrarily associated with non-spatial cues in the conditional motor task. Removal of areas 7a, 7ab and LIP caused marked inaccuracy in reaching in the light to visual targets but had no effect on reaching in the dark. Removal of areas 5, 7b and MIP caused misreaching in the dark but had little effect on reaching in the light. The results suggest that the two divisions of the parietal cortex organize limb movements in distinct spatial coordinate systems. Area 7a/7ab/LIP is essential for spatial coordination of visual motor transformations. Area 5/7b/MIP is essential for the spatial coordination of arm movements in relation to proprioceptive and efference copy information. Neither part of the parietal lobe appears to be important for the non-standard, non-spatial transformations of response selection.

Associative learning in patients with cerebellar ataxia.

It has been claimed that patients with cerebellar pathology are impaired at associative learning. Patients with cerebellar ataxia (n = 7) were taught a visual-motor associative task. The task was chosen so as to allow comparisons with data currently being collected on the effects of cerebellar lesions on associative learning in monkeys. As a group the patients were as impaired at learning the task as a group of 8 patients with Huntington's disease. When each patient was individually matched with a control of the same age and IQ, some patients with cerebellar ataxia were found to be clearly impaired, but 2 were not. Of the 4 patients who were most clearly impaired, 2 had brainstem pathology and 2 did not. The relevance of these findings is discussed in relation to views concerning the functions of the cerebellum.

The functions of the medial premotor cortex. II. The timing and selection of learned movements.

Monkeys with medial premotor cortex (MPC) lesions are impaired on a simple learned task that requires them to raise their arm at their own pace. However, they can succeed on this task if they are given tones to guide performance. In the externally paced task the tones could aid performance in several ways. They tell the animal when to act (trigger), they remind the animal that food is available and so motivate (predictor), and they remind the animal of what to do (instruction). Monkeys with MPC lesions can respond quickly to visual cues (experiment 1), and they can respond as well as normal monkeys when there is no immediate trigger (experiment 2). They are also quick to relearn a task in which external cues tell them what to do (experiment 5). However, they are poor at selecting between movements on a simple motor sequence task (experiment 3), and they are poor at changing between two movements (experiment 4). On these tasks there were cues to act as triggers and predictors, but there were no external instructions. We conclude that the reason why animals with MPC lesions perform better with external cues is that these cues act as instructions. The cues prompt retrieval of the appropriate action. This is true whether the task requires the animal to perform one action (experiments 1 and 2) or to select between actions (experiments 3 and 4).

The functions of the medial premotor cortex. I. Simple learned movements.

We report several studies on the effects of removing the medial premotor cortex (supplementary motor area) in monkeys. The removal of this area alone does not cause either paralysis or akinesia. However, the animals were poor at performing a simple learned task in which they had to carry out an arbitrary action: they were taught to raise their arm in order to obtain food in a foodwell below. They were impaired whether they worked in the light or the dark. They were impaired when they had to perform the movements at their own pace, but much less impaired when a tone paced performance. Monkeys with lesions in the anterior cingulate cortex were as impaired as monkeys with medial premotor lesions at performing this task at their own pace. However, monkeys with lateral premotor lesions were less impaired. We conclude that the medial premotor areas play a crucial role in the performance of learned movements when there is no external stimulus to prompt performance.

Motor sequence learning: a study with positron emission tomography.

