Background: The retina has gained increasing attention in non-ophthalmological research in recent years. The pattern electroretinogram (PERG), a method to evaluate retinal ganglion cell function, has been used to identify objective correlates of the essentially subjective state of depression. A reduction in the PERG contrast gain was demonstrated in patients with depression compared to healthy controls with normalization after remission. PERG responses are not only modulated by stimulus contrast, but also by check size and stimulation frequency. Therefore, the rationale was to evaluate potentially more feasible procedures for PERG recordings in daily diagnostics in psychiatry. Methods: Twenty-four participants (12 patients with major depression (MDD) and 12 age- and sex-matched healthy controls) were examined in this pilot study. We investigated PERG amplitudes for two steady-state pattern reversal frequencies (12.5/18.75 rps) and four sizes of a checkerboard stimulus (0.8°, 1.6°, 3.2°, and 16°) to optimize the PERG recordings in MDD patients. Results: Smaller PERG amplitudes in MDD patients were observed for all parameters, whereby the extent of the reduction appeared to be stimulus-specific. The most pronounced decline in the PERG of MDD patients was observed at the higher stimulation frequency and the finest pattern, whilst responses for the largest check size were less affected. Following the PERG ratio protocol for early glaucoma, where similar stimulus dependent modulations have been reported, we calculated PERG ratios (0.8°/16°) for all participants. At the higher frequency (18.75 rps), significantly reduced ratios were observed in MDD patients. Conclusion: The “normalization” of the PERG responses—via building a ratio—appears to be a very promising approach with regard to the development of an objective biomarker of the depressive state, facilitating inter-individual assessments of PERG recordings in patients with psychiatric disorders.

Background: Chronic depression is characterized by persistent or recurrent depressive symptoms, defined according to DSM criteria, and is associated with lack of empathy; deficits in social perception, interaction, and communication; and social withdrawal. These symptoms are reminiscent of autism spectrum disorders, yet the co-occurrence of autistic traits and chronic depression has been rarely explored. We explored measures of autistic traits in chronically depressed adult patients in order to further define and delineate the overlap of symptoms between chronic depression and autism spectrum disorders. Method: Three groups were tested: 31 patients with chronic depression, 27 patients with autism spectrum disorder, and 31 healthy controls. The Autism Spectrum Quotient (AQ) and the Empathy Quotient (EQ) were used to measure autistic traits. The severity of depression was measured by Beck's Depression Inventory. Results: The group of chronically depressed patients showed significantly elevated autistic traits according to both AQ and EQ measures. In addition, 48.4% of the patients with chronic depression showed AQ scores within the range of the broader autistic phenotype. Similar scores were found among 3.2% of the healthy controls and 100% of the patients with autism spectrum disorder. Conclusions: About half of the chronically depressed patients showed elevated autistic or autism-like traits. It remained unclear whether this was due to the state of chronic depression or a kind of premorbid autistic personality trait. The findings illustrate the need for further research to clarify the possible role of autistic traits in the development of chronic depression. Furthermore, they reveal that it might be clinically useful to focus on autism-like social impairments in therapy for chronic depression.

Inattention, distractibility, and problems inhibiting irrelevant information impose a large disease burden in atten- tion de ficit hyperactivity disorder (ADHD). Problems with cognitive function are found in many major psychiatric disorders, and our understanding of ADHD might add to our knowledge of other neuropsychiatric disorders. De- spite the high impact of ADHD, the pathophysiology and the mechanism of treatment action remains poorly un- derstood. Increasing evidence suggests that elevated neuronal and retinal background noise plays a prominent role in ADHD. However, the effect of treatment (e.g., methylphenidate) on noise remains unclear. For this study, retinal background noise was assessed with the pattern-electroretinogram (PERG) in 20 drug -na?ve adults with ADHD before and after treatment with methylphenidate and in 21 control subjects. Background noise was identi fied using the Fourier magnitude at frequencies adjacent to the stimulus -response frequency of 12.5 Hz. At baseline, we found an elevated retinal background noise in ADHD patients ( Mdn = 0.079 ?V) compared to con- trols ( Mdn = 0.062 ?V; z = -2.79, p = 0.016, r = -0.44). The noise in the ADHD group decreased signi ficantly at follow-up after treatment with methylphenidate ( Mdn = 0.069 ?V, z = -2.39, p = 0.035, r = -0.39) while there was no change in the control group. PERG-based retinal noise is increased in adult ADHD and normalizes along with clinical symptoms following treatment with methylphenidate. The retinal noise level might be a promising marker of ADHD in clinical and basic research and illustrates the biological match with nonhuman ADHD models.

