Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

Prefrontal cortex recruitment during naturalistic remote memory: a factorial block-event fMRI study.

Most classical neuroimaging studies of human memory require the subject to follow task instructions, discriminate stimuli, make a decision and, finally, press a button to respond. To which extent does such a cognitive sequence influence neural correlates of recognition memory especially with respect to the prefrontal cortex (PFC) is not clear yet. We set up a naturalistic recognition task. Personal photographs were mixed with photographs from family albums of people who were not known to the participant. The subjects alternated a recognition task (recognition and response) with a mere observational one (simple recognition). This factorial block-event functional MRI design allowed us to disentangle the regions related to memory (personal photographs vs. distracters under both conditions) from those related to the response (responding vs. observing) as well as to examine the interaction between the two factors. Only medial and left orbito-frontal regions were transiently active during successful recognition in the two task conditions. Memory and responding interacted in the left lateral PFC within the middle and inferior gyrus. These regions were more active for personal photographs than for distracters only when the subject had to respond. Sustained activations spread bilaterally whatever the task. Such a design that encompasses personal photographs, an observation period for recognition as well as a mixed-design may have led to a better isolation of the neural network underlying remote autobiographical memory. Recruitment within the PFC during retrieval was only limited to its medial and left anterior parts. Sustained activation did not differ between the discrimination and the observation period. This original design might be valuable for further dissociation between decision, self, autobiographical memory and the PFC.

Low time resolution in schizophrenia Lengthened windows of simultaneity for visual, auditory and bimodal stimuli.

The guarantee of perceptual coherence for events through everyday life situations depends upon the capacity to correctly integrate series of multi-sensory experiences. Patients with schizophrenia have been shown to reveal a deficit in integrating, i.e., "binding", perceptual information together. However, results in the literature have also suggested the reverse effect. Indeed, in certain paradigms patients have revealed more binding phenomenon than healthy controls and reported experiencing two distinct events as occurring "together". This finding suggests that patients may require longer time intervals between two distinct events before being able to perceive them as "one-after-the-other". The question here was to test whether this perceptual binding abnormality in schizophrenia is confined to events within the same modality or whether it is also present across sensory modalities. Thirty patients with schizophrenia were compared with 33 normal controls using a simultaneity judgement paradigm. There were two uni-modal conditions in which stimuli were presented in the same modality (visual or auditory) and one bimodal condition (audio-visual). Participants were presented with stimuli varying across a range of inter-stimulus intervals (ISI). They were required to judge whether they experienced two stimuli as occurring "together" or "one-after-the-other". Compared to controls and in all conditions, patients needed larger ISI to experience two stimuli as "one-after-the-other" (all ISI x Group interactions p<5 x 10(-5)). These abnormalities correlated with the disorganization dimension but not with the dosage of chlorpromazine equivalent. The increase of the time interval needed to perceive two stimuli as "one-after-the-other", reflect an abnormally low time resolution in patients with schizophrenia. We discuss the possible involvement of anatomical disconnectivity in schizophrenia which would specifically affect the time integration properties of neural assemblies.

Optimisation of a post-processing method to remove the pulse artifact from EEG data recorded during fMRI: an application to P300 recordings during e-fMRI.

In functional cerebral studies, it has been established that co-registered electroencephalography (EEG) measurements and functional magnetic resonance imaging (fMRI) were complementary. However, EEG data recorded inside an MRI scanner are heavily distorted, mainly by the most prominent artifact, the cardiac pulse artifact (PA). We describe an original algorithm which yields a high-quality PA filter and demonstrates how this tool can be used to improve the quality of P300 ERP measurements during event-related fMRI (e-fMRI) experiments. EEG data were acquired in interleaved mode during e-fMRI while six healthy volunteers performed a visual odd-ball task, involving Distractors, Target and Novel stimuli, to elicit P300 components. The PA was corrected with the original algorithm. The temporal variations in the PA were evidenced using a principal component analysis (PCA), on each EEG channel. The procedure yielded several PA templates, which were regressed from the EEG data. The PA removal procedure was optimised, and then implemented to improve the measured P300 components. Regressing the most adequate PA template resulted in a high-quality reduction in spectral power at frequencies associated with the cardiac PA. More reliable P300 component measurements were obtained, evidencing higher amplitudes for Novels (9.76-11.20 microV) than for to Targets (6.3-9.09 microV) in centro-parietal and prefrontal areas. The improvement of the processing of EEG data acquired simultaneously with fMRI data provides a new tool and casts perspectives to study the functional organisation of the brain.

[What is needed for rTMS to become a treatment?]. / Que manque-t-il à la rTMS pour devenir une thérapie?

