Learning- and expectation-related changes in the human brain during motor learning.

We have studied a simple form of motor learning in the human brain so as to isolate activity related to motor learning and the prediction of sensory events. Whole-brain, event-related functional magnetic resonance imaging (fMRI) was used to record activity during classical discriminative delay eyeblink conditioning. Auditory conditioned stimulus (CS+) trials were presented either with a corneal airpuff unconditioned stimulus (US, paired), or without a US (unpaired). Auditory CS- trials were never reinforced with a US. Trials were presented pseudorandomly, 66 times each. The subjects gradually produced conditioned responses to CS+ trials, while increasingly differentiating between CS+ and CS- trials. The increasing difference between hemodynamic responses for unpaired CS+ and for CS- trials evolved slowly during conditioning in the ipsilateral cerebellar cortex (Crus I/Lobule HVI), contralateral motor cortex and hippocampus. To localize changes that were related to sensory prediction, we compared trials on which the expected airpuff US failed to occur (Unpaired CS+) with trials on which it occurred as expected (Paired CS+). Error-related signals in the contralateral cerebellum and somatosensory cortex were seen to increase during learning as the sensory prediction became stronger. The changes seen in the ipsilateral cerebellar cortex may be due either to the violations of sensory predictions, or to learning-related increases in the excitability of cerebellar neurons to presentations of the CS+.

Temporary inactivation in the primate motor thalamus during visually triggered and internally generated limb movements.

To better understand the contribution of cerebellar- and basal ganglia-receiving areas of the thalamus [ventral posterolateral nucleus, pars oralis (VPLo), area X, ventral lateral nucleus, pars oralis (VLo), or ventral anterior nucleus, pars parvicellularis (VApc)] to movements based on external versus internal cues, we temporarily inactivated these individual nuclei in two monkeys trained to make visually triggered (VT) and internally generated (IG) limb movements. Infusions of lignocaine centered within VPLo caused hemiplegia during which movements of the contralateral arm rarely were performed in either task for a short period of time ( approximately 5-30 min). When VT responses were produced, they had prolonged reaction times and movement times and a higher incidence of trajectory abnormalities compared with responses produced during the preinfusion baseline period. In contrast, those IG responses that were produced remained relatively normal. Infusions centered within area X never caused hemiplegia. The only deficits observed were an increase in reaction time and movement amplitude variability and a higher incidence of trajectory abnormalities during VT trials. Every other aspect of both the VT and IG movements remained unchanged. Infusions centered within VLo reduced the number of movements attempted during each block of trials. This did not appear to be due to hemiplegia, however, as voluntary movements easily could be elicited outside of the trained tasks. The other main deficit resulting from inactivation of VLo was an increased reaction time in the VT task. Finally, infusions centered within VApc caused IG movements to become slower and smaller in amplitude, whereas VT movements remained unchanged. Control infusions with saline did not cause any consistent deficits. This pattern of results implies that VPLo and VLo play a role in the production of movements in general regardless of the context under which they are performed. They also suggest that VPLo contributes more specifically to the execution of movements that are visually triggered and guided, whereas area X contributes specifically to the initiation of such movements. In contrast, VApc appears to play a role in the execution of movements based on internal cues. These results are consistent with the hypothesis that specific subcircuits within the cerebello- and basal ganglio-thalamo-cortical systems preferentially contribute to movements based on external versus internal cues.

Microstimulation of movements from cerebellar-receiving, but not pallidal-receiving areas of the macaque thalamus under ketamine anaesthesia.

The motor thalamic areas receiving input from the globus pallidus (VA) and the cerebellar nuclei (VL) appear to have different roles in the generation and guidance of movements. In order to further test these differences, we used electrical stimulation to map the ventro-anterior and ventro-lateral nuclei of the thalamus in three ketamine anaesthetised monkeys. Movements were readily evoked from VL at currents of down to 10 microA. The movements were typically multijoint, and stimulation could evoke arm and trunk or arm and facial movement at the same current threshold. Evoked arm movements often involved multiple joints, with or without finger movements. Facial movements included the lips, tongue, jaw, eyebrows and, occasionally, the eyes. The thalamic map was topographic, but complex with at least two separate regions related to arm movement. Very few sites within the VA could stimulate movement, even at high currents. We therefore suggest that the cerebellar projections to motor regions of the cortex, which pass through the VL thalamic nuclei, have a different relationship and are closer to movement execution than the projections from basal ganglia via the ventro-anterior nucleus.

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.

Anatomy of motor learning. II. Subcortical structures and learning by trial and error.