Problems with cognitive function are found in many major psychiatric disorders. In schizophrenia and attention deficit hyperactivity disorder (ADHD), they are among the core symptoms. Based on a growing recognition that there is little diagnostic specificity for any single cognitive impairment, there is an increasing emphasis on investigating impairments across psychiatric disorders. This approach, which is consistent with the NIMH Research Domain Criteria initiative, is expected to lead to a better understanding of the neurobiological mechanisms involved in cognitive deficits. An increase in neuronal background noise has been identified as a neuronal correlate of inattention. Because the dopamine system has been found to play a critical role in modulating neuronal noise, dopamine dysfunction may play a substantial role in generating the excessive noise that has been found to characterize information processing in both schizophrenia and ADHD. This issue can be studied noninvasively via electrophysiological examination of the retina, a distinct neural network. Both basic research and human studies indicate that retinal information processing is under strong dopaminergic modulation (Bubl, Biol. Psychiatry, 2010; Bubl, Br J Psychiatry, 2012). We have previously demonstrated an elevated level of background noise at a very early stage in visual information processing in untreated patients with ADHD (Bubl, Plos One, 2015). Moreover, background noise was associated with inattention measures in these subjects. To further address the hypothesis that elevated retinal noise reflects dopaminergic dysfunction, we report here on a new study that compared retinal background noise in patients with ADHD both before and after therapy, as well as in patients with schizophrenia. Neuronal noise was assessed using pattern electroretinogram (PERG), an objective electrophysiological measure for retinal network function from the photoreceptors to the retinal ganglion cells. A total of 20 patients diagnosed with ADHD were tested both before and after treatment with methylphenidate (MPH). The control group consisted of 21 healthy subjects. The PERGs were recorded in a steady state mode in response to checkerboard stimuli of 12 reversals/s. Data collection with people with schizophrenia is ongoing, and results will be reported at SIRS. Before treatment, the patients with ADHD presented with elevated background noise (higher by 127%) in comparison to the control group. After treatment, noise level did not differ from what was observed in the control group. Retinal background noise was found to be highly correlated with the severity of the ADHD symptoms. The results will be discussed in relationship to our findings in patients with schizophrenia. These data provide further evidence for the hypothesis that elevated background noise is linked to ADHD and cognitive deficits. The findings are of special relevance because ADHD is a disorder with a dedicated treatment option for cognitive symptoms. Interestingly, a similar pathophysiological mechanism for cognitive dysfunction has been proposed for both schizophrenia and ADHD. However, because ADHD medications, such as MPH, typically elevate dopamine levels, potentially leading to exacerbation of psychotic symptoms, different approaches for treating cognitive symptoms in schizophrenia need to be explored. On this basis, current approaches used to target neuronal noise and cognitive symptoms in patients with schizophrenia will be discussed and their relevance for future research will be addressed.

“Depression feels grey” – this frequent description by patients with major depressive disorder (MDD) may have a neural basis in impaired contrast processing, possibly due to altered dopamine levels. We here present extended evidence that the Pattern Electroretinogram (PERG – a ganglion cell function correlate) is markedly reduced, relevant even on a single patient basis.

Psychiatry and neuroscience research need novel approaches to indirectly investigate brain function. As the retina is an anatomical and developmental extension of the central nervous system (CNS), changes in retinal function may reflect neurological dysfunctions in psychiatric disorders. The last and most integrated retinal relay before visual information transfer to the brain is the ganglion cell layer. Here, based on collected arguments, we argue that these cells offer a crucial site for indirectly investigating brain function. We describe the anatomical and physiological properties of these cells together with measurements of their functional properties named pattern electroretinogram (PERG). Based on ganglion cell dysfunctions measured with PERG in neurological disorders, we argue for the relevance of studying ganglion cell function in psychiatric research. We review studies that have evaluated ganglion cell function in psychiatric and addictive disorders and discuss how changes in PERG measurements could be functional markers of pathophysiological mechanisms of psychiatric disorders.

