Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG–BOLD–CBF study in humans

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n = 0.91 ± 0.04, M = 10.45%) than in the contralateral S1/M1 (n = 0.65 ± 0.03, M = 10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8–13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR

Global signal modulation of single-trial fMRI response variability: effect on positive vs negative BOLD response relationship

In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of average responses

Late onset retinitis pigmentosa.

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Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations