Vincent Laprevote

Patients with schizophrenia are biased toward low spatial frequency to decode facial expression at a glance.

Whereas patients with schizophrenia exhibit early visual processing impairments, their capacity at integrating visual information at various spatial scales, from low to high spatial frequencies, remains untested. This question is particularly acute given that, in ecological conditions of viewing, spatial frequency bands are naturally integrated to form a coherent percept. Here, 19 patients with schizophrenia and 16 healthy controls performed a rapid emotion recognition task with hybrid faces. Because these stimuli displayed in a single image two different facial expressions, in low (LSF) and high (HSF) spatial frequencies, the selected emotion probes which spatial scale is preferentially perceived. In a control experiment participants performed the same task with either low or high spatial frequency filtered faces. Results show that patients have a strong bias towards LSF with hybrid faces compared to healthy controls. However, both patients and healthy controls performed better with HSF filtered faces than with LSF filtered faces in the control experiment, demonstrating that the bias found with hybrid stimuli in patients was not due to an inability to process HSF. Whereas previous works found a LSF contrast deficit in schizophrenia, our results suggest a deficit in the normal time course of concurrently perceiving LSF and HSF. This early visual processing impairment is likely to contribute to the difficulties of patients with schizophrenia with facial processing and therefore social interaction.

The cannabinoid system and visual processing: A review on experimental findings and clinical presumptions

Cannabis is one of the most prevalent drugs used worldwide. Regular cannabis use is associated with impairments in highly integrative cognitive functions such as memory, attention and executive functions. To date, the cerebral mechanisms of these deficits are still poorly understood. Studying the processing of visual information may offer an innovative and relevant approach to evaluate the cerebral impact of exogenous cannabinoids on the human brain. Furthermore, this knowledge is required to understand the impact of cannabis intake in everyday life, and especially in car drivers. Here we review the role of the endocannabinoids in the functioning of the visual system and the potential involvement of cannabis use in visual dysfunctions. This review describes the presence of the endocannabinoids in the critical stages of visual information processing, and their role in the modulation of visual neurotransmission and visual synaptic plasticity, thereby enabling them to alter the transmission of the visual signal. We also review several induced visual changes, together with experimental dysfunctions reported in cannabis users. In the discussion, we consider these results in relation to the existing literature. We argue for more involvement of public health research in the study of visual function in cannabis users, especially because cannabis use is implicated in driving impairments.

Low Spatial Frequency Bias in Schizophrenia is Not Face Specific: When the Integration of Coarse and Fine Information Fails

Studies have shown that patients with schizophrenia exhibit visual processing impairments, particularly regarding the processing of spatial frequencies. In a previous work, we found that, compared to healthy volunteers, patients were biased toward low spatial frequencies (LSF) to identify facial expression at a glance. Given the ubiquity of faces in visual perception, it remains an open question whether the LSF bias is face specific or also occurs with other visual objects. Here, 15 patients with schizophrenia and 11 healthy control adults performed a categorization task with hybrid stimuli. These stimuli were single images consisting of two different objects, a fruit and an animal, each in a specific spatial frequency range, either low (LSF) or high (HSF). Observers were asked to report if they saw an animal or a fruit. The reported category demonstrated which spatial scale was preferentially perceived in each trial. In a control experiment, participants performed the same task but with images of only a single object, either a LSF or HSF filtered animal or fruit, to verify that participants could perceive both HSF or LSF when presented in isolation. The results on the categorization task showed that patients chose more frequently LSF with hybrid stimuli compared to healthy controls. However, both populations performed equally well with HSF and LSF filtered pictures in the control experiment, demonstrating that the LSF preference found with hybrid stimuli in patients was not due to an inability to perceive HSF. The LSF preference found in schizophrenia confirms our previous study conducted with faces, and shows that this LSF bias generalizes to other categories of objects. When a broad range of spatial frequencies are present in the image, as in normal conditions of viewing, patients preferentially rely on coarse visual information contained in LSF. This result may be interpreted as a dysfunction of the guidance of HSF processing by LSF processing.

Flash electroretinogram and addictive disorders.