Introduction: An increased prevalence of pathological electroencephalography (EEG) signals has been reported in patients with borderline personality disorder (BPD). In an elaborative case description of such a patient with intermittent rhythmic delta and theta activity (IRDA/IRTA), the BPD symptoms where linked to the frequency of the IRDAs/IRTAs and vanished with the IRDAs/IRTAs following anticonvulsive therapy. This observation raised a question regarding the prevalence of such EEG abnormalities in BPD patients. The aim of this retrospective study was to identify the frequency of EEG abnormalities in a carefully analyzed psychiatric collective. Following earlier reports, we hypothesized an increased prevalence of EEG abnormalities in BPD patients.Participants and Methods: We recruited 96 consecutive patients with BPD from the archive of a university clinic for psychiatry and psychotherapy, and compared the prevalence of EEG abnormalities to those of 76 healthy controls subjects. The EEGs were rated by three different blinded clinicians, including a consultant specializing in epilepsy from the local epilepsy center.Results: We found a significant increase in the prevalence of IRDAs and IRTAs in BPD patients (14.6%) compared to the control subjects (3.9%; p=0.020). Discussion: In this blinded retrospective case-control study, we were able to confirm an increased prevalence of pathological EEG findings (IRDAs/IRTAs only) in BPD patients. The major limitation of this study is that the control group was not matched on age and gender. Therefore, the results should be regarded as preliminary findings of an open uncontrolled, retrospective study. Future research performing prospective, controlled studies is needed to verify our findings and answer the question of whether such EEG findings might predict a positive response to anticonvulsive pharmacological treatment.

Depressive disorder is often associated with the subjective experience of altered visual perception. Recent research has produced growing evidence for involvement of the visual system in the pathophysiology of depressive disorder. Using the pattern electroretinogram (PERG), we found reduced retinal contrast response in patients with major depression. Based on this observation, the question arises whether this change has a cortical correlate. To evaluate this, we analyzed the visual evoked potential (VEP) of the occipital cortex in 40 patients with depressive disorder and 28 healthy controls. As visual stimuli, checkerboard stimuli of 0.51° check size, 12.5 reversals per second and a contrast of 3–80 % was used. In addition to the PERG, we recorded the VEP with an Oz versus FPz derivation. The amplitude versus contrast transfer function was compared across the two groups and correlated with the severity of depression, as measured by the Hamilton Depression Rating Scale and the Beck Depression Inventory. Patients with major depression displayed significantly reduced VEP amplitudes at all contrast levels compared to control subjects (p = 0.029). The VEP amplitude correlated with psychometric measures for severity of depression. The degree of depression reduced the contrast transfer function in the VEP to a lesser extent than in the PERG: While the PERG is reduced to ≈50 %, the VEP is reduced to 75 %. Our results suggest that depression affects the cortical response in major depression, but less so than the retinal responses. Modified contrast adaptation in the lateral geniculate nucleus or cortex possibly moderates the increased losses in the retina.

BACKGROUND:Based on clinical experience there is a discrepancy between the educational records and vocational performance in patients with high functioning autism spectrum disorder (ASD).METHOD:In order to assess psychosocial and vocational specificities of adult ASD patients we analyzed the demographic and hospital data of consecutively diagnosed patients employing descriptive statistics.RESULTS:We were able to include 255 patients into our sample who were consecutively diagnosed between October 2009 and October 2011. The gender ratio was 162:93 in favor of male patients. The educational records of our patient sample was comparatively good [50 % highest level of German schooling system (allgemeine Hochschulreife), 39 % university degree], however, the vocational records were poor with 58 % of our patients being unemployed. The psychiatric comorbidity was high, 57 % of the patients suffered from depression.CONCLUSION:There is a high need for special support programs for adult high functioning ASD patients focusing on adaptive vocational skills to avoid unemployment and secondary psychiatric problems.

A common neurodevelopmental disorder, autism spectrum disorder (ASD), is defined by specific patterns in social perception, social competence, communication, highly circumscribed interests, and a strong subjective need for behavioral routines. Furthermore, distinctive features of visual perception, such as markedly reduced eye contact and a tendency to focus more on small, visual items than on holistic perception, have long been recognized as typical ASD characteristics. Recent debate in the scientific community discusses whether the physiology of low-level visual perception might explain such higher visual abnormalities. While reports of this enhanced, “eagle-like” visual acuity contained methodological errors and could not be substantiated, several authors have reported alterations in even earlier stages of visual processing, such as contrast perception and motion perception at the occipital cortex level. Therefore, in this project, we have investigated the electrophysiology of very early visual processing by analyzing the pattern electroretinogram-based contrast gain, the background noise amplitude, and the psychophysical visual acuities of participants with high-functioning ASD and controls with equal education. Based on earlier findings, we hypothesized that alterations in early vision would be present in ASD participants. This study included 33 individuals with ASD (11 female) and 33 control individuals (12 female). The groups were matched in terms of age, gender, and education level. We found no evidence of altered electrophysiological retinal contrast processing or psychophysical measured visual acuities. There appears to be no evidence for abnormalities in retinal visual processing in ASD patients, at least with respect to contrast detection.

