An investigation of the integrity of two components of the cerebellar neurocircuitry involved in classical eyeblink conditioning in children prenatally exposed to alcohol: a magnetic resonance spectroscopy and functional magnetic resonance imaging study

Doctoral Thesis


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University of Cape Town

Impairment in classical eyeblink conditioning (EBC) has previously been reported in children with fetal alcohol spectrum disorders (FASD) (Jacobson et al., 2008). The deep cerebellar nuclei and cerebellar cortex are critical elements of the cerebellar-brainstem circuitry that mediates EBC (Green et al., 2002a; Yeo and Hardiman, 1992; Perret et al., 1993). In this study, we used magnetic resonance spectroscopy (MRS) and functional MRI (fMRI) to assess the effects of prenatal alcohol exposure on brain metabolism in the cerebellar deep nuclei and brain function in the cerebellar cortex, respectively. We found that higher levels of prenatal alcohol exposure were associated with lower levels of both N-Acetylaspartate (NAA) and choline-containing metabolites, and with higher levels of glutamate plus glutamine (Glx), suggesting a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission. Since the interpositus nucleus is one of the most crucial structures in the acquisition of the EBC response, abnormal metabolism in this region could be responsible for altered synaptic plasticity in children with FASD. Of the four cerebellar regions that were identified as being activated more by control children during rhythmic vs. non-rhythmic finger tapping, smaller differences in BOLD (blood oxygenation level dependent) activation were observed in children with FASD in two, namely vermis IV-V and right Crus I. Increasing levels of prenatal alcohol exposure were, however, associated with smaller differences in activation in all four regions, all of which have previously been linked to timed responses. In the paced/unpaced finger tapping fMRI study, we found four regions where increased BOLD activation during unpaced tapping compared to rest was associated with improved ability to maintain rhythm as evidenced by lower intertapping variability - right VIIIa and b, left VIIIa and right VI. These regions have previously been implicated in motor control with additional evidence of timing in lobule VI. In three of the regions, all except right VIIIa, increasing alcohol exposure was related to smaller increases in activation during unpaced tapping, with the strongest relations seen in the dosage dependent variable. Interestingly, the location of the activation in right VI is similar to a region that has been implicated in studies of EBC (Blaxton et al., 1996; Cheng et al., 2008). Our results point to altered metabolic levels in the deep nuclei and reduced functioning of several cerebellar cortical regions in children with FASD, highlighting the extensive damage caused by prenatal alcohol exposure. Although we did not find associations of EBC performance with either metabolite levels or activity in these regions, suggesting that damage to these areas are not primarily responsible for the observed EBC deficit, the extent of this damage could play a role in the impaired EBC performance seen in these children.

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