Kikuro Fukushima

The neuronal substrate of integration in the oculomotor system

Abbreviations

The interstitial nucleus of Cajal in the midbrain reticular formation and vertical eye movement

Bilateral lesions of the midbrain reticular formation within, and in the close vicinity of, the interstitial nucleus of Cajal (INC) result in the severe impairment of the ability to hold eccentric vertical eye position after saccades, phase advance and decreased gain of the vestibulo-ocular reflex (VOR) induced by sinusoidal vertical rotation. In addition, the INC region of alert animals contains many burst-tonic and tonic neurons whose activity is closely correlated with vertical eye movement, not only during spontaneous saccades, but also during the VOR, smooth pursuit and optokinetic eye movements. Although their activity is closely related to these conjugate vertical eye movements, it is different from the oculomotor motor neuron activity. These results indicate that the INC region is involved in, and indispensable for, some aspects of eye position generation during vertical eye movement. Further comparison of INC neuron discharge with eye movements during two special conditions indicates that the INC region alone cannot produce eye position signals. First INC neuron discharge shows no response or an 80 degrees phase advance (close to the expected value if there is no integration) in the dark compared to the light during sinusoidal vertical linear acceleration in alert cats. Second, during rapid-eye-movement (REM) sleep, the discharge of INC neurons is no longer correlated with eye position. These results imply that the INC is not the entire velocity-to-position integrator, but that it has to work with other region(s) to perform the integration. A close functional linkage has been described between vertical-eye-movement-related neurons in the INC region and vestibulo-ocular relay neurons related to the vertical semicircular canals in the vestibular nuclei. It has been suggested that both are the major constituents of the common neural integrator circuits for vertical eye movements.

Responses of floccular Purkinje cells to sinusoidal vertical rotation and effects of muscimol infusion into the flocculus in alert cats

To understand how the flocculus is involved in the integration process in the vertical VOR, we examined the responses of floccular Purkinje cells during whole-body rotation in many vertical and horizontal planes in alert cats. The great majority of cells that responded to pitch rotation received excitation from the contralateral posterior canal, whereas the minority received excitation from the anterior canal, either on the ipsilateral or contralateral side; 35% of these vertical canal responding cells received convergent inputs, either from the ipsilateral or contralateral horizontal canal. After infusion of a GABA agonist (muscimol) into the area where many posterior canal responding Purkinje cells were recorded, the downward VOR induced by nose-up pitch was selectively impaired at low stimulus frequencies, together with an impairment of gaze holding after downward saccades. These results indicate a crucial role for posterior canal responding floccular Purkinje cells in generating downward eye position signals. Since the flocculus inhibits VOR interneurons related to the anterior and horizontal canals but not the posterior canal (Ito, 1984), our results suggest the possibility that posterior canal responding floccular Purkinje cells may form a transfloccular inhibitory pathway to anterior canal related VOR interneurons. This pathway may facilitate the positive feedback effect in the vestibular commissural inhibitory pathway between the co-planar vertical canals for the posterior canal signal, and may thereby be specifically involved in integration in the vertical VOR.

Ocular torsion produced by unilateral chemical inactivation of the interstitial nucleus of Cajal in chronically labyrinthectomized cats

Unilateral lesions of the rostral midbrain involving the interstitial nucleus of Cajal (INC) have been known to produce ocular torsion in alert animals including humans, which has been assumed to be the result of an impaired otolith-ocular reflex. We examined the effects of chemical deactivation of the INC using a gamma-aminobutyric acid (GABA) agonist (muscimol) in cats that had received bilateral labyrinthectomy, and compared the results with those in normal cats. Ocular torsion with a magnitude similar to that observed in normal cats appeared in chronically labyrinthectomized cats after unilateral muscimol infusion into the INC, indicating that ocular torsion following unilateral INC deactivation can be produced by a mechanism independent of the otolith-ocular reflex.

