Christophe Orssaud

Functional Neuroanatomy of the Human Visual Fixation System

The regional cerebral blood flow correlates of the active fixation of an imagined target were studied in five healthy humans using the positron emission tomography activation paradigm. The fixation task was contrasted to a passive control condition, both tasks being performed in total darkness. Blood flow increases were observed in the frontal eye fields and supplementary eye fields and in the median cingulate gyrus. We suggest that the network of these activated regions mediates the interactions between ocular fixation, eye movements and directed visual attention.

Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Leber's Hereditary Optic Neuropathy

Background Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. Methodology/Principal Findings In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. Conclusions/Significance Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

Role of the Posterior Parietal Cortex in the Initiation of Saccades and Vergence: Right/Left Functional Asymmetry

Abstract: This study explored in humans the role of the posterior parietal cortex (PPC) in saccades, vergence, and combined saccade‐vergence movements by means of transcranial magnetic stimulation (TMS). TMS was applied to the right PPC at 80 ms, 90 ms, or 100 ms after target onset in experiment 1, and to the left PPC in experiment 2. Control experiments were also run in which TMS was applied over the primary motor cortex at 90 ms after target onset. Relative to no‐TMS trials, TMS over the right PPC prolonged significantly the latency of almost all eye movements (saccades in either direction, convergence, divergence, and components of combined eye movements). Such latency increase was significant mostly when TMS was delivered 90 ms after target onset. In contrast, TMS of the left PPC increased the latency only for saccades to right, convergence, and convergence combined with rightward saccades; latency increase occurred for all time windows of TMS deliver (80, 90, or 100 ms after target onset). TMS over the vertex had no effect on the latency for any type of eye movement. TMS of either the left or the right PPC or of the motor cortex did not alter the accuracy of any type of eye movement. Thus, the effects of TMS on latency are time‐, area‐, and eye‐movement‐specific. We suggest that the right PPC is involved primarily in the processing of fixation disengagement, whereas the left PPC participates in the initiation of eye movements via different spatial selective mechanisms that concern exclusively targets to the right and/or to near.

Use of anatomical parcellation to catalog and study structure-function relationships in the human brain.

We describe a functional neuroanatomy approach that combines structural (MRI) and functional (PET) data at the individual level. For each subject MRI dataset, sulci are first localized using hemisphere surface rendering and sections and stored. Using these landmarks, the subject brain volume is then divided in 100 anatomical volumes of interest (AVOI). AVOI morphometric measurements are readily obtained as well as functional parameters (CBF) after MRI‐PET alignment. This approach allows structure‐function relationship investigations both at the single case and at the intersubject average level; in addition, individual morphometric and functional parameters can be easily archieved in a database for further meta‐analysis. This approach is applicable to all imaging modalities and is especially suited for a priori hypothesis testing and for the investigation of interindividual functional neuroanatomy variability. Hum. Brain Mapping 5:228–232, 1997.

Prolongation of latency of horizontal saccades in elderly is distance and task specific.

The present study examined horizontal saccades in healthy subjects: 9 adults (20-32 years) and 10 aged subjects (63-83 years), under gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). The gap paradigm is known to promote fast initiation of saccades while the overlap paradigm promotes voluntary saccades with longer latency. In real life we perform saccades at various distances. In this study each paradigm was run at three viewing distances-20, 40 and 150 cm, corresponding to a convergence angle of 17.1 degrees, 8.6 degrees and 2.3 degrees, respectively. Eye movements were recorded with the Chronos video eye tracker or with the photoelectric IRIS. The main findings are: (i) increase in latency of saccades with age, with distance and with the overlap condition; (ii) evidence for interaction between these factors, indicating the following anomaly: in the gap condition and at near, aged subjects show short latencies similar to those of young adults; (iii) express type of latencies (between 80 and 120 ms) occur most frequently at near in the gap condition and at similar rates in young (25%) and aged subjects (20%). The specificity of close distance combined with the gap for triggering short latency saccades could be related to both attention and oculomotor fixation disengagement. The strength of coupling between fixation-eye movement control and visual attention control varies for different locations in space, and its decline with aging can be also different.