In an exciting article, Lavoie et al. (2014) recently presented theflash electroretinogram as an innovative method to understand the cerebral functioning in psychiatric disorders. The retina is an accessible part of the central nervous system and its measure is well standardized, allowing good reproducibility (Marmor et al., 2008). Retinal processing may therefore reflect the neurochemistry of the brain. Concerning addictive disorders, Lavoie et al. suggested that substance abuse may contribute to ERG abnormalities via dopaminergic neurotransmission. However,we affirm that retinal processingmay also be affected through the direct action of substances on other neurotransmitters implied in retinal functioning. The impact of regular Cannabis use on retinal functioning fits with this approach. The main psychoactive action of Cannabis is due to the action of tetrahydrocannabinol (THC) through G protein coupled receptors, the CB1 receptors. Several studies have shown that CB1 receptors were detectable in the human retina, suggesting a potential effect of exogenous cannabinoids on the retina (Porcella et al., 2000; Straiker et al., 1999). Natural ligands of CB1 receptors such as anandamide or 2-arachidonoylglycerol (2-AG) are also present in the human retina (Chen et al., 2005). Their expressionmay vary across pathological conditions such as diabetic retinopathy suggesting that they could play a role in the control of retinal function (Matias et al., 2006). In animal Progress in Neuro-Psychopharmacology & Biological Psychiatry 56 (2015) 264

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

The emerging field of retinal electrophysiological measurements in psychiatric research: A review of the findings and the perspectives in major depressive disorder

Major depressive disorder (MDD) is a severe mental illness leading to long-term disabilities. One of the current challenges in psychiatric research is to develop new approaches to investigate the pathophysiology of MDD and monitor drug response in order to provide better therapeutic strategies to the patients. Since the retina is considered as part of the central nervous system, it was suggested that it constitutes an appropriate site to investigate mental illnesses. In the past years, several teams assessed the retinal function of patients with mood disorders and many relevant abnormalities have been reported. Investigation of the retinal electrophysiological abnormalities in MDD remains a young emerging field, but we believe that the current findings are very promising and we argue that objective retinal electrophysiological measurements may eventually become relevant tools to investigate the pathophysiology of MDD. Here, we review the retinal abnormalities detected with objective electrophysiological measurements such as the flash electroretinogram (fERG), the pattern electroretinogram (PERG) and the electrooculogram (EOG) in patients with MDD. We discuss how these changes might reflect the pathophysiology of MDD in both clinical and scientific points of view, according especially to the monoamine neurotransmission deficiency hypothesis. We also discuss the technical details that must be taken into consideration for a potential use of the objective retinal electrophysiological measurements as tools to investigate the pathophysiology of MDD.

Association Between Regular Cannabis Use and Ganglion Cell Dysfunction

Importance Because cannabis use is a major public health concern and cannabis is known to act on central neurotransmission, studying the retinal ganglion cells in individuals who regularly use cannabis is of interest. Objective To determine whether the regular use of cannabis could alter the function of retinal ganglion cells in humans. Design, Setting, and Participants For this case-control study, individuals who regularly use cannabis, as well as healthy controls, were recruited, and data were collected from February 11 to October 28, 2014. Retinal function was used as a direct marker of brain neurotransmission abnormalities in complex mental phenomena. Main Outcomes and Measures Amplitude and implicit time of the N95 wave on results of pattern electroretinography. Results Twenty-eight of the 52 participants were regular cannabis users (24 men and 4 women; median age, 22 years [95% CI, 21-24 years]), and the remaining 24 were controls (20 men and 4 women; median age, 24 years [95% CI, 23-27 years]). There was no difference between groups in terms of age (P = .13) or sex (P = .81). After adjustment for the number of years of education and alcohol use, there was a significant increase for cannabis users of the N95 implicit time on results of pattern electroretinography (median, 98.6 milliseconds [95% CI, 93.4-99.5]) compared with controls (median, 88.4 milliseconds [95% CI, 85.0-91.1]), with 8.4 milliseconds as the median of the differences (95% CI, 4.9-11.5; P < .001, Wald logistic regression). A receiver operating characteristic curve analysis (area under the curve, 0.84 [95% CI, 0.73-0.95]; P < .001) revealed, for a cutoff value of 91.13 milliseconds, a sensitivity of 78.6% (95% CI, 60.5%-89.8%) and a specificity of 75.0% (95% CI, 55.1%-88.0%) for correctly classifying both cannabis users and controls in their corresponding group. The positive predictive value was 78.6% (95% CI, 60.5%-89.8%), and the negative predictive value was 75.0% (95% CI, 55.1%-88.0%). Conclusions and Relevance Our results demonstrate a delay in transmission of action potentials by the ganglion cells in regular cannabis users, which could support alterations in vision. Our findings may be important from a public health perspective since they could highlight the neurotoxic effects of cannabis use on the central nervous system as a result of how it affects retinal processing.

