Sensory Motor Lab

  Department of Psychology, Princeton University, Princeton, NJ 08544

Michael Graziano, Phone : (609) 258-7555, Fax : (609)258-1113, Email : graziano@princeton.edu

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Summary

The work in my lab focuses on functional imaging of the human motor cortex and computational models of the motor cortex. This current work rests on a set of previous experiments done on the motor cortex of monkeys. The following brief description provides some background on the motor cortex from its discovery in 1870 to the present and places our work in conceptual context.

Evoking movements by electrically stimulating motor cortex
In 1870, Fristch and Hitzig discovered the motor cortex. They used electrical stimulation to evoke movements from the dog brain. Since then, many investigators used electrical stimulation to map the motor cortex in monkeys and humans (Ferrier, 1874; Penfield and Boldrey, 1937; Woolsey et al., 1952; Asanuma, 1975; Gould et al., 1996). Brief bursts of electrical stimulation were applied to the cortex and the evoked muscle twitches were studied. The experiments focused on anatomical mapping – determining the connectivity from points in cortex, via the spinal cord, to muscles. Most investigators concluded that the map of muscles in the cortex was overlapping and blurred. Individual muscles did not have separated cortical representations (e.g. Donoghue et al. 1992; Gould et al. 1986; Park et al. 2001; Sessle and Wiesendanger 1982; Woolsey et al. 1952).

Electrical stimulation was also widely used outside of motor cortex. The oculomotor system in particular was initially mapped through stimulation (e.g. Bruce et al. 1985; Gottlieb et al. 1993; Robinson 1972; Robinson and Fuchs 1969; Schiller and Stryker 1972; Tehovnik and Lee, 1993; Thier and Andersen 1998). The approach, however, was different. In a cortical eye movement area such as the frontal eye field (FEF) or the supplementary eye field (SEF), a single site does not map in a specific manner to the eye muscles. Instead, stimulation of a site evokes a coordinated eye movement such as a saccade, a smooth pursuit movement, or a conjoint head and eye movement. To evoke a meaningful behavior, the stimulation must be on a behavioral time scale. A stimulation train much shorter than a normal saccade will evoke a truncated eye movement resembling an eye twitch.

The question arose therefore whether stimulation of motor cortex on a behaviorally relevant time scale might evoke coordinated movements from the animal’s normal repertoire. Since monkeys reach and grasp over a time scale of approximately half a second, we applied half-second stimulation trains to the motor cortex of monkeys (Graziano et al. 2002, 2005). The methods were taken directly from the eye movement literature. The stimulation consisted of trains of biphasic pulses, each pulse 0.2 ms wide. The amplitude varied between 20 and 150 microamps. The frequency was typically set at 200 Hz though similar results were obtained with a range of frequencies. The duration of the train was typically 0.5 s though shorter and longer trains were also tested.

The evoked movements involved integrated action of many body parts and resembled common movements in a monkey’s normal repertoire. They included ethologically relevant behaviors such as closing the hand in a grip while bringing the hand to the mouth and opening the mouth; extending the hand away from the body with the palm facing away from the body and the grip opened as if in preparation to grasp an object; bringing the hand inward to a region just in front of the chest while shaping the fingers, as if to manipulate an object; squinting the facial muscles while turning the head sharply to one side and flinging up the arm, as if to protect the face from an impending impact; and moving all four limbs as if leaping or climbing. The behavioral repertoire of the animal seemed to be rendered onto the cortical sheet (see Figure 1 above).

Other studies have since shown similar results in a range of species. Stimulation in cortical motor areas evokes complex, ethologically relevant behaviors in cats, rats, and Gallegos (Brecht et al., 2004; Ethier et al., 2004; Stepniewska et al., 2005; Haiss and Schwarz, 2005). For example, in rats, reaching actions of the forepaws, rhythmic whisking actions, and facial defensive-like movements can be evoked from specific zones in motor cortex (Ethier et al., 2004, Ramanathan et al., 2006). When the reaching zone was lesioned, the rat’s ability to reach was impaired. When a lesioned rat was re-trained to reach, the motor cortex developed new regions from which reaching could be evoked (Ramanathan et al., 2006).

