Junko Fukushima

Paranodal junction formation and spermatogenesis require sulfoglycolipids

Mammalian sulfoglycolipids comprise two major members, sulfatide (HSO3-3-galactosylceramide) and seminolipid (HSO3-3-monogalactosylalkylacylglycerol). Sulfatide is a major lipid component of the myelin sheath and serves as the epitope for the well known oligodendrocyte-marker antibody O4. Seminolipid is synthesized in spermatocytes and maintained in the subsequent germ cell stages. Both sulfoglycolipids can be synthesized in vitro by using the isolated cerebroside sulfotransferase. To investigate the physiological role of sulfoglycolipids and to determine whether sulfatide and seminolipid are biosynthesized in vivo by a single sulfotransferase, Cst-null mice were generated by gene targeting. Cst−/− mice lacked sulfatide in brain and seminolipid in testis, proving that a single gene copy is responsible for their biosynthesis. Cst−/− mice were born healthy, but began to display hindlimb weakness by 6 weeks of age and subsequently showed a pronounced tremor and progressive ataxia. Although compact myelin was preserved, Cst−/− mice displayed abnormalities in paranodal junctions. On the other hand, Cst−/− males were sterile because of a block in spermatogenesis before the first meiotic division, whereas females were able to breed. These data show a critical role for sulfoglycolipids in myelin function and spermatogenesis.

Disturbances of voluntary control of saccadic eye movements in schizophrenic patients

To study whether or not schizophrenic patients have disturbances in voluntary control of saccades, we examined visually elicited saccade and antisaccade tasks in 10 normal control subjects and 12 schizophrenic patients. The latencies of saccades in the schizophrenic patients were not significantly different from those of normal controls. However, 6 of the 12 schizophrenics showed significant abnormalities in the antisaccade task; 6 made more errors and 3 of them showed longer latencies than normal controls. Five of these 6 patients revealed an atrophy of the frontal cortex on computed tomography (CT) scans. These results indicate that many schizophrenics show difficulties in voluntary control of saccades, suggesting a dysfunction of the frontal cortex.

Voluntary control of saccadic eye movement in patients with frontal cortical lesions and Parkinsonian patients in comparison with that in Schizophrenics

To investigate whether the abnormalities of antisaccades in schizophrenics could be explained by a dysfunction of the frontal cortex, we examined 10 patients with frontal cortical lesions and 22 patients with idiopathic Parkinsons disease with mild symptoms (Yahr I-II) using the same tasks, and compared the results with those obtained in schizophrenics. The frontal patients with lesions covering the frontal eye field and prefrontal cortex showed more errors, longer latencies, and lower peak velocities in the antisaccade task, despite giving normal results in the visually guided saccade task. This was similar to the results observed in schizophrenics. Parkinsonian patients did not consistently show a significant difference in the antisaccade task. These results indicate specific abnormalities of antisaccades in schizophrenics and patients with frontal cortical lesions but not consistently in Parkinsonian patients. This suggests that the abnormalities of antisaccades in schizophrenics might be explained by a frontal cortical dysfunction.

VOLUNTARY CONTROL OF SACCADIC EYE MOVEMENTS IN PATIENTS WITH SCHIZOPHRENIC AND AFFECTIVE DISORDERS

We have examined visually guided saccade and antisaccade tasks in 32 schizophrenics, 13 patients with affective disorders and 36 normal controls. Latencies of saccades were within the normal range in all patients examined. In the antisaccade task, 26/32 schizophrenics showed more errors and/or longer latencies, whereas 11/13 patients with affective disorders showed normal results. One manic patient showed significantly longer latency, and one bipolar patient showed a borderline error rate (15%). These results indicate that the antisaccade abnormalities in schizophrenics were not correlated with age, duration of illness, length of education or quantities of medication. None of the schizophrenics with normal antisaccades showed abnormalities in CT scans, while 73% of the schizophrenics who showed both higher error rate and longer latencies showed atrophy of the frontal cortex. The scores of conceptual disorganization and motor retardation in Brief Psychiatric Rating Scale (BPRS) were significantly higher in schizophrenics with abnormal antisaccades, while acute symptoms such as delusions and hallucinations were not correlated with the abnormalities.