Cross axis vestibulo-ocular reflex induced by pursuit training in alert monkeys

We examined the effect of conflicting vestibular and smooth pursuit information on the vestibulo-ocular reflex (VOR) in alert monkeys. Sinusoidal whole body rotation was applied either in the pitch or yaw plane while presenting a target spot that moved orthogonally to the rotation plane. The monkeys were rewarded for tracking the spot and eye movements induced by rotation alone were examined every 15-30 min in complete darkness. Orthogonal eye movement responses to rotation were not observed before training but appeared after about 30 min of training. The gains (eye/chair) of the orthogonal component increased up to 0.2 after 1-2 h and were largest at the training frequency and approximately in phase with the stimulus; phase advanced at lower frequencies and lagged at higher frequencies. Amplitude tuning was also demonstrated when examined using different amplitudes at a constant frequency after training. Two hours of training to fixate an earth-stationary spot projected onto a patterned visual background that moved orthogonally to the rotation plane during rotation, did not induce a cross axis response. These results indicate that pursuit training during VOR is effective in inducing cross-axis eye movement responses that are tuned to the metrics of the training stimulus.

The interstitial nucleus of Cajal is involved in generating downward fast eye movement in alert cats.

We examined whether or not the interstitial nucleus of Cajal (INC) is involved in generating vertical fast eye movement. We used a gamma-aminobutyric acid (GABA) agonist (muscimol) to deactivate the INC cell bodies bilaterally in alert head-fixed cats. The INC was identified by recording vertical eye position-related burst-tonic neurons. Following muscimol infusion into the bilateral INC, the cats were unable to hold eccentric upward eye position after saccades, and the mean time constant of postsaccadic drift was 0.4 sec. In addition, downward saccades were virtually lost without clear impairment of horizontal saccades. Muscimol infusion into the Forels field H resulted in loss of both upward and downward fast eye movement as reported previously. Bilateral electrolytic INC lesions produced results similar to those after muscimol infusion into the INC, suggesting that the cutting of passing fibers in the INC alone cannot explain the selective loss of downward fast eye movement. These results indicate that the INC itself is involved in generating downward fast eye movement. We propose that the loss of activity in possible downward burster-driving neurons in the INC can explain the selective loss of downward fast eye movement after bilateral INC lesions.

Otolith-visual interaction in the control of eye movement produced by sinusoidal vertical linear acceleration in alert cats

Summary1. Eye movement responses were examined in alert cats during sinusoidal vertical linear acceleration. Stimulus frequencies of 0.20–0.85 Hz with a constant amplitude of 10.5 cm (corresponding to 0.02–0.31 g) were used. A random visual pattern was presented to give sinusoidal vertical optokinetic stimuli of similar amplitude and frequency to the up-down motion of the cat. 2. Sinusoidal linear acceleration in the presence of a stationary visual pattern produced robust eye movement responses with near compensatory phase at all stimulus frequencies tested. With both eyes covered, a vertical linear vestibulo-ocular reflex (LVOR) was frequently produced at a stimulus strength corresponding to 0.04–0.31 g. The evoked LVOR was always small, and the overall mean response phase values advanced by as much as 70 ° at frequencies below 0.56 Hz, indicating that the otolith signals activated by sinusoidal linear acceleration were not, by themselves, converted into compensatory eye position signals under these experimental conditions. 3. Optokinetic stimulation alone produced more lag of response phase as stimulus frequency increased, and the gain of evoked eye movement responses was smaller at higher stimulus frequencies compared to the gain during linear acceleration in the light. Bilateral labyrinthectomies resulted in a significant change of the eye movement responses during linear acceleration when visual inputs were allowed: there was more phase lag at higher stimulus frequencies and a decreased gain at all frequencies tested. These results indicate that the interaction of otolith and visual inputs produces robust eye movement responses with near compensatory phase during sinusoidal linear acceleration in the light.

Possible downward burster-driving neurons related to the anterior semicircular canal in the region of the interstitial nucleus of Cajal in alert cats

It is well known that vestibular nystagmus evoked by head rotation occurs in the plane specific to that in which head rotation was applied in three-dimensional space. Although burster-driving neurons (BDN) have been demonstrated for a quick phase of horizontal nystagmus, it is not yet known where the counterpart for vertical nystagmus is located. We analyzed the activity of a class of neurons in the region within, and in the close vicinity of, the interstitial nucleus of Cajal (INC) in alert cats. Their activity gradually increased during an upward slow phase evoked by nose-down pitch. This increased activity was further followed by burst discharge shortly before and during the downward quick phase. Gradually increased activity was also evoked by contralateral roll. These results suggest that the gradually increased activity was evoked by activation of the contralateral anterior canal. Many of these cells were fired by electrical stimulation of the contralateral vestibular nerve with short latencies. These cells also showed burst discharge shortly before and during downward saccades induced by visual stimuli, and the number of spikes during bursts was correlated with saccade amplitudes. Although all had irregular resting discharges, eye-position-related activity was rarely obtained. The characteristic behavior of these cells is very similar, except for their on-directions, to the behavior of horizontal BDNs, suggesting that these INC cells are a candidate for downward BDNs related to the anterior canal.