Electrical stimulation therefore appears to reveals maps of complex, behaviorally useful actions arranged in motor cortex. Yet legitimate questions remain about how exactly to integrate these surprising new findings with more traditional views of motor cortex. Some of these questions and issues are discussed in the following sections.

How do we account for the division between premotor cortex and primary motor cortex?
A surprising result from our stimulation mapping studies was that complex, ethologically relevant movements could be evoked from the primary motor cortex, caudal premotor cortex, and SMA, areas that all have a direct and substantial projection to the spinal cord. How can this single, encompassing map of behavioral repertoire be reconciled with the large body of evidence indicating that these cortical areas are distinct in structure, connectivity, and function, and moreover that the SMA and premotor cortex can be further subdivided into many smaller functional areas (see Figure 2 below)?

Perhaps the best explanation thus far is that a mapping of behavioral repertoire across the cortical surface does not argue against functional cortical subdivisions. On the contrary, it provides a deep underlying explanation for the subdivisions. In this hypothesis, the separation among areas is driven by the statistical clustering within the movement repertoire. For example, in PMDc or F2, stimulation tends to evoke movements resembling a forward reaching of the arm and shaping of the hand as if in preparation to grasp. In PMVc or F4, neurons respond to sensory stimuli, typically to tactile stimuli on the face or arms and to visual stimuli moving in the space near the tactile receptive field. Stimulation here evokes defensive-like movements such as squinting, ducking, or blocking with the arm. Stimulation in the primary motor hand area evokes movements that resemble fine manipulation of objects, movements that normally require control of individual joint rotations and control of forces applied to objects. In SMA, stimulation evokes movements that resemble complex locomotion such as climbing or leaping; these movements incorporate both sides of the body, and sometimes integrate the entire body from head to tail. Perhaps these sectors in motor cortex differ from each other partly because they emphasize different segments of the animal’s movement repertoire that require different control strategies and different patterns of sensory input and motor output. The view of a map of behavioral repertoire may therefore be complementary to, rather than in conflict with, more traditional views of functional divisions in the motor cortex.

How do we account for direction tuning?
One of the most important contributions to motor cortex physiology was the discovery of direction tuning by Georgopoulos et al. (1986, 1988). When a monkey reaches from a central location in a variety of directions, neurons in motor cortex are tuned to the direction of hand movement, broadly preferring one direction over the others. Yet on stimulating the motor cortex, we tended not to evoke a hand movement in a specific direction. Instead, the joints of the arm tended to seek a specific posture, regardless of the initial posture. As a result, the hand tended to move from any initial position toward a specific final position. The hand-to-mouth movements are an especially clear example of this apparent goal-directedness. How can a directional code for hand movement be reconciled with the stimulation-evoked movements to a goal posture? We performed a single neuron experiment to track down the reason for this apparent discrepancy (Aflalo and Graziano, 2007). In summary, we found direction tuning in local regions of space and tuning to the posture of the arm across the global workspace of the arm. Tuning to hand direction was not consistent over the entire workspace. Tuning to the posture of the arm was too broad to be observed over local regions of the workspace. Our suggestion was that direction tuning may pertain more to the task of moving the hand from point to point in local regions of space; and in contrast, the postures that we obtained on stimulation may be more related to the canonical postures of the arm typical of general classes of behavior.

Why don’t lesions remove specific behaviors?
If zones within motor cortex relatively emphasize different categories of behavior, then why don’t lesions in motor cortex result in permanent loss of specific behavioral functions? Two studies address this question. We found that chemical inhibition of the defense-related zone in motor cortex had a selective effect, reducing the monkey’s ability to flinch (Cook and Graziano, 2004). Perhaps the best answer to the question comes from a study by Ramanathan et al. (2006). They found that electrical stimulation of the rat cortex evoked complex movements including reaching movements of the forepaw. When the reaching zone was lesioned, the rat’s ability to reach was selectively impaired. Yet the impairment was temporary. The rats were able to re-learn the action. Once the rat re-learned, the motor cortex was found to have developed new regions from which reaching could be evoked. The extent of the rat’s recovery of reaching ability correlated with the size of the new reaching representation in cortex. These results suggest that local lesions to specific zones in motor cortex do cause selective impairment of action types, but the deficit recovers rapidly.