Development of voluntary control of saccadic eye movements. I. Age-related changes in normal children.

To investigate the development of the voluntary control of saccadic eye movement, we examined eye movements in 99 normal children (4-13 years of age). Subjects were asked to fixate a central light for 3-5 s. A target was then presented, either to its right or left. In visually guided saccades, the mean latencies of the child group were longer than those of the adults, and decreased with age until the age of 12 where they reached adult levels. On the other hand, their peak saccadic velocities were not different from those of the adults. In the antisaccade task, they showed a higher rate of directional errors, indicating an inability to suppress reflexive saccades to the target. Mean latencies of correct antisaccades were significantly longer in the children than in the adults. Error rates and antisaccadic latency tended to decrease with age. We also examined the effects of an auditory warning signal during the fixation period and compared the results with those without. The warning stimulus was less effective in children than in adults in both tasks. Similar peak saccadic velocities between children and adults suggest the earlier development of the saccadic burst generator in the brainstem. In contrast, the delayed development of latency of saccades and antisaccades and the error rates of antisaccades suggest delayed maturation of the cerebral cortex, particularly the frontal association areas that are involved in both eye movement control and attentional processes.

Further analysis of the control of voluntary saccadic eye movements in schizophrenic patients

Many schizophrenic patients reveal abnormalities in the antisaccade task. To better understand the nature of these abnormalities, in the present study we have assigned to schizophrenics the no-saccade task (subjects were required to remain fixated without being disturbed by a reflexive saccade) and memory-saccade task (subjects were required to look at a remembered target) in addition to the antisaccade and saccade tasks used previously. Many schizophrenics revealed higher error rates in the no-saccade task, and latencies of saccades to a memorized target were significantly longer than controls in the memory-saccade task. Peak velocities of saccades of large amplitudes in the memory-saccade and antisaccade tasks (but not in the saccade task) were significantly slower and durations of such saccades were longer than normal controls despite the similarity between the distributions of amplitudes of such saccades between the patients and controls. These results suggest that many schizophrenics have difficulty suppressing reflexive saccades and initiating and executing appropriate volitional saccades when the goal for the movements is known but not visible.

Coding of smooth eye movements in three-dimensional space by frontal cortex

Through the development of a high-acuity fovea, primates with frontal eyes have acquired the ability to use binocular eye movements to track small objects moving in space. The smooth-pursuit system moves both eyes in the same direction to track movement in the frontal plane (frontal pursuit), whereas the vergence system moves left and right eyes in opposite directions to track targets moving towards or away from the observer (vergence tracking). In the cerebral cortex and brainstem, signals related to vergence eye movements—and the retinal disparity and blur signals that elicit them—are coded independently of signals related to frontal pursuit. Here we show that these types of signal are represented in a completely different way in the smooth-pursuit region of the frontal eye fields. Neurons of the frontal eye field modulate strongly during both frontal pursuit and vergence tracking, which results in three-dimensional cartesian representations of eye movements. We propose that the brain creates this distinctly different intermediate representation to allow these neurons to function as part of a system that enables primates to track and manipulate objects moving in three-dimensional space.

Relationship between antisaccades and the clinical symptoms in Parkinson's disease

We studied voluntary control of saccadic eye movement in 32 parkinsonian patients using the antisaccade task (the subjects were instructed not to look at the target but to look in the opposite direction). Mean latencies and error rates in the antisaccade task were significantly increased in advanced parkinsonian patients. The latencies of the antisaccades correlated with the severity of bradykinesia as well as the results of the Wisconsin Card Sorting Test. Patients taking anticholinergics showed significantly higher error rates. These results suggest that disturbance in the initiation of voluntary saccades in advanced patients may be associated with frontal lobe dysfunction, while anticholinergics may affect the inhibitory control of reflexive saccades.