We have used positron emission tomography to study the functional anatomy of motor sequence learning. Subjects learned sequences of keypresses by trial and error using auditory feedback. They were scanned with eyes closed under three conditions: at rest, while performing a sequence that was practiced before scanning until overlearned, and while learning new sequences at the same rate of performance. Compared with rest, both sequence tasks activated the contralateral sensorimotor cortex to the same extent. Comparing new learning with performance of the prelearned sequence, differences in activation were identified in other areas. (1) Prefrontal cortex was only activated during new sequence learning. (2) Lateral premotor cortex was significantly more activated during new learning, whereas the supplementary motor area was more activated during performance of the prelearned sequence. (3) Activation of parietal association cortex was present during both motor tasks, but was significantly greater during new learning. (4) The putamen was equally activated by both conditions. (5) The cerebellum was activated by both conditions, but the activation was more extensive and greater in degree during new learning. There was an extensive decrease in the activity of prestriate cortex, inferotemporal cortex, and the hippocampus in both active conditions, when compared with rest. These decreases were significantly greater during new learning. We draw three main conclusions. (1) The cerebellum is involved in the process by which motor tasks become automatic, whereas the putamen is equally activated by sequence learning and retrieval, and may play a similar role in both. (2) When subjects learn new sequences of motor actions, prefrontal cortex is activated. This may reflect the need to generate new responses. (3) Reduced activity of areas concerned with visual processing, particularly during new learning, suggests that selective attention may involve depressing the activity of cells in modalities that are not engaged by the task.

Control of arm movement after bilateral lesions of area 5 in the monkey (Macaca mulatta).

The effect of bilateral area 5 lesions on the analysis of proprioceptive information and the guidance of reaching movements was studied in three rhesus monkeys. In the first paradigm (Proprioceptive discrimination test) the monkeys were trained to discriminate between movements of a joystick to the right or left without visual control; they reported the direction of movement by touching or not touching a screen (go/no-go task). After area 5 had been removed, the monkeys were only mildly impaired on this test. It is concluded that such simple joint movement could be analysed in area 2, area 5 being concerned with more complex arm movements. In the second paradigm (Searching test) the monkey had to find a peanut on a board in the dark using proprioceptive information stored in memory during previous trials. After area 5 lesions, the number of correct reaches was not modified but the number of errors after an incorrect trial (correcting movement) was significantly increased. The data suggests that when visual input is not available, area 5 is involved in the guidance of arm movements on the basis of proprioceptive inputs.

Cortical areas and the selection of movement: a study with positron emission tomography.

Regional cerebral blood flow was measured in normal subjects with positron emission tomography (PET) while they performed five different motor tasks. In all tasks they had to moved a joystick on hearing a tone. In the control task they always pushed it forwards (fixed condition), and in four other experimental tasks the subjects had to select between four possible directions of movement. These four tasks differed in the basis for movement selection. A comparison was made between the regional blood flow for the four tasks involving movement selection and the fixed condition in which no selection was required. When selection of a movement was made, significant increases in regional cerebral blood flow were found in the premotor cortex, supplementary motor cortex, and superior parietal association cortex. A comparison was also made between the blood flow maps generated when subjects performed tasks based on internal or external cues. In the tasks with internal cues the subjects could prepare their movement before the trigger stimulus, whereas in the tasks with external cues they could not. There was greater activation in the supplementary motor cortex for the tasks with internal cues. Finally a comparison was made between each of the selection conditions and the fixed condition; the greatest and most widespread changes in regional activity were generated by the task on which the subjects themselves made a random selection between the four movements.

Motor learning in monkeys (Macaca fascicularis) with lesions in motor thalamus.

The study examines the nature of the influence that the basal ganglia exert on frontal cortex via the motor nuclei of the thalamus. Twelve monkeys were trained to pull a handle given one colour cue and to turn it given another. Bilateral lesions were then placed in the ventral thalamus. Four monkeys with large anterior lesions including the VA nucleus and the anterior part of VLo were severely impaired at relearning the task. Monkeys with small lesions in VAmc or with lesions centred on VLo were not impaired. The analysis of the histology suggests that the impairment in the four monkeys did not result from involvement of the cerebellar relay through nucleus X. It is argued that the animals are not impaired because of faulty execution. This suggests that the basal ganglia have an influence on motor learning.

Reorganization in the human brain as illustrated by the thalamus.

A comparison is made between the relative size of the various thalamic nuclei in man and other primates. Using data for non-human primates predictions are made as to the expected size of the nuclei for the human brain. Of the nuclear groupings five are of the size predicted but three are not. The lateral geniculate is proportionately smaller than predicted, but it is argued that this need not imply a radical change.