BackgroundInattention and distractibility are core symptoms of attention deficit hyperactivity disorder (ADHD). Still the neuronal organization is largely unknown. Previously we studied the electrophysiological activity of a distinct neuronal network-the retina-and found no change in stimulus-driven neural activity in patients with ADHD. However there is growing evidence for an elevated non stimulus-driven neural activity, or neuronal background noise, as underlying pathophysiological correlate. To further examine the biological bases that might underlie ADHD and problems with inattention, we performed a new analysis to test the hypothesis of an elevated background noise as underlying neuronal correlate for ADHD and problems with inattention in humans. A direct measure of background noise in patients with ADHD has not been described yet.MethodsThe retinal background noise was assessed based on pattern electroretinogram (PERG) data in 20 unmedicated ADHD patients and 20 healthy controls. The PERG is an electrophysiological measure for retinal ganglion cell function. ADHD severity was assessed by interview and questionnaire.ResultsNoise amplitude was significantly higher (138%) in patients with ADHD compared to the control group (p = 0.0047). Noise amplitude correlated significantly with psychometric measures for ADHD (CAARS) especially inattention (r = 0.44, p = 0.004).ConclusionsThe data provide evidence that an elevated background noise is associated with symptoms of inattention in ADHD and support the use of therapeutic interventions that reduce noise and distraction in patients with ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. In an attempt to extend earlier neurochemical findings, we organized a magnetic resonance spectroscopy (MRS) study as part of a large, government-funded, prospective, randomized, multicenter clinical trial comparing the effectiveness of specific psychotherapy with counseling and stimulant treatment with placebo treatment (Comparison of Methylphenidate and Psychotherapy Study). We report the baseline neurochemical data for the anterior cingulate cortex (ACC) and the cerebellum in a case-control setting. For the trial, 1,480 adult patients were contacted for participation, 518 were assessed for eligibility, 433 were randomized, and 187 were potentially eligible for neuroimaging. The control group included 119 healthy volunteers. Single-voxel proton MRS was performed. In the patient group, 113 ACC and 104 cerebellar spectra fulfilled all quality criteria for inclusion in statistical calculations, as did 82 ACC and 78 cerebellar spectra in the control group. We did not find any significant neurometabolic differences between the ADHD and control group in the ACC (Wilks' lambda test: p = 0.97) or in the cerebellum (p = 0.62). Thus, we were unable to replicate earlier findings in this methodologically sophisticated study. We discuss our findings in the context of a comprehensive review of other MRS studies on ADHD and a somewhat skeptical neuropsychiatric research perspective. As in other neuropsychiatric disorders, the unclear nosological status of ADHD might be an explanation for false-negative findings.

Recent studies of contrast response functions have found: 1) Separate cortical processes mediate amplitudes at high and low contrasts, as revealed by principal component analysis (PCA) of individual differences in visual evoked potentials (VEPs) (Hamer, Souza et al. 2013). 2) There is a strong reduction in contrast perception and retinal contrast gain in patients with major depression, which normalizes after antidepressive therapy and remission of depression (Bubl et al. 2009; 2010; 2012). The current analysis examines processes (statistical factors) underlying cortical and retinal contrast response functions. Further, it examines which of these processes change with depression. Thirty-five patients with a diagnosis of major depression (26 with and 9 without medication) and 21 healthy subjects participated. Pattern electroretinograms (PERGs) were recorded from both eyes. To quantify PERG and VEP based contrast responses, a sequence of five checkerboard stimuli was presented with 0.5° check size, contrast-reversing at 12 reversals per second, and Michelson contrasts of 3.2%, 7.3%, 16.2%, 36%, and 80%. Individual differences in left and right eye responses were highly intercorrelated, and thus averaged. Principal components were computed from log amplitudes and rotated to approximate simple structure using a Varimax rotation. (1) Two retinal (PERG) and two cortical (VEP) factors were found. The two cortical processes mediate high and low contrasts, consitent with Hamer et al. The two retinal factors also mediate high and low contrasts, but are independent of (uncorrelated with) cortical factors. The four factors were distinct from three additional factors found for VEP noise and PERG noise in left and right eyes. (2) The only factor of the four that changes significantly with depression is a retinal factor tuned to high contrasts. Our analysis identifies probable contrast-sensitive mechanisms, and shows a surprising independence of retinal and cortical gains. Changes in contrast perception in depression may be linked to a single retinal process. Meeting abstract presented at VSS 2015

