Automatic rating of incomplete hippocampal inversions evaluated across multiple cohorts.

Incomplete Hippocampal Inversion (IHI), sometimes called hippocampal malrotation, is an atypical anatomical pattern of the hippocampus found in about 20% of the general population. IHI can be visually assessed on coronal slices of T1 weighted MR images, using a composite score that combines four anatomical criteria. IHI has been associated with several brain disorders (epilepsy, schizophrenia). However, these studies were based on small samples. Furthermore, the factors (genetic or environmental) that contribute to the genesis of IHI are largely unknown. Large-scale studies are thus needed to further understand IHI and their potential relationships to neurological and psychiatric disorders. However, visual evaluation is long and tedious, justifying the need for an automatic method. In this paper, we propose, for the first time, to automatically rate IHI. We proceed by predicting four anatomical criteria, which are then summed up to form the IHI score, providing the advantage of an interpretable score. We provided an extensive experimental investigation of different machine learning methods and training strategies. We performed automatic rating using a variety of deep learning models ("conv5-FC3", ResNet and "SECNN") as well as a ridge regression. We studied the generalization of our models using different cohorts and performed multi-cohort learning. We relied on a large population of 2,008 participants from the IMAGEN study, 993 and 403 participants from the QTIM and QTAB studies as well as 985 subjects from the UKBiobank. We showed that deep learning models outperformed a ridge regression. We demonstrated that the performances of the "conv5-FC3" network were at least as good as more complex networks while maintaining a low complexity and computation time. We showed that training on a single cohort may lack in variability while training on several cohorts improves generalization (acceptable performances on all tested cohorts including some that are not included in training). The trained models will be made publicly available should the manuscript be accepted.

Oxidative stress induced by sustained supraphysiological intrastriatal GDNF delivery is prevented by dose regulation.

Despite its established neuroprotective effect on dopaminergic neurons and encouraging phase I results, intraputaminal GDNF administration failed to demonstrate significant clinical benefits in Parkinson's disease patients. Different human GDNF doses were delivered in the striatum of rats with a progressive 6-hydroxydopamine lesion using a sensitive doxycycline-regulated AAV vector. GDNF treatment was applied either continuously or intermittently (2 weeks on/2 weeks off) during 17 weeks. Stable reduction of motor impairments as well as increased number of dopaminergic neurons and striatal innervation were obtained with a GDNF dose equivalent to 3- and 10-fold the rat endogenous level. In contrast, a 20-fold increased GDNF level only temporarily provided motor benefits and neurons were not spared. Strikingly, oxidized DNA in the substantia nigra increased by 50% with 20-fold, but not 3-fold GDNF treatment. In addition, only low-dose GDNF allowed to preserve dopaminergic neuron cell size. Finally, aberrant dopaminergic fiber sprouting was observed with 20-fold GDNF but not at lower doses. Intermittent 20-fold GDNF treatment allowed to avoid toxicity and spare dopaminergic neurons but did not restore their cell size. Our data suggest that maintaining GDNF concentration under a threshold generating oxidative stress is a pre-requisite to obtain significant symptomatic relief and neuroprotection.

Temporo-basal sulcal connections: a manual annotation protocol and an investigation of sexual dimorphism and heritability.

The temporo-basal region of the human brain is composed of the collateral, the occipito-temporal, and the rhinal sulci. We manually rated (using a novel protocol) the connections between rhinal/collateral (RS-CS), collateral/occipito-temporal (CS-OTS) and rhinal/occipito-temporal (RS-OTS) sulci, using the MRI of nearly 3400 individuals including around 1000 twins. We reported both the associations between sulcal polymorphisms as well with a wide range of demographics (e.g. age, sex, handedness). Finally, we also estimated the heritability, and the genetic correlation between sulcal connections. We reported the frequency of the sulcal connections in the general population, which were hemisphere dependent. We found a sexual dimorphism of the connections, especially marked in the right hemisphere, with a CS-OTS connection more frequent in females (approximately 35-40% versus 20-25% in males) and an RS-CS connection more common in males (approximately 40-45% versus 25-30% in females). We confirmed associations between sulcal connections and characteristics of incomplete hippocampal inversion (IHI). We estimated the broad sense heritability to be 0.28-0.45 for RS-CS and CS-OTS connections, with hints of dominant contribution for the RS-CS connection. The connections appeared to share some of their genetic causing factors as indicated by strong genetic correlations. Heritability appeared much smaller for the (rarer) RS-OTS connection.