Repetitive trans-cranial magnetic stimulation (rTMS) can modulate cortical excitability. Consequently, it appears appealing for the treatment of some affections such as depression or hallucinations. There is already some proof that the concept is valid, but rTMS is slow in progressing in the therapeutic field as a true armamentum. Indeed its effects are of short duration and even inconstant from one patient to the next. These drawbacks depend on certain factors that we will discuss. Until now, there has been inadequate control of the stimulation site. It is possible that this site could vary on an individual basis. It seems logical to propose the use of functional imaging for such a purpose, but its use should be adapted to the symptom. Even after localizing the site, the coil has to be placed accurately. This could be facilitated by a neuronavigator. Stimulation protocols are currently defined by three parameters: the frequency modulating the cortical action either as a stimulation (>5 Hz) or an inhibition (<1 Hz), the intensity and the number of stimuli influencing, notably, the amplitude and duration of the effect. Unfortunately, the effect is inconstant in a given patient and paradoxical reactions have been observed in more than 15% of normal individuals. Improved reliability and amplification of the effect rely on the better control of other parameters: pattern of stimulation, pre and post-conditioning, state of the cortex during stimulation, associated medications, endogenous idiosyncratic factors and related pathology. We will review the current physiological literature to discuss the possible options that would constitute a rational basis for setting up more efficient protocols.

Functional integration in schizophrenia: too little or too much? Preliminary results on fMRI data.

The disconnectivity hypothesis proposes that schizophrenia results from poor or miswired anatomical connections. Theoretically, its functional counterpart should be disintegration. Integration is thought to allow segregated neurons to interact as a coherent whole, referred to as the "core", while the non-interacting part of the brain is referred to as the "rest". In this study, it is suggested that schizophrenia is the result of rest noise interfering with core activity. Two possible causes are assessed: (i) defective core integration, making the core more vulnerable to noise from the rest, or (ii) the rest being too highly integrated, meaning that it can interfere with the core. These hypotheses were tested using fMRI data acquired from 13 stabilized medicated schizophrenic subjects compared to 11 matched controls. Subjects were required to perform a series of lexical decision and retrieval tasks in separate sessions. The brain was divided into 90 components. Integration was defined as the amount of information shared between the components of a sub-system. An iterative aggregation procedure made it possible to identify a core on the basis of the functional clustering index, which assesses the integration of the core relative to its integration with the rest. Correlation of component-pairs within the core was also compared between the two groups. This procedure was repeated for each subject and for each task. Cores did not differ between the two groups, either in terms of integration or in terms of functional clustering index. However, the core was still highly integrated with the rest and the rest was overly integrated in schizophrenic subjects. Both anomalies were correlated with the negative symptoms. These findings were consistent regardless of the task considered. Furthermore, within the core, anterior-posterior correlations were lower in patients (between the frontal and the parietal and posterior cingulate cortices), whereas frontal left-right correlations were excessive. No significant correlation was found with the medication. Thus, it appears that schizophrenia entails a deleterious combination of too much "noisy" integration (from the rest) and too little "significant" integration (anterior-posterior functional connectivity).

P300 recordings during event-related fMRI: a feasibility study.

Analysis of combined event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) can provide a high temporal and high spatial resolution to study functional cerebral processes. However, EEG data recorded inside an MR scanner is heavily distorted by artifacts. It is important in cognitive studies to ensure that recorded data reflect the same brain activity, and this is achieved through interleaved electroencephalographic (EEG) and fMRI measurements. Here, we demonstrate the feasibility of recording P300 ERPs during fMRI using a three-stimulus visual oddball task and involving a small number of trials for each stimulus. Ten EEG channels were acquired interleaved with fMRI images in five healthy subjects. The stimuli, including rare targets "X," frequent repetitive distractors "O," and rare distractors referred to as novels, were randomly presented every 2 +/- 1 s. The post hoc filter presented here was designed and applied to EEG data to remove the cardiac pulse artifact. Interleaved EEG/fMRI acquisition evidenced two P300 ERPs evoked at Fz, Cz, and Pz by targets and novels. Novel-related ERPs were of higher amplitude than their target-related counterparts. The fMRI maps acquired concurrently showed stronger BOLD response for target condition. We have shown that interleaved acquisition allows to obtain reliable P300 data and fMRI results, likely to shed light on the anatomical location of brain regions involved in cognitive ERPs relevant to many disorders affecting CNS functions. These noninvasive multimodal neuroimaging techniques can be used to explore and better understand processes underlying the functional brain organization.

Where arousal meets attention: a simultaneous fMRI and EEG recording study.

In this fMRI study, we looked for the regions supporting interaction between cortical arousal and attention during three conditions: detection, observation, and rest. Arousal measurements were obtained from the EEG low-frequency (LF) power (5-9.5 Hz) recorded continuously together with fMRI. Whatever the condition, arousal was positively correlated with the fMRI signal of the right dorsal-lateral prefrontal and superior parietal cortices, closely overlapping regions involved in the maintenance of attention. Although the inferior temporal areas also presented a correlation with arousal during detection, path analysis suggests that this influence may be indirect, through the top-down influence of the previously mentioned network. However, those visual-processing areas could account for the correlation between arousal and performances. Lastly, the medial frontal cortex, frontal opercula, and thalamus were inversely correlated with arousal but only during detection and observation so that they could account for the control of arousal.

Synchrony, from cognition to seizure.

It could seem strange that a same neuro-physiological mechanism provides for both normal and critical cerebral activity. While describing the basics of "cognitive" synchronies we will contrast them with the "critical" one for their differentiation and their non-rhythmic properties. Lastly we will speculate on their significance in the recently described seizure anticipation paradigm and on the possibility that they could share common generators.