Cognitive processing speed deficits in multiple sclerosis: Dissociating sensorial and motor processing changes from cognitive processing speed.

BACKGROUND: The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. OBJECTIVE: We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). METHODS: All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. CONCLUSION: Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.

Synapse-to-neuron ratios of the frontal and cerebellar cortex of 30-day-old and adult rats undernourished during early postnatal life.

Male rats undernourished from birth to 30 days were nutritionally rehabilitated till 160 days of age. Quantitative stereological procedures at the light and electron microscopical levels were employed to estimate, among other things, the synapse-to-neuron ratios in the frontal cortex and granular layer of the cerebellum. In the frontal cortex, the 30-day-old undernourished rat had a mean +/- SE of about 14,020 +/- 1,540 synapses-per-neuron compared with 22,270 +/- 3,250 for the controls. This was a deficit of 37% (p < 0.05). By 160 days of age the previously undernourished rats showed no statistically significant deficit in this ratio compared with controls (11,800 +/- 690 and 13,360 +/- 1,110 respectively, p > 0.1). This was due mainly to a fall in the synapse-to-neuron ratio with age. A much larger fall in the ratio occurred in the control than in the previously undernourished group. In the granular layer of the cerebellum the 30-day-old undernourished rats had 341 +/- 17 synapses-per-neuron compared with 495 +/- 25 for the controls. This was a deficit of 31% (p < 0.01). By 160 days of age the previously undernourished rats again showed no statistically significant deficit in this ratio compared with controls (627 +/- 56 and 688 +/- 38, respectively (p > 0.1). These results show that the previously undernourished rats are capable of at least some (if not complete) "catch-up" with regard to the synapse-to-neuron ratio.

A stereological analysis of the cerebellar granule and Purkinje cells of 30-day-old and adult rats undernourished during early postnatal life.

Male rats undernourished from birth to 30 days of age were nutritionally rehabilitated till 160 days of age. Quantitative stereological procedures at the light microscope level were used to estimate, among other things, the numerical densities of cerebellar granule and Purkinje cells on a "per unit volume of cortex" basis. These were subsequently used to calculate granule-to-Purkinje cell ratios. The 30-day-old undernourished rats had a mean +/- S.E. of 290 +/- 27 granule cells for every Purkinje cell present, compared to 395 +/- 34 for the controls. This was a deficit of about 27% (p < 0.05). At 160 days of age, the previously undernourished rats still showed a persisting deficit of about 25% (p < 0.05) in this ratio, despite the lengthy nutritional rehabilitation. There were no statistically significant age-related changes in this ratio. The numerical density of Purkinje cells, but not that of granule cells, was significantly greater in the previously undernourished rats than in controls, for both age groups, Increasing age caused a fall in the numerical density of both cell types. Granule and Purkinje cell nuclear diameters were unaffected by nutrition. However, Purkinje cell nuclei decreased in size by between 7%--13% with increasing age. These results indicate that undernutrition during early life can cause a permanent distortion of the relative number of the various cell types in the cerebellum.

A comparison of the effects of cytosine arabinoside and adenine arabinoside on some aspects of brain growth and development in the rat.

1. Treatment of pregnant rats with cytosine arabinoside (ara-C, 50 mg/kg, i.p.)at 14 days of gestation severely impaired both prenatal and postnatal whole brain growth in their offspring, although the cerebellum was relatively less affected than whole brain. 2. Rats treated at 5 days of age with ara-C (250 mg/kg, i.p.) showed an impairment in growth of the cerebellum relative to the rest of the brain. 3. Adenine arabinoside (ara-A) treatment, either prenatally or postnatally, had negligible effect on brain growth, even at doses considerably higher than those of ara-C. 4. Adult rats, previously treated with ara-C (50 mg/kg, i.p.) at 14 days of gestation, showed an impairment in discrimination learning when tested in a water T-maze. 5. These results are discussed in relation to the proposed use of ara-C or ara-A as antiviral agents, particularly against intrauterine infection with cytomegalovirus.

Continuing growth and development of the third-trimester human placenta.

Two hundred and nineteen human placentae of well ascertained gestational age were measured for weight and nuclear number. Contrary to previous reports, analysis of the results showed no faltering in either parameter, however expressed. The placentae from babies exhibiting intrauterine growth retardation were appropriate to the size of the babies. However else the placenta ages it does not do so in respect of the rate of increase in the number of its nuclei.

Motor co-ordination and cerebellar size in adult rats undernourished in early life.

The male progeny of mother rats which had been undernourished during most of gestation and all of lactation were divided into two groups when weaned at 25 days. One group was nutritionally rehabilitated (G-L-) while the other was underfed for a further 9 weeks (G-L-W-) before nutritional rehabilitation. Despite this further undernutrition the G-L-W- rats eventually caught up in both body and brain weight with the G-L- group. Compared with control rats of the same age that had been well fed throughout life, the G-L- and G-L-W- animals had permanent deficits in body and regional brain weights. At 36 weeks rats were given two tests of motor co-ordination. They were required (a) to run backwards on a revolving drum and (b) to cross a chasm bridged by a ladder or parallel rods for a food reward. Both previously undernourished groups did consistently worse than controls of the same age or of similar body weight on two measures of co-ordination: falls from the revolving drum and stumbles on the bridge-crossing test. It is postulated that these differences indicate impaired cerebellar function in the prevously undernourished rats.

Head circumference, biparietal diameter and brain growth in fetal and postnatal life.

The curves for biparietal diameter, head circumference and brain weight with increasing age have different shapes, and these differences have been explained. Interconversion procedures are suggested. One important consequence of changing growth velocities relates to assessing prognosis for catch-up following adversity. On the assumption that catch-up of brain growth must occur within the period of the brain weight growth spurt, the interpretation of head circumference charts is discussed.

Deciduous teeth contain histories of developmental disturbances.

The crowns of the deciduous teeth are permanent structures which form by incremental growth during the second half of pregnancy and first year of life. These structures become available between the ages of 6 and 12 years with normal exfoliation and can then be studied histologically to demonstrate evidence of metabolic disturbances occurring during tooth development. As the chronology of disturbances can be assessed with reasonable accuracy, such studies provide a potentially valuable research tool.

A stereological analysis of the neuronal and synaptic content of the frontal and cerebellar cortex of weanling rats undernourished from birth.

The frontal cortex and granular layer of the cerebellum have been examined in 30-day-old rats undernourished from birth. Quantitative stereological procedures at the light microscopical level have been used to estimate the volume proportion and numerical densities of neuronal nuclei. Similar methods at the electron microscopical level were employed to calculate the numerical densities of synapses. Hence, synapse-to-neuron ratios have been calculated in these brain regions. In the frontal cortex, the undernourished group of rats showed a 37% deficit (P less than 0.05) in the synapse-to-neuron ratio. This was due to a combination of an increase in the numberical density of neurons and a decrease in the numerical density of synapses, although, individually, neither of these reached statistical significance at the 5% level. In the granular layer of the cerebellum there was a 31% (P less than 0.01) deficit in the synapse-to-neuron ratio. This was a function of the reduced numerical density of synapses, with no difference in the numerical density of granule cells between groups. For the frontal cortex, the volume proportion of neuronal nuclei was significantly greater in the undernourished group of rats. There were no significant differences between control and undernourished rats in the volume of the 'forebrain' occupied by cortex. The mean diameters of neuronal nuclei and synaptic discs did not differ in any given region between treatment groups. These observations are discussed in context with the previously published results on synapses and neurons in undernourished animals.