The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys

Abstract

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

Figure 1.

Experimental paradigm and cortical labeling. A, Diagram of anterograde transneuronal transport of virus from spinothalamic neurons in laminae I, V, and VII to thalamus and then from thalamus to cerebral cortex. The gray area in the spinal cord represents the virus injection site. B, C, Photomicrographs of third-order neurons labeled in the cingulate sulcus after anterograde transneuronal transport of virus from cervical segments of the spinal cord. The boxed area in B is enlarged in C. CgS, Cingulate sulcus.

Figure 2.

Virus injection sites in the spinal cord. Upper left: We divided the gray matter of the spinal cord into eight regions and determined the extent of the spread of virus at the injection site into each region. Upper right and bottom panels, Each panel displays the injection site of a separate animal. Dark gray shading indicates the central zone of virus labeling and light gray indicates the peripheral zone. The injection was considered to be the central zone of labeling (see Materials and Methods for details). The segments sampled are indicated along the abscissa of each chart. We sampled each segment at 1 mm intervals.

Figure 3.

Distribution of virus infected neurons in the thalamus. Photomicrographs show neurons in various nuclei of the thalamus that were infected by anterograde transneuronal transport of virus from the cervical spinal cord. A, B, Nissl stained sections of the thalamus show nuclear borders. Some gliosis is evident in regions where virus infected neurons are located (e.g., VPI in A; MD in B). C, D, Sections reacted to demonstrate virus infected neurons. Section C is near section A; section D is near section B. Black arrows mark distinct patches of labeled neurons. Open arrows in C and D mark blood vessels that are also present in A and B. E, F, Digitally merged photographs of the sections A + C and B + D. The calibration in F applies to all sections. CM, Centromedian nucleus; fr, fasciculus retroflexus; Hb, habenular nucleus; LP, lateral posterior nucleus; Pf, parafasciculus nucleus; VPM, ventral posterior medial nucleus.

Figure 4.

Virus infected neurons in thalamic nuclei. Photomicrographs of virus infected neurons in thalamic nuclei. VPI and VLc/VPLc are taken from the dashed boxes in Figure 3C. Po-SG and MD are taken from the dashed boxes in Figure 3D. The inset in Po-SG displays a higher-magnification view of an infected neuron (marked by the small arrow). The calibration for all sections is shown in MD. Abbreviations as in Figure 3.

Figure 5.

Distribution of cortical neurons labeled by anterograde transneuronal transport of virus from the spinal cord. Charts display dense clusters of labeled neurons (small black dots) found on coronal sections at various levels of the cerebral cortex. The numbers below each section indicate their location (marked in Figs. 6, 7). ArSi, ArSs, Inferior and superior limbs of the arcuate sulcus; ArSpur, spur of the arcuate sulcus; CgS, cingulate sulcus; LS, lateral sulcus; 1, 3a, 3b, 4, cytoarchitectonic areas.

Figure 6.

ST projections to cortical areas in the lateral sulcus. A, Lateral view of the left hemisphere from a cebus monkey. The lateral sulcus is unfolded to show the cortical areas buried in it. The lateral sulcus is unfolded downward from its dorsal edge. The dorsal and ventral edges of the sulcus are represented by solid lines and various bends in the sulcus are represented by dashed lines. Dotted lines enclose S2 on the dorsal bank of the lateral sulcus (LSd) and Ig on the Insula. B, C, Location and density of neurons labeled in the lateral sulcus following anterograde transneuronal transport of virus from the spinal cord (B, animal DL2; C, animal DL3). The density of labeled neurons was determined by counting the number of labeled cells within 200 μm bins along each section. The number of cells per bin was divided into five levels and color coded: white, top 5% of bins (95–100%); yellow, 90–95%; red, 80–90%; large blue squares, 40–80%; 0–40%, omitted. The numbered arrows refer to sections illustrated in Figure 5. AC, Level of the anterior commissure; ArS, arcuate sulcus; CSl, lateral extent of central sulcus; Ia, agranular insular cortex; Id, dysgranular insular cortex; IPS, intraparietal sulcus; LSv, lateral sulcus, ventral bank; PS, principal sulcus; 7op, opercular portion of area 7. Other abbreviations and conventions as in Figures 4 and 5.

Figure 7.

