Jerome N. Sanes

Dopaminergic effects on simple and choice reaction time performance in Parkinson's disease.

The present study examined whether premovement central neural processing in Parkinsons disease was related to functional motor disability and plasma L-dopa concentration. Reaction time (RT) performance in simple and choice RT tasks was assessed while plasma L-dopa levels were controlled by continuous IV L-dopa infusion in five parkinsonian patients. Five age-matched controls performed the same RT tasks for comparison. Simple RT for the patients was longer than the normal control RT at all infusion levels (p ≤ 0. 005). However, choice RT was normal when the patients were “on,” but became prolonged as plasma L-dopa levels decreased (p ≤ 0. 01). The results show that there are abnormalities of premovement central neural processing in Parkinsons disease, and that simple and choice RTs are differentially affected by L-dopa replacement. This suggests that different neural mechanisms may be involved in the processing of these tasks.

Cerebral activation covaries with movement rate.

An important aspect in brain activation studies is the relationship between neuronal activity and measurable indices of function. We applied functional magnetic resonance imaging (fMRI) to investigate blood flow- related MR signal changes in response to different rates of repetitive movements of the index finger. The contralateral precentral gyrus and the posterior frontomesial cortex revealed a significant increase in MR signal over baseline for 1, 2 and 3 Hz finger movements, with a linear effect of rate in the precentral gyrus. Increased firing of neuronal aggregates or recruitment of additional neuronal units within the primary motor cortex necessary for increased output to target neurons and maintaining posture of nearby distal and proximal joints may contribute to the activation pattern.

Information processing deficits in Parkinson's disease during movement

The capacity to process information during movement selection and execution was studied in Parkinsonian patients and controls in a task involving movement of a hand-held stylus between two targets whose size and separation could be systematicaly varied. Movement time and accuracy were evaluated when the size and required accuracy of movements were changed to modify movement difficulty. Movement time and inaccuracy of patients with Parkinsons disease were exaggerated by increasing target separation so as to increase movement extent (target size held constant) or by decreasing target size (target separation held constant). The fact that these changes in task difficulty caused greater deterioration of performance for patients than for controls is consistent with previous studies indicating that Parkinsonian patients have deficits in executing high-velocity movements. These data also show that performance deficits by Parkinsonian patients can be brought out by increasing movement difficulty through requiring increased movement accuracy. These findings are interpreted in relation to the relative contribution of deficits in movement execution vs motor programming in the motor disorders of Parkinsons disease.

Spatial coding of visual and somatic sensory information in body-centred coordinates

Because sensory systems use different spatial coordinate frames, cross‐modal sensory integration and sensory–motor coordinate transformations must occur to build integrated spatial representations. Multimodal neurons using non‐retinal body‐centred reference frames are found in the posterior parietal and frontal cortices of monkeys. We used functional magnetic resonance imaging to reveal regions of the human brain using body‐centred coordinates to code the spatial position of both visual and somatic sensory stimuli. Participants determined whether a visible vertical bar (visual modality) or a location touched by the right index finger (somatic sensory modality) lay to the left or to the right of their body mid‐sagittal plane. This task was compared to a spatial control task having the same stimuli and motor responses and comparable difficulty, but not requiring body‐centred coding of stimulus position. In both sensory modalities, the body‐centred coding task activated a bilateral fronto‐parietal network, though more extensively in the right hemisphere, to include posterior parietal regions around the intraparietal sulcus and frontal regions around the precentral and superior frontal sulci, the inferior frontal gyrus and the superior frontal gyrus on the medial wall. The occipito‐temporal junction and other extrastriate regions exhibited bilateral activation enhancement related to body‐centred coding when driven by visual stimuli. We conclude that posterior parietal and frontal regions of humans, as in monkeys, appear to provide multimodal integrated spatial representations in body‐centred coordinates, and these data furnish the first indication of such processing networks in the human brain.

On Somatotopic Representation Centers for Finger Movements in Human Primary Motor Cortex and Supplementary Motor Area

We used functional magnetic resonance imaging to examine the representation pattern for repetitive voluntary finger movements in the primary motor cortex (M1) and the supplementary motor area (SMA) of humans. Healthy right-handed participants performed repetitive individuated flexion-extension movements of digits 1, 2, and 3 using the dominant hand. Contralateral functional labeling for the group indicated a largely overlapping activation pattern in M1 and SMA for the three digits. Consistent with recent findings, the geographic activation center in M1 for each finger differed, and we found some evidence of a homunculus organization pattern in M1 and SMA, but only for the central location of the representations. However, the statistical power for the homunculus pattern was weak, and the distance separating the digit geographical centers was typically less than 15% of the entire extent of digit representations in M1 or SMA. While separations for digit representations occurred, the entire data set provided more support for the concept of distributed, overlapping representations than for a classic homunculus organization for voluntary finger movements.

Orderly Somatotopy in Primary Motor Cortex: Does It Exist?

In the current issue of NeuroImage and an upcoming issue of Cerebral Cortex appear data relevant to a fundamental question about the functional organization of the primary motor cortex (M1) of primates (Beisteiner et al., 2001; Hlustik et al., 2001; Indovina and Sanes, 2001), that is, does there exist an orderly somatotopy in M1 and, by extension, in other major motor areas of the brain. A fundamental finding of these papers provides support for separation between representations for finger and hand movement that adheres to a somatotopic organization. The new findings extend previous reports of somatotopically ordered representations for voluntary movements of various joints of the human upper extremity, fingers, wrist, elbow, and shoulder (Grafton et al., 1993; Kleinchmidt et al., 1997; Lotze et al., 2000), but conflict with thers (Rao et al., 1995; Sanes et al., 1995). However, as others and we have noted, the degree of somatotopic representation within the upper extremity representation appears rather limited (Schieber, 1999; Sanes and Donoghue, 2000). Clearly the major body parts—lower limb (hindlimb), upper limb (forelimb), and head—have functional and largely independent subdivisions to represent the muscles and movements controlled by the respective parts of M1. These functional subdivisions of M1 are commonly laid out along the cortical surface of primates with the lower (hind) limb most medial, the head most lateral, and the upper (fore) limb in between; they have acquired the designation of “areas,” such as the “M1 arm area,” though the term “representation” might provide a more suitable functional name. No serious challenge has emerged for this basic large-scale organization pattern in M1, but

Neocortical mechanisms in motor learning

The ability to learn novel motor skills has fundamental importance for adaptive behavior. Neocortical mechanisms support human motor skill learning, from simple practice to adaptation and arbitrary sensory-motor associations. Behavioral and neural manifestations of motor learning evolve in time and involve multiple structures across the neocortex. Modifications of neural properties, synchrony and synaptic efficacy are all related to the development and maintenance of motor skill.

Improved detection of event-related functional MRI signals using probability functions.

Selecting an optimal event distribution for experimental use in event-related fMRI studies can require the generation of large numbers of event sequences with characteristics hard to control. The use of known probability distributions offers the possibility to control event timing and constrain the search space for finding optimal event sequences. We investigated different probability distributions in terms of response estimation (estimation efficiency), detectability (detection power, parameter estimation efficiency, sensitivity to true positives), and false-positive activation. Numerous simulated event sequences were generated selecting interevent intervals (IEI) from the uniform, uniform permuted, Latin square, exponential, binomial, Poisson, chi(2), geometric, and bimodal probability distributions and fixed IEI. Event sequences from the bimodal distribution, like block designs, had the best performance for detection and the poorest for estimation, while high estimation and detectability occurred for the long-decay exponential distribution. The uniform distribution also yielded high estimation efficiency, but probability functions with a long tail toward higher IEI, such as the geometric and the chi(2) distributions, had superior detectability. The distributions with the best detection performance also had a relatively high incidence of false positives, in contrast to the ordered distributions (Latin square and uniform permuted). The predictions of improved sensitivities for distributions with long tails were confirmed with empirical data. Moreover, the Latin square design yielded detection of activated voxels similar to the chi(2) distribution. These results indicate that high detection and suitable behavioral designs have compatibility for application of functional MRI methods to experiments requiring complex designs.

Motor skill learning in Parkinson's disease

The motor performance of patients with Parkinsons disease is degraded, but it is unclear whether their motor learning (adaptation learning and skill learning) ability is impaired. To assess the ability of these patients to learn motor tasks, we studied nine Parkinsons disease patients and eight age-matched normal (control) subjects who repetitively traced, as rapidly and accurately as possible, irregular geometric patterns with normal and mirror-reversed vision. The outcome was measured by statistical analysis and graphic plotting of values for actual and standardized performance variables and correlation of data from initial and final performance variables with indicators of disease severity. The results showed that, with normal vision, total movement time was reduced in both patients and normal subjects, but movement errors increased with repetition, apparently reflecting a speed-accuracy trade-off and adaptation learning. With mirror-reversed vision, total movement time and movement errors were reduced equally with repetition in both groups. These concomitant improvements in time and accuracy violate the rule of speed-accuracy trade-off and suggest that this behavior reflects true motor skill learning. We conclude that patients with Parkinsons disease do not differ from normal subjects in the processes of motor adaptation and motor skill learning.

Human brain activation accompanying explicitly directed movement sequence learning

Abstract. We examined brain activation patterns occurring during the production and encoding of a motor sequence. Participants performed a variant of the serial reaction-time task under two conditions. The first condition was designed to foster the engagement of explicit mechanisms of knowledge acquisition. The second condition was intended to encourage the engagement of implicit learning mechanisms that would be more typical of the standard serial reaction-time task. In the first condition, the acquisition of explicit knowledge about an 8-element ordered sequence led to a significant and rapid decline in reaction time. By contrast, the second condition, the task in which a sequence was presented unbeknownst to participants, did not yield changes in reaction time. Several brain regions, including prefrontal cortex, superior and inferior parietal lobules, and cerebellum, exhibited explicit learning-related activation. The prefrontal cortex and inferior parietal lobules increased their levels of activation between the beginning and end of the experiment, while primary motor, primary sensory, and cerebellar cortex decreased their levels of activation from the beginning to the end of the experiment. We propose a model in which two processes, a learning-related increase and a habituation process might interact to produce the activation patterns observed during movement sequence acquisition. In short, the prefrontal cortex and inferior parietal lobule together direct and recruit superior parietal lobule and cerebellum to encode and perform the sequence. The increased activation in prefrontal cortex and inferior parietal lobule may represent the activity of a working memory circuit that functions in the acquisition and recall of sequence information.