Are we studying the function of local neurons or of widespread networks?
Electrical stimulation must affect many connected structures. How does one know if an evoked movement is truly a function of the directly stimulated neurons around the electrode tip, or instead a function of the structures connected to those neurons? Perhaps the evoked movement is actually caused by spinal circuits, basal ganglia circuits, cerebellar circuits, or other motor circuits.

In the use of electrical stimulation, it is necessary to distinguish between two kinds of signal spread. Direct spread, sometimes called passive spread, is the spread of the electrical field around the electrode tip that activates neighboring neurons. Indirect or active spread is the spread of neuronal signals across synapses and through networks. Ideally the passive spread is minimized, or at least restricted to the experimentally targeted neurons. The active spread, the percolation of signal through connected networks, is the goal of the technique, allowing function to be probed. It is not an error or artifact to be avoided. The evoked movement is a function of the directly stimulated neurons because of their effect on connected structures. The most basic truth of the brain is that no neuron has a function by itself. Its function is defined by its connections with, and therefore its influence on, other neurons.

Does motor cortex contain modules for the control of discrete movement types?
Are we proposing that the motor cortex can be divided into isolated areas, each of which controls a separate type of action, providing the animal with a limited number of action primitives? No. The fundamental code in motor cortex is probably a population code. In our hypothesis, a hand-to-mouth movement may involve neuronal activity across a wide extent of motor cortex, with a hill or peak near the hand-to-mouth area. Activity in the hand-to-mouth area, such as through electrical stimulation, evokes a specific movement partly because of the manner in which it recruits the rest of motor cortex. Loss of the hand-to-mouth area should remove the most efficient, centralized representation of that movement and therefore reduce performance, but surrounding cortical regions can presumably combine their outputs to produce a less skilled hand-to-mouth movement. The view suggested here is therefore a combination of localized function and distributed population, an approach that was successful in explaining the maps and population codes present in eye movement areas such as the superior colliculus.

Beyond stimulation?
Stimulation appears to crudely mimic normal function. This crude approximation to normal function has been observed in a great range of brain systems. The effect of stimulation, however, is by no means an exact match to normal function and should not be taken too literally. The evoked movements provide useful hypotheses about function that require further study using a range of convergent techniques. For example, a function suggested by stimulation may be tested through single neuron recording, chemical inhibition of a cortical site, and chemical excitation. Comparison to natural behavior may provide insight into the stimulation-evoked movement. Modeling studies may help to determine if the hypothesized function is plausible given the known circuitry. We used all of these techniques to study the unexpected functional organization of motor cortex that was suggested by our initial stimulation experiments. These experiments are described in our publications, and are now described in a book, The Intelligent Movement Machine, scheduled for publication in 2008.

References

Aflalo TN and Graziano MSA. 2007. Relationship between unconstrained arm movement and single neuron firing in the macaque motor cortex. Journal of Neuroscience, 27: 2760-2780.

Asanuma H. 1975. Recent developments in the study of the columnar arrangement of neurons within the motor cortex. Physiol Rev 55: 143-156.

Brecht M, Schneider M, Sakmann B, and Margrie TW. 2004. Whisker movements evoked by stimulation of single pyramidal cells in rat motor cortex. Nature 427: 704-710.

Bruce CJ, Goldberg ME, Bushnell MC, and Stanton GB. 1985. Primate frontal eye fields. II. Physiological and anatomical correlates of electrically evoked eye movements. J Neurophysiol 54: 714-734.

Cooke DF and Graziano MSA. 2004b. Super-flinchers and nerves of steel: Defensive movements altered by chemical manipulation of a cortical motor area. Neuron 43: 585-593.

Donoghue JP, Leibovic S, and Sanes JN 1992. Organization of the forelimb area in squirrel monkey motor cortex: representation of digit, wrist, and elbow muscles. Exp. Brain Res. 89: 1-19.