We used positron emission tomography to study motor learning by trial and error. Subjects learned sequences of eight finger movements. Tones generated by a computer told the subjects whether any particular move was correct or incorrect. A control condition was used in which the subjects generated moves, but there was no feedback to indicate success or failure, and so on learning occurred. In this condition (free selection) the subjects were required to make a finger movement on each trial and to vary the movements randomly over trials. The subjects had a free choice of which finger to move on any one trial. On this task there was no systematic change in responses over trials and no change in the response times. Two other conditions were included. In one the subjects repetitively moved the same finger on all trials and in a baseline condition the subjects heard the pacing tones and auditory feedback but made no movements. Comparing new learning with the free selection task, there was a small activation in the right prefrontal cortex. This may reflect the fact that in new learning, but not free selection, the subject rehearse past moves and adapt their responses accordingly. The caudate nucleus was strongly activated during new learning. It is suggested that this activity may be related either to mental rehearsal or to reinforcement of the movements as a consequence of the outcomes. The putamen was activated anteriorly on the free selection task and more posteriorly when the subjects repetitively made the same movement. It is suggested that the differences in the location of the peak activation in the striatum may represent the operation of different corticostriatal loops. The cerebellar nuclei (bilaterally) and vermis were more active in the new learning condition than during the performance of the free selection task. There was no difference in the activation of the cerebellum when the free selection task was compared with repetitive performance of the same movement. We tentatively suggest that the basal ganglia may be involved in the specification of movement on the basis of memory of either the movements or the outcomes, but that the cerebellum may be more directly involved in changes in the parameters of movement execution.

Functional anatomy of the mental representation of upper extremity movements in healthy subjects.

1. Differences in the distribution of relative regional cerebral blood flow during motor imagery and execution of a joy-stick movement were investigated in six healthy volunteers with the use of positron emission tomography (PET). Both tasks were compared with a common baseline condition, motor preparation, and with each other. Data were analyzed for individual subjects and for the group, and areas of significant flow differences were related to anatomy by magnetic resonance imaging (MRI). 2. Imagining movements activated a number of frontal and parietal regions: medial and lateral premotor areas, anterior cingulate areas, ventral opercular premotor areas, and parts of superior and inferior parietal areas were all activated bilaterally when compared with preparation to move. 3. Execution of movements compared with imagining movements led to additional activations of the left primary sensorimotor cortex and adjacent areas: dorsal parts of the medial and lateral premotor cortex; adjacent cingulate areas; and rostral parts of the left superior parietal cortex. 4. Functionally distinct rostral and caudal parts of the posterior supplementary motor area (operationally defined as the SMA behind the coronal plane at the level of the anterior commissure) were identified. In the group, the rostral part of posterior SMA was activated by imagining movements, and a more caudoventral part was additionally activated during their execution. A similar dissociation was observed in the cingulate areas. Individual subjects showed that the precise site of these activations varied with the individual anatomy; however, a constant pattern of preferential activation within separate but adjacent gyri of the left hemisphere was preserved. 5. Functionally distinct regions were also observed in the parietal lobe: the caudal part of the superior parietal cortex [medial Brodmann area (BA) 7] was activated by imagining movements compared with preparing to execute them, whereas the more rostral parts of the superior parietal lobe (BA 5), mainly on the left, were additionally activated by execution of the movements. 6. Within the operculum, three functionally distinct areas were observed: rostrally, prefrontal areas (BA 44 and 45) were more active during imagined than executed movements; a ventral premotor area (BA 6) was activated during both imagined and executed movements; and more caudally in the parietal lobe, an area was found that was mainly activated by execution presumably SII. 7. These data suggest that imagined movements can be viewed as a special form of "motor behavior' that, when compared with preparing to move, activate areas associated heretofore with selection of actions and multisensory integration.(ABSTRACT TRUNCATED AT 400 WORDS)

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).

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.

Cortical and subcortical afferents to the amygdala of the rhesus monkey (Macaca mulatta).

The afferent projections to the primate amygdala were studied using horseradish peroxidase. The potential advantages of this technique are discussed compared with those previously used to determine amygdaloid afferents. The findings indicate that certain agranular or dysgranular cortical regions may project directly to the amygdala: in particular, the orbital frontal cortex, anterior cingulate gyrus, subcallosal gyrus, temporal pole and anterior insula. These projections probably terminate predominantly in either the lateral or accessory basal nuclei. Other cortical projections from the inferotemporal and superior temporal gyri are described. Evidence was found for a heavy projection from the superior temporal sulcus to the lateral nucleus. Subcortical afferents were found from the hypothalamus, substantia innominata, diagonal band, thalamus, periaqueductal central gray, peripeduncular nucleus and from a band of cells extending medially from the peripeduncular nucleus to the midline, just ventral to the thalamus. In the thalamus, labelled cells were restricted to the non-specific nuclei, and were common in the rostral midline nuclei. No projection was observed from the dorsomedial nucleus of the thalamus. We discuss the implications of these results for interpreting the functions of the amygdala.