Transcranial magnetic stimulation of the posterior parietal cortex delays the latency of both isolated and combined vergence–saccade movements in humans

To explore the 3D visual environment most frequently we make combined saccade-vergence eye movements. We studied the effect of transcranial magnetic stimulation (TMS) of the right posterior parietal cortex (rPPC) on such combined eye movements versus isolated saccade and vergence. In the main experiment, TMS was applied on the rPPC 80, 90 or 100 ms after target onset. In a control experiment, TMS was applied over the primary motor cortex at 90 ms after the target presentation. TMS trials were compared with no-TMS trials. TMS of the motor cortex had no effect at all on eye movements. TMS of the rPPC had no effect on the accuracy of eye movements, but it caused a latency increase: the increase was similar for the two components of the combined saccade-vergence movements, and it did not alter the naturally existing tight relationship of latency between the two components. Furthermore, the amount of latency prolongation was similar to that of isolated vergence, and of saccades in either direction (ipsilateral or contralateral relative to the stimulated site). Latency prolongation was time-specific but in a different way for different types of eye movements: for combined and convergence eye movements, the critical time window was -130 ms or more prior to the onset of eye movement, while for saccades and divergence TMS was disruptive later, -110 ms or more prior to the onset of eye movements. The latency increase is attributed to the interference by the TMS with the fixation disengagement process, for which the rPPC is believed to be instrumental. These results suggest that fixation disengagement occurs earlier for convergence and combined eye movements than for saccades and divergence.

How the Brain Obeys Hering's Law: A TMS Study of the Posterior Parietal Cortex

PURPOSE Human ocular saccades are not perfectly yoked; the origin of this disconjugacy (muscular versus central) remains controversial. The purpose of this study was to test a cortical influence on the binocular coordination of saccades. METHODS The authors used a gap paradigm to elicit vertical or horizontal saccades of 10 degrees , randomly interleaved; transcranial magnetic stimulation (TMS) was applied on the posterior parietal cortex (PPC) 100 ms after the target onset. RESULTS TMS of the left or right PPC increased (i) the misalignment of the eyes during the presaccadic fixation period; (ii) the size difference between the saccades of the eyes, called disconjugacy; the increase of disconjugacy was significant for rightward and downward saccades after TMS of the right PPC and for downward saccades after TMS of the left PPC. CONCLUSIONS The authors conclude that the PPC is actively involved in maintaining eye alignment during fixation and in the control of binocular coordination of saccades.

Postural control in nonamblyopic children with early-onset strabismus.

PURPOSE In healthy subjects, the postural stability in orthostatic position is better when fixating at near than at far. Increase in the convergence angle contributes to this effect. Children with strabismus present a deficit in vergence. We evaluated postural control in children with respect to the vergence angle as they fixated at different depths, thereby engaging in active vergence movements. METHODS A TechnoConcept platform was used to record the postural stability of 11 subjects (mean age 11.18 ± 4.02 years) with convergent strabismus and 13 (mean age 11.31 ± 3.54 years) with divergent strabismus in 3 conditions: fixation at 40 cm, at 2 m, and active vergence movements between 20 and 50 cm. RESULTS The mediolateral body sway decreased significantly with proximity for convergent strabismus (from 3.78-2.70 mm) but increased significantly for divergent strabismus (from 3.27-3.97). Relative to fixation, vergence eye movements resulted in a statistically significant increase in mediolateral body sway for convergent strabismus (3.55 vs. 2.70) and a decrease for divergent strabismus (3.11 vs. 3.97, P = 0.047). Vergence eye movements were associated with the least variance of speed (99 mm(2)/s(2) for convergent and 117 mm(2)/s(2) for divergent strabismus), so less energy was required to control body sway. CONCLUSIONS The fixation depth at which postural stability is best is proximal for convergent strabismus and distal for divergent strabismus. Optimal postural stability might be mediated by preponderant eye movement signals related to the angle of strabismus. Reduction of variance of speed in the active vergence condition corroborates our hypothesis.

Medio-Lateral Postural Instability in Subjects with Tinnitus

Background: Many patients show modulation of tinnitus by gaze, jaw or neck movements, reflecting abnormal sensorimotor integration, and interaction between various inputs. Postural control is based on multi-sensory integration (visual, vestibular, somatosensory, and oculomotor) and indeed there is now evidence that posture can also be influenced by sound. Perhaps tinnitus influences posture similarly to external sound. This study examines the quality of postural performance in quiet stance in patients with modulated tinnitus. Methods: Twenty-three patients with highly modulated tinnitus were selected in the ENT service. Twelve reported exclusively or predominately left tinnitus, eight right, and three bilateral. Eighteen control subjects were also tested. Subjects were asked to fixate a target at 40 cm for 51 s; posturography was performed with the platform (Technoconcept, 40 Hz) for both the eyes open and eyes closed conditions. Results: For both conditions, tinnitus subjects showed abnormally high lateral body sway (SDx). This was corroborated by fast Fourrier Transformation (FFTx) and wavelet analysis. For patients with left tinnitus only, medio-lateral sway increased significantly when looking away from the center. Conclusion: Similarly to external sound stimulation, tinnitus could influence lateral sway by activating attention shift, and perhaps vestibular responses. Poor integration of sensorimotor signals is another possibility. Such abnormalities would be accentuated in left tinnitus because of the importance of the right cerebral cortex in processing both auditory–tinnitus eye position and attention.

International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

Abstract: Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000–45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone–Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.