Latencies of response of eye movement-related neurons in the region of the interstitial nucleus of Cajal to electrical stimulation of the vestibular nerve in alert cats.

SummaryRecent studies have shown that the interstitial nucleus of Cajal (INC) in the midbrain reticular formation is involved in the conversion of vertical semicircular canal signals into eye position during vertical vestibuloocular reflexes. Secondary vestibulo-ocular relay neurons related to the vertical canals, which constitute the majority of output neurons sending signals from the vestibular nuclei directly to the oculomotor nuclei, have been shown to project axon collaterals to the region within and near the INC. To understand how the INC is involved in the signal conversion, latencies of response of neurons in the INC region to electrical stimulaton of the vestibular nerve were examined in alert cats. The responses of 96 cells whose activity was clearly modulated by sinusoidal pitch rotation (at 0.31 Hz) were analyzed. These included 41 cells whose activity was closely correlated with vertical eye movement (38 burst-tonic and 3 tonic neurons), and 55 other cells (called pitch cells as previously). Twenty nine of the 96 cells (30%) were activated at disynaptic latencies following single shock stimulation of the contralateral vestibular nerve. Disynaptically activated cells were significantly more frequent for pitch cells than for eye movement-related cells (25/55 = 45% vs 4/41 = 10%; p < 0.001, Chi-square test). Conversely, cells that did not receive short-latency activation (< 6 ms) were more frequent among eye movement-related cells than pitch cells (26/41 = 63% vs 13/55 = 24%; p < 0.001, Chi-square test). Pitch cells showed significantly less phase lag (re head acceleration) than eye movement-related cells during sinusoidal pitch rotation (mean ± SD 124° ± 17° vs 138° ± 14°. p < 0.01, t-test). These results suggest that 1) cells in the INC region other than burst-tonic and tonic neurons mainly receive direct inputs from secondary vestibulo-ocular relay neurons, and that 2) vertical canal signals reach eye movement-related neurons mainly polysynaptically.

Activity of eye movement-related neurons in and near the interstitial nucleus of Cajal during sinusoidal vertical linear acceleration and optokinetic stimuli

Summary1. A total of 43 neurons that showed a close correlation with vertical eye movement with a burst-tonic or tonic type response during spontaneous saccades, were recorded within, and in the close vicinity of, the interstitial nucleus of Cajal (INC) in alert cats. Neuronal responses to sinusoidal vertical linear acceleration (0.2–0.85 Hz, amplitude 10.5 cm) and optokinetic stimuli (0.1–1.0 Hz, amplitude 10.5 cm), were examined. 2. All 43 eye movement-related neurons responded to sinusoidal vertical linear acceleration in the presence of a stationary visual pattern in correlation to robust eye movement responses with compensatory phase. Phase and gain values (re stimulus position) of response of individual cells were independent of the stimulus frequencies tested. Of these, 33 cells were examined during linear acceleration without visual input. Most cells (27/33) did not respond even when a weak linear vestibulo-ocular reflex was present (6/27). The remaining 6 cells (6/33) responded to linear acceleration. Their mean phase values advanced by 80 ° and gain dropped by 55% compared to the responses with visual inputs. 3. Twenty eight of the 43 cells were examined during vertical optokinetic stimuli. The activity of all 28 cells was modulated in correlation to eye movement responses. Response phase showed more lag, and gain decreased as stimulus frequencies increased, similar to optokinetic eye movement responses. 4. The close correlation between the activity of eye movement-related neurons in the INC region and robust eye movements during linear acceleration with visual inputs and optokinetic stimuli suggest that these neurons are involved in some aspect of vertical eye position generation during such stimuli.