Sensory representation abnormalities that parallel focal hand dystonia in a primate model

Abstract

In our hypothesis of focal dystonia, attended repetitive behaviors generate aberrant sensory representations. Those aberrant representations interfere with motor control. Abnormal motor control strengthens sensory abnormalities. The positive feedback loop reinforces the dystonic condition. Previous studies of primates with focal hand dystonia have demonstrated multi-digit or hairy-glabrous responses at single sites in area 3b, receptive fields that average ten times larger than normal, and high receptive field overlap as a function of horizontal distance. In this study, we strengthen and elaborate these findings. One animal was implanted with an array of microelectrodes that spanned the border between the face and digits. After the animal developed hand dystonia, responses in the initial hand representation increasingly responded to low threshold stimulation of the face in a columnar substitution. The hand-face border that is normally sharp became patchy and smeared over 1 mm of cortex within 6 weeks. Two more trained animals developed a focal hand dystonia variable in severity across the hand. Receptive field size, presence of multi-digit or hairy-glabrous receptive fields, and columnar overlap covaried with the animal's ability to use specific digits. A fourth animal performed the same behaviors without developing dystonia. Many of its physiological measures were similar to the dystonic animals, but receptive field overlap functions were minimally abnormal, and no sites shared response properties that are normally segregated such as hairy-glabrous combined fields, or multi-digit fields. Thalamic mapping demonstrated proportionate levels of abnormality in thalamic representations as were found in cortical representations.

Figure 1

Apparati for tasks. A. In the palmar grasp task, the animal pulls the two rods together with a palmar grasp. Once the rods are closed, a 20 Hz vibration occurs. Upon cessation of vibration, the animal releases the rods within reaction time limits. B. In the hand positioning task, the animal contacts the tips of two probes with the distal phalanges of digits one and two. Contact detectors on the probe tips detect contact, and an LED turns on when contact is established. The animal must hold the hand position for one second. In a more advanced version of the task, the animal releases its hand after detecting a temporal pattern of taps delivered by the motors.

Figure 2

Mean digital receptive field area as a function of time. The digital receptive fields becomes rapidly localized on the points of stimulation in the first two weeks of behavior, without enlarging. The digital receptive fields enlarged substantially after threshold behavior. Receptive fields are four times larger than normal at week two, and more than ten times normal size at week seven.

Figure 3

Cortical surface maps in area 3 at different times after focal hand dystonia onset. A. Two months before focal dystonia. B. Two weeks after focal dystonia. C. Six weeks after focal dystonia. Note that receptive fields representing the face region invaded territory that previously represented the hand. Abbreviations: lowlip: lower lip, lip-L: lateral lips, PR: proprioceptive, fhead: forehead, orbit: skin surrounding the eye, d1: digit one, d1p: proximal phalange digit one.

Figure 4

Receptive fields on four consecutive recording sessions shown superimposed on the hand on the left. In the fifth recording session, the electrical activity on the electrode sounded similar to the first four days, but no receptive field could be drawn. On the sixth day, the receptive fields reappeared on the lower lip. The following day a single unit receptive field was mapped on the whiskers just superior to the lateral mouth. The eighth day the receptive field was on the lower lip and whiskers just inferior to the lower lip. Recording sessions three through seven occurred at 24 hour intervals; two day gaps separated these from other recordings.

Figure 5

One representative plane of thalamic penetrations in omt592. Electrode penetrations were vertical in a 250 μm horizontal grid. Receptive field samples were derived each 125 μm. Different colors indicate each digit’s responses. Abbreviations: d1, digit one; d2, digit two; d1d, digit one, distal phalange; H, hairy skin response; G, glabrous skin response; w, whole. All responses were evoked by glabrous skin stimulation unless otherwise indicated.

Figure 6

Area 3b maps from om574, om311 and om624. The incidence of multi-digit and hairy/glabrous mixed responses is prominent in the animals with focal dystonia. The control animal, om624, had only one penetration with either hairy/glabrous mixed responses or multi-digit receptive fields. Anterior is left, medial is up. The right hemisphere map of om624 is left-right reflected, for direct comparison with the other left hemisphere maps.

Figure 7

om311 and om574 receptive field areas by digit. om311 developed a focal dystonia prominent only on digit 4. om574 developed a focal dystonia primarily affecting digits 1,2, and 5.

Figure 8

A collection of receptive fields for d1/2 and d4 for om574. After focal dystonia onset, the animal principally used digits 3 and 4 in the task. Receptive field sizes parallel the spatial distribution of dystonia as d4 receptive fields are smaller than d1/2 receptive fields. Note also that some d1/2 receptive fields are multidigit, or combine hairy and glabrous skin surfaces in the same receptive field. Each color represents one receptive field.

Figure 9

Receptive field overlap as a function of cortical distance. The animal without focal dystonia, om624, has less receptive field overlap than the three animals with focal dystonia, and less than a hand representation ipsilateral to the focal dystonia in om311 (see OM311R in figure).

Figure 10

Receptive field overlap maps for dystonic animal om311 and control animal om624. Each square marks the position of a microelectrode penetration. For each pair of receptive fields for which the shared receptive field area was at least 5 % of the union of the two areas, a line was drawn between the squares for the two penetrations. Line width is proportional to receptive field overlap. Both animals have mean digital receptive fields close to 20 mm², approximately 2.5 times larger than normal. Both animals trained on the palmar grasp task. Om624 went on to train on the precision hand positioning task. Om311 developed a focal hand dystonia prominent on d4. The right hemisphere map of om624 is left-right reflected to allow direct comparison with the left hemisphere map of om311.