Differential item functioning (DIF) of SF-12 and Q-LES-Q-SF items among french substance users

BackgroundDifferential Item Functioning (DIF) is investigated to ensure that each item displays a consistent pattern of responses irrespective of the characteristics of the respondents. Assessing DIF helps to understand the nature of instruments, to assess the quality of a measure and to interpret results. This study aimed to examine whether the items of the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) and Short-Form 12 (SF-12) exhibit DIF.MethodA total of 124 outpatients diagnosed with substance dependence participated in a cross-sectional, multicenter study. In addition to the Q-LES-Q-SF and SF-12 results, demographic data such as age, sex, type of substance dependence and education level were collected. Rasch analysis was conducted (using RUMM2020 software) to assess DIF of the Q-LES-Q-SF and SF-12 items.ResultsFor SF-12, significant age-related uniform DIF was found in two of the 12 items, and sex-related DIF was found in one of the 12 items. All of the observed DIF effects in SF-12 were found among the mental health items. Three items showed DIF on the Q-LES-Q-SF; however, the impact of DIF item on the delta score calculation for the comparisons of self-reported health status between the groups was minimal in the SF-12 and small in the Q-LES-Q-SF.ConclusionThese results indicated that no major measurement bias affects the validity of the self-reported health status assessed using the Q-LES-Q-SF or SF-12. Thus, these questionnaires are largely robust measures of self-reported health status among substance users.

Combination of classical test theory (CTT) and item response theory (IRT) analysis to study the psychometric properties of the French version of the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF)

ObjectiveThe study aimed to examine the construct validity and reliability of the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) according to both classical test and item response theories.MethodThe psychometric properties of the French version of this instrument were investigated in a cross-sectional, multicenter study. A total of 124 outpatients with a substance dependence diagnosis participated in the study. Psychometric evaluation included descriptive analysis, internal consistency, test–retest reliability, and validity. The dimensionality of the instrument was explored using a combination of the classical test, confirmatory factor analysis (CFA), and an item response theory analysis, the Person Separation Index (PSI), in a complementary manner.ResultsThe results of the Q-LES-Q-SF revealed that the questionnaire was easy to administer and the acceptability was good. The internal consistency and the test–retest reliability were 0.9 and 0.88, respectively. All items were significantly correlated with the total score and the SF-12 used in the study. The CFA with one factor model was good, and for the unidimensional construct, the PSI was found to be 0.902.ConclusionThe French version of the Q-LES-Q-SF yielded valid and reliable clinical assessments of the quality of life for future research and clinical practice involving French substance abusers. In response to recent questioning regarding the unidimensionality or bidimensionality of the instrument and according to the underlying theoretical unidimensional construct used for its development, this study suggests the Q-LES-Q-SF as a one-dimension questionnaire in French QoL studies.

Commentary: Anatomical constitution of sense organs as a marker of mental disorders.