ST projections to cortical areas in the cingulate sulcus. A, Unfolded map of medial wall of the hemisphere. The medial wall is unfolded and reflected upward from the midline. The edges of the cingulate sulcus are represented by solid lines and the fundus is represented by a dashed line. A dotted line encloses the portion of the primary motor cortex that extends onto the medial wall. The numbers and letters in italics indicate the relative location of the various cortical areas that are on the medial wall. B, Location and density of neurons labeled in the cingulate sulcus following anterograde transneuronal transport of virus from the spinal cord (animal DL3). The numbered arrows refer to sections illustrated in Figure 5. ArG, Level of the genu of the arcuate sulcus; CC, corpus callosum; CgSd, dorsal bank of the cingulate sulcus; CgSv, ventral bank of the cingulate sulcus; CgG, cingulate gyrus; CMAd, dorsal cingulate motor area; CMAr, rostral cingulate motor area; CMAv, ventral cingulate motor area; PreSMA, presupplementary motor area; SGm, medial portion of the superior frontal gyrus; SMA, supplementary motor area. Other abbreviations and conventions as in Figures 4–6.

Figure 8.

Injection site in the arm representation of the PMv. The arm representation of the PMv was identified using intracortical stimulation. Then, it was injected with a conventional tracer (diamidino yellow). A, Lateral view of the left hemisphere from a cebus monkey. The dashed box on the brain outline indicates the region magnified in B. B, Motor responses and injection site in the PMv (animal DL7). Symbols indicate the movement evoked at each site of intracortical stimulation (see key at lower right). The size of each symbol indicates the threshold (large = <10 μA, medium = 10–20 μA, small = >20 μA). A small “x” indicates each of the 3 sites of tracer injection. The spread of the tracer is indicated by the gray shading. Abbreviations and conventions as in Figures 5 and 6.

Figure 9.

Overlap between ST projections to the cingulate sulcus and the cingulate motor areas. In animal DL7, a conventional tracer (diamidino yellow) was injected into the arm representation of the PMv. In the same animal, the H129 strain of HSV1 was injected into cervical segments of the spinal cord. A, Unfolded map of neurons on the medial wall of the hemisphere that project to the PMv (the injection site is shown in Fig. 8). These neurons are located in each of the cortical motor areas in and adjacent to the cingulate sulcus, i.e., SMA, CMAr, CMAd, CMAv. A separate small patch of labeled neurons (*) is located in the caudal part of the CMAd. B, Location and density of neurons labeled in the cingulate sulcus following anterograde transneuronal transport of virus from the spinal cord. C, Overlap map of the cortical regions that project to the PMv and the cortical regions that are the target of the ST system. Blue bins indicate cortical regions containing only neurons labeled by anterograde transneuronal transport of virus from the spinal cord. Yellow bins indicate cortical regions containing only neurons labeled by retrograde transport of a conventional tracer from the PMv. Red bins indicate cortical regions containing both types of labeled neurons. The numbered arrow marks the location of the section illustrated in Figure 10. Abbreviations and conventions as in Figures 6 and 7.

Figure 10.

Overlap between ST projections to the cingulate sulcus and the CMAd and CMAv. Neurons labeled by anterograde transneuronal transport from the spinal cord (black dots) and neurons labeled retrograde transport from the PMv (gray dots) are plotted on a single cortical section. Abbreviations and conventions as in Figure 5.

Figure 11.

Relationship between pain-related and motor-related activations on the medial wall of the hemisphere in humans. Pain-related activations on or near the midline of the contralateral hemisphere are indicated by red symbols. The numbers in the symbols refer to the references listed in Table 2. These “pain” sites were overlapped on a map of the sites of activation associated with the performance of “simple” (blue circles) and “complex” (blue diamonds) movements [taken from Picard and Strick (1996), their Fig. 5]. The summary map also includes the outlines of the cingulate motor areas in humans (gray shading; Picard and Strick, 1996). CA-CP, Horizontal line passing through the anterior and posterior commissures; CCZ, caudal cingulate zone; RCZa, anterior subdivision of the rostral cingulate zone; RCZp, posterior subdivision of rostral cingulate zone; Vca, vertical line through the anterior commissure; Vcp, vertical line through the posterior commissure.

Figure 12.

Major cortical targets of the ST system and their thalamic inputs. The percentage of the total ST input to each cortical area is indicated (“%”). This number is based on the average of two animals (DL2 and DL3, see Results for further details). The thalamic nuclei that are most likely to mediate this input are listed below each cortical area. These thalamic nuclei: (1) receive ST terminations (see Results for references), (2) contain infected neurons in the present study, and (3) are known to project to the relevant cortical area. The following references provide the basis for these thalamocortical linkages: Po-SG to Ig (Mufson and Mesulam, 1984; Friedman and Murray, 1986); VPI to S2 (Friedman and Murray, 1986; Stevens et al., 1993); MDvc to CMA (Hatanaka et al., 2003); VPLc to S1 (Gingold et al., 1991; Jones, 2007). CMA, Cingulate motor areas; MDvc, ventrocaudal portion of medial dorsal nucleus.