Cerebellar Growth Impairment Characterizes School-Aged Children Born Preterm without Perinatal Brain Lesions.

BACKGROUND AND PURPOSE: Infants born preterm are commonly diagnosed with structural brain lesions known to affect long-term neurodevelopment negatively. Yet, the effects of preterm birth on brain development in the absence of intracranial lesions remain to be studied in detail. In this study, we aim to quantify long term consequences of preterm birth on brain development in this specific group. MATERIALS AND METHODS: Neonatal cranial sonography and follow-up T1-weighted MR imaging and DTI were performed to evaluate whether the anatomic characteristics of the cerebrum and cerebellum in a cohort of school-aged children (6-12 years of age) were related to gestational age at birth in children free of brain lesions in the perinatal period. RESULTS: In the cohort consisting of 36 preterm (28-37 weeks' gestational age) and 66 term-born infants, T1-weighted MR imaging and DTI at 6-12 years revealed a reduction of cerebellar white matter volume (ß = 0.387, P < .001), altered fractional anisotropy of cerebellar white matter (ß = -0.236, P = .02), and a reduction of cerebellar gray and white matter surface area (ß = 0.337, P < .001; ß = 0.375, P < .001, respectively) in relation to birth age. Such relations were not observed for the cerebral cortex or white matter volume, surface area, or diffusion quantities. CONCLUSIONS: The results of our study show that perinatal influences that are not primarily neurologic are still able to disturb long-term neurodevelopment, particularly of the developing cerebellum. Including the cerebellum in future neuroprotective strategies seems therefore essential.

Recent advancements in diffusion MRI for investigating cortical development after preterm birth-potential and pitfalls.

Preterm infants are born during a critical period of brain maturation, in which even subtle events can result in substantial behavioral, motor and cognitive deficits, as well as psychiatric diseases. Recent evidence shows that the main source for these devastating disabilities is not necessarily white matter (WM) damage but could also be disruptions of cortical microstructure. Animal studies showed how moderate hypoxic-ischemic conditions did not result in significant neuronal loss in the developing brain, but did cause significantly impaired dendritic growth and synapse formation alongside a disturbed development of neuronal connectivity as measured using diffusion magnetic resonance imaging (dMRI). When using more advanced acquisition settings such as high-angular resolution diffusion imaging (HARDI), more advanced reconstruction methods can be applied to investigate the cortical microstructure with higher levels of detail. Recent advances in dMRI acquisition and analysis have great potential to contribute to a better understanding of neuronal connectivity impairment in preterm birth. We will review the current understanding of abnormal preterm cortical development, novel approaches in dMRI, and the pitfalls in scanning vulnerable preterm infants.

Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning.

Cerebellar motor learning is required to obtain procedural skills. Studies have provided supportive evidence for a potential role of kinase-mediated long-term depression (LTD) at the parallel fiber to Purkinje cell synapse in cerebellar learning. Recently, phosphatases have been implicated in the induction of potentiation of Purkinje cell activities in vitro, but it remains to be shown whether and how phosphatase-mediated potentiation contributes to motor learning. Here, we investigated its possible role by creating and testing a Purkinje cell-specific knockout of calcium/calmodulin-activated protein-phosphatase-2B (L7-PP2B). The selective deletion of PP2B indeed abolished postsynaptic long-term potentiation in Purkinje cells and their ability to increase their excitability, whereas LTD was unaffected. The mutants showed impaired "gain-decrease" and "gain-increase" adaptation of their vestibulo-ocular reflex (VOR) as well as impaired acquisition of classical delay conditioning of their eyeblink response. Thus, our data indicate that PP2B may indeed mediate potentiation in Purkinje cells and contribute prominently to cerebellar motor learning.

Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control.

While firing rate is well established as a relevant parameter for encoding information exchanged between neurons, the significance of other parameters is more conjectural. Here, we show that regularity of neuronal spike activities affects sensorimotor processing in tottering mutants, which suffer from a mutation in P/Q-type voltage-gated calcium channels. While the modulation amplitude of the simple spike firing rate of their floccular Purkinje cells during optokinetic stimulation is indistinguishable from that of wild-types, the regularity of their firing is markedly disrupted. The gain and phase values of tottering's compensatory eye movements are indistinguishable from those of flocculectomized wild-types or from totterings with the flocculus treated with P/Q-type calcium channel blockers. Moreover, normal eye movements can be evoked in tottering when the flocculus is electrically stimulated with regular spike trains mimicking the firing pattern of normal simple spikes. This study demonstrates the importance of regularity of firing in Purkinje cells for neuronal information processing.

Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression.

Cerebellar long-term depression (LTD) at parallel fibre-Purkinje cell (P-cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7-protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo-ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7-PKCI transgene is probably activated from the early stages of P-cell development, an alternative could be that P-cells develop abnormal signals in L7-PKCI mutants, disturbing mechanisms of motor learning that rely on proper P-cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P-cells in the flocculus of L7-PKCI mice and their wild-type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild-type and transgenic P-cells at all stimulus frequencies (0.05-0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165-180 degrees. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by approximately 15 degrees. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7-PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.