Research in neuroscience and psychiatry is limited by the difficulty to accurately access brain functioning. There is currently a need to develop new methods assessing the neurobiological underpinning of brain dysfunctions (London et al., 2013; Lavoie et al., 2014; Guell and Bernacer, 2015; Laprevote et al., 2015; Schwitzer et al., 2015a,b). On this basis, Guell and Bernacer in an exciting article recently discussed the relevance of studying visual perception in mental disorders and especially in schizophrenia (Guell and Bernacer, 2015). Among other deficits, they outlined retinal functional and anatomical deficits detected in schizophrenia using respectively flash electroretinogram (fERG) and optical coherence tomography (OCT). However, we would like to suggest herein that the pattern electroretinogram (PERG), a retinal functional recording, might provide a relevant complementary measurement to enhance understanding of biological mechanisms underlying brain disorders in schizophrenia. Flash and pattern ERG allow for the assessment of specific cell types of the neural retina and give different information on the pathophysiology. Using a light stimulation, the fERG mainly assesses the electric biopotential evoked by the first stages of visual processing namely photoreceptors and bipolar-Muller cell complex (Holder et al., 2010). As previously found, these first stages are altered in schizophrenia (Warner et al., 1999; Balogh et al., 2008; Hebert et al., 2015). However, the fERG does not significantly provide information concerning the ganglion cells, the axons of which form the optic nerve. The ganglion cells constitute the ultimate retinal relay before the transmission of the visual information from the retina to the visual cortex. The functional properties of these cells can be assessed by the PERG using the central presentation of reversing black and white checkerboards (Bach et al., 2013). The On-Off organization of the ganglion cells receptive fields makes these cells particularly sensitive to the alternate changes in contrast levels of the checkerboards, and leads to large responses in the PERG (Holder et al., 2010). The electrical signal transmitted to ganglion cells originates from photoreceptor and bipolar cells and is under the influence of interneurons cells (amacrine and horizontal cells). The signal elicited at the ganglion cell level thus results from the integration of several retinal stages. Since it is more integrated there than at the photoreceptor and bipolar cell level we suggest that its measurement might be a useful complementary test to approach the neural function in schizophrenia. Furthermore, the layer of the ganglion cells is the first retinal stage providing information in the form of action potentials. Trustworthy evidence underlines that PERG protocols are good candidates to investigate dopamine transmission, a neurotransmitter known to be involved in schizophrenia. Indeed, the manipulation of the contrast level of the reversing black and white checkerboards during PERG informs on retinal contrast processing, which is largely influenced by retinal dopaminergic amacrine cells (Djamgoz et al., 1997). Moreover, alterations of retinal contrast processing detected with reversal PERG stimulation were found in Parkinsons disease, a dopaminergic pathology (Garcia-Martin et al., 2014). Importantly, these changes appear to be good biological markers, inasmuch as they predict quality of life and disease severity in Parkinsons disease. PERG shares several advantages with fERG. Measurements of PERG are non-invasive, relatively fast, easy-to-use, and inexpensive. Importantly, PERG also has some additional advantages relative to fERG. Unlike most protocols of fERG, there is no need to dilate the pupil, making the PERG less invasive than fERG, with no alteration of visual perception. Second, whereas the fERG is evaluated after adaptation periods in darkness and light, the PERG is entirely measured in light conditions without any adaptation period (Bach et al., 2013; McCulloch et al., 2015). These methodological advantages may facilitate the use of PERG in patients with schizophrenia. As the PERG contrast processing appears sensitive to dopaminergic dysfunction, it might represent a suitable approach for monitoring anti-psychotic response, an important part of patient care. Finally, the PERG can be coupled with other retinal measurements such as the fERG to provide a more thorough picture of the pathophysiology of the disease. As previously described, measures of PERG assess the functional properties of the retinal ganglion cells, the axons of which form the optic nerve. Anatomical constitution and organization of these cells can be evaluated by retinal imaging techniques, namely OCT. Several studies found retinal nerve fiber layer (RNFL) thinning in schizophrenia, which was observed with spectral domain OCT (Chu et al., 2012; Lee et al., 2013; Silverstein et al., 2015). RNFL is constituted by the fibers of the optic nerve and its thinning is a direct reflection of a loss of ganglion cell axons. We suppose that anatomical alterations of retinal ganglion cells observed in schizophrenia could lead to functional deficits of these cells. Such impairments could be detected by PERG. Importantly, adding functional measurements like PERG to imaging techniques such as OCT may provide a potential structure-function correlation. Although PERG might appear as a relevant measure to indirectly approach the pathophysiology of schizophrenia, there are several limitations and a large number of steps required to demonstrate the usefulness of this exam in the better understanding of the disease. To this date, PERG measurements have not been evaluated in schizophrenia patients yet and consequently there is no certainty that differences between patients and healthy controls would be observed. Accordingly, case-control studies with a large number of subjects and standardized protocols are needed to eventually demonstrate differences between patients and controls. This constitutes the starting point to investigate the relevance of this method. Additionally, the pathophysiology of schizophrenia remains to this date elusive and involves more complex mechanisms than only dopaminergic dysfunctions (Khandaker et al., 2015). As a consequence, only one exam such as PERG does not alone give sufficient information on central dysfunctions but should be coupled with other assessments to provide a clearer picture of the disease. Then, in the case where differences between groups would be observed, control groups of patients with other dopaminergic pathologies are crucial to conclude on the specificity of PERG. Also, as we can consider that it is impossible to have medication-free schizophrenia patients, the effects of different types of psychotropic drugs such as antipsychotics must be tested on PERG recordings to differentiate the potential effects of medications or disease. Finally, although there is currently an increasing interest for PERG assessments in psychiatric research (Schwitzer et al., 2015a, 2016), the precise mechanisms underlying PERG anomalies should be investigated to understand the biological underpinning of brain dysfunctions. Approximately 0.5% of the population suffers from schizophrenia, which has psychiatric and cognitive consequences. A current challenge in neuroscience research is to develop reproducible measures providing an indirect access to the brain functioning. In the case of schizophrenia, there is an urgent need for biological markers enabling early detection of the disease. Eventually, the PERG might be used as a useful complementary measurement to allow a better understanding of the pathophysiology of schizophrenia.