Neuronal activity related to vertical eye movement in the region of the interstitial nucleus of Cajal in alert cats

Summary(1) Discharge characteristics of neurons in the region of the interstitial nucleus of Cajal (INC) were studied in alert cats during spontaneous or visually induced eye movement and sinusoidal vertical (pitch) rotation. Activity of a majority of cells (n = 68) was closely related to vertical eye position with or without bursting activity during on-direction saccades. They were called vertical burst-tonic (n = 62) and tonic (n = 6) neurons. Mean discharge rates for individual cells when the eye was near the primary position ranged from 35 to 133 (mean 75) spikes/s with a coefficient of variation (CV) ranging from 0.04 to 0.29 (mean 0.15). Average rate position curves were linear for the great majority of these cells with a mean slope of 3.9 ± 1.2 SD spikes/s/deg. (2) The burst index was defined as the difference in discharge rate between maximal rate during an on-direction saccade and the tonic rate after the saccade. The values of mean burst index for individual cells ranged from 8 to 352 (mean 135) spikes/s. Tonic neurons had a burst index lower than 60 spikes/s and were distributed in the lower end of the continuous histogram, suggesting that burst-tonic and tonic neurons may be a continuous group with varying degrees of burst components. During off-direction saccades, a pause was not always observed, although discharge rate consistently decreased and pauses were seen when saccades were made further in the off-direction toward recruitment thresholds. Significant positive correlation was observed between average discharge rate during off- as well as on-direction saccades and tonic discharge rate after saccades for individual cells, which was not due to cats making saccades mainly from the primary position. (3) During pitch rotation at 0.11 Hz (±10 deg), burst-tonic and tonic neurons had mean phase lag and gain of 128 (±13 SD) deg and 4.2 (±1.7 SD) spikes/s/deg/s2 relative to head acceleration. During pitch rotation of a wide frequency range (0.044–0.495 Hz), the values of phase lag were mostly constant (120–140 deg), while simultaneously recorded vertical VOR showed the mean phase lag of 178 deg. Vertical eye position sensitivity and pitch gain (re head position) showed significant positive correlation. (4) Comparison of the discharge characteristics of vertical burst-tonic and tonic neurons with those of secondary vestibulo-ocular neurons (Perlmutter et al. 1988) and extraocular motoneurons (Delgado-Garcia et al. 1986) in alert cats suggests that signals carried by burst-tonic and tonic neurons are partially processed signals in vertical VOR and saccades, and different from oculomotor signals. (5) The INC region also contained many cells that did not belong to the above groups but whose activity was clearly modulated by pitch rotation (called pitch cells for the present study, n = 44). Many (n = 23) showed some correlation with vestibular quick phases, and some (n = 12) with visually elicited eye movement, although they showed significantly lower and more irregular discharge rates than burst-tonic and tonic neurons (mean discharge rate when the eye was near the primary position 34, range 3–91, spikes/s; mean CV 0.61, range 0.15–1.7). During pitch rotation they showed the mean phase lag and gain of 119(±26 SD) deg and 3.2(±2.1 SD) spikes/s/deg/s2. Some cells showed a much lower phase lag of about 90 deg. (6) More than half the burst-tonic, tonic and pitch cells tested were antidromically activated by stimuli applied to the ponto-medullary medial longitudinal fasciculus at the level of abducens nucleus, while none of them were activated from the inferior olive, suggesting that vertical eye position signals carried by some burst-tonic and tonic neurons are carried to the lower brainstem.

Adaptive changes in human smooth pursuit eye movement

Adaptive changes in initial eye velocity of pursuit eye movement were examined in nine normal subjects using a target that moved in a multiple ramp fashion. Significant changes in initial eye velocity occurred rapidly after training in six of the subjects. The magnitude and direction of the induced changes were a function of the training conditions. Adaptive changes started 100-200 ms after onset of pursuit eye movement (usually 140 ms), suggesting that the late (but not early) component of initial eye velocity was under adaptive control by our training paradigms.