Ethier C, Brizzi L, Darling WG, and Capaday C. 2006. Linear summation of cat motor cortex outputs. J Neurosci 26: 5574-5581.

Ferrier D. 1874. Experiments on the brain of monkeys – No. 1. Proc R Soc Lond 23: 409-430.

Fritsch G and Hitzig E. 1870. Uber die elektrishe Erregbarkeit des Grosshirns. Arch. f. Anat., Physiol und wissenchaftl. Mediz., Leipzig, 300-332. (On the electrical excitability of the cerebrum.) Translated by G. von Bonin. In Some Papers on The Cerebral Cortex. WW Nowinski, Ed. 73-96. Springfield IL: Thomas.

Georgopoulos AP, Kettner RE, and Schwartz AB. 1988. Primate motor cortex and free arm movements to visual targets in three-dimensional space. II. Coding of the direction of movement by a neuronal population. J. Neurosci. 8: 2928-2937.

Georgopoulos AP, Schwartz AB, and Kettner RE. 1986. Neuronal population coding of movement direction. Science 233: 1416-1419.

Gottlieb JP, Bruce CJ, and MacAvoy MG. 1993. Smooth eye movements elicited by microstimulation in the primate frontal eye field. J. Neurophysiol. 69: 786-799.

Gould HJ 3rd, Cusick CG, Pons TP, and Kaas JH. 1986. The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eye fields in owl monkeys. J. Comp. Neurol. 247: 297-325.

Graziano MSA and Aflalo TN. 2007. Mapping behavior repertoire onto the cortex. Neuron 56: 239-251.

Graziano MSA, Aflalo T, and Cooke DF. 2005. Arm movements evoked by electrical stimulation in the motor cortex of monkeys. J Neurophys 94: 4209-4223.

Graziano MSA, Taylor CSR, and Moore T. 2002. Complex movements evoked by microstimulation of precentral cortex. Neuron 34: 841-851.

Haiss F and Schwarz C. 2005. Spatial Segregation of Different Modes of Movement Control in the Whisker Representation of Rat Primary Motor Cortex. J Neurosci 25: 1579-1587.

Park MC, Belhaj-Saif A, Gordon M, and Cheney PD. 2001. Consistent features in the forelimb representation of primary motor cortex in rhesus macaques. J. Neurosci. 21: 2784-2792.

Penfield W and Boldrey E. 1937. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 60: 389-443.

Ramanathan D, Conner JM, and Tuszynski MH. 2006. A form of motor cortical plasticity that correlates with recovery of function after brain injury. Proc Natl Acad Sci USA 103:11370-11375.

Robinson DA. 1972. Eye movements evoked by collicular stimulation in the alert monkey. Vis Res 12:1795-1808.

Robinson DA and Fuchs AF. 1969. Eye movements evoked by stimulation of the frontal eye fields. J Neurophysiol 32: 637-648.

Schiller PH and Stryker M. 1972. Single-unit recording and stimulation in superior colliculus of the alert rhesus monkey. J Neurophysiol 35: 915-924.

Sessle BJ and Wiesendanger M. 1982. Structural and functional definition of the motor cortex in the monkey (Macaca fascicularis). J. Physiol. 323: 245-265.

Stepniewska I, Fang PC, and Kaas JH. 2005. Microstimulation reveals specialized subregions for different complex movements in posterior parietal cortex of prosimian galagos. Proc Natl Acad Sci USA 102: 4878-4883.

Tehovnik EJ and Lee K. 1993. The dorsomedial frontal cortex of the rhesus monkey: topographic representation of saccades evoked by electrical stimulation. Exp. Brain Res. 96: 430-442.

Thier P and Andersen RA. 1998. Electrical microstimulation distinguishes distinct saccade-related areas in the posterior parietal cortex. J Neurophys 80: 1713-1735.

Woolsey CN, Settlage PH, Meyer DR, Sencer W, Hamuy TP, and Travis AM. 1952. Pattern of localization in precentral and "supplementary" motor areas and their relation to the concept of a premotor area. In: Association for Research in Nervous and Mental Desease, Vol. 30. New York, NY: Raven Press, pp. 238-264.