Background The prevalence of negative symptoms in schizophrenic patients seems to be an important indicator for treatment response and prognosis. Although negative symptoms have often been attributed to frontal lobe anomalies, neuropsychological and anatomical findings do not explicitly support this assumption. Since knowledge about the cerebral correlate of negative symptoms in schizophrenia might have a strong impact on therapeutic and psychopharmacological interventions, we aimed to answer this question by investigating the relationship between negative symptoms, neuropsychological functioning and cerebral volumes in schizophrenic patients. Methods Twenty schizophrenic patients and 32 healthy controls were examined using a neuropsychological test battery for the assessment of temporal (mnestic) and frontal (executive) faculties. Volumetric measurements of temporal (hippocampus and amygdala) and frontal (orbitofrontal, dorsolateral prefrontal, and anterior cingulate area) brain areas were performed. Negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS). Results Schizophrenic patients performed worse than healthy controls in tests assessing verbal and visuospatial learning and memory functions and on the Stroop interference task. After dividing the schizophrenic group in patients with high and low SANS scores almost all of these deficits were restricted to the former group. There were no overall group differences regarding cerebral subarea volumes. Overall negative symptoms were significantly correlated with verbal memory functions but not with frontal lobe faculties. Conclusions Negative symptoms in schizophrenia could specifically associated with verbal memory deficits.

Background Asperger’s Syndrome (AS) is an autism spectrum disorder that is characterized by significant difficulties in social interaction and nonverbal communication, and restricted and repetitive patterns of behavior and interests. Difficulties with respect to pragmatic speech, reading emotional and social cues, differentiating between fact and fiction, and taking into account the influence of context on a statement are commonly described features. However, hitherto established questionnaires did not focus on these symptoms. Methods In this study we present a short (11 questions) questionnaire which focuses on self-rated pragmatic speech abilities, the Freiburg Questionnaire of linguistic pragmatics (FQLP). Psychometric properties of the questionnaire were explored in a sample of 57 patients with Asperger’s Syndrome, 66 patients with other psychiatric disorders, and a convenience sample of 56 people. Results Reliability analysis showed a high Cronbach’s α. Strong correlations could be demonstrated for the FQLP with the Autism Quotient and the Empathy Quotient. Concerning divergent validity a moderate correlation was found between the FQLP and self-rated symptoms of personality disorders. No significant correlation was found between the FQLP and the vocabulary skills. The receiver operating characteristics curve showed an excellent diagnostic accuracy of the FQLP (.97). Conclusions As the control group consisted of people without mental disorder and patients with different psychiatric disorders, the results indicate that the construct examined by the FQLP is quite specific to the peculiarities of AS. The FQLP is a reliable, brief and valid instrument. First results regarding sensitivity and specificity are highly promising.

In previous studies, we found a strong reduction in contrast perception and retinal contrast gain in patients with major depression, which normalized after remission of depression. We also identified a possible role of the dopaminergic system in this effect, because visual contrast perception depends on dopaminergic neurotransmission. Dopamine is also known to play an important role in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Therefore, in order to explore the specificity of retinal contrast gain as a marker of depression in comparison with other psychiatric diseases, we recorded the pattern electroretinogram (PERG) in patients with ADHD. Twenty patients diagnosed with ADHD and 20 matched healthy subjects were studied. Visual pattern electroretinograms were recorded from both eyes. The contrast gain of the patients with attention deficit disorder (ADD) did not differ from the control group, nor did the contrast gain of any ADHD subgroup (predominantly inattentive or combined patients). In the healthy subjects, a significant correlation between depression score and contrast gain was found. As the contrast gain in an earlier study clearly separated the patients with depression from the controls, we assume that retinal contrast gain might be a specific marker in depression.

Background Recently, we reported a reduced retinal contrast gain in unmedicated and medicated patients with major depression. Aims To analyse whether the contrast gain normalises after successful antidepressive therapy by recording the pattern electroretinogram (PERG) in healthy controls and patients with depression before and after antidepressive therapy. Method Fourteen patients diagnosed with major depression were repeatedly scanned and the results compared with that from 40 matched controls. Results The retinal contrast gain was lower at baseline in patients with depression, was normalised with remission and correlated with the severity of depression. Patients who did not achieve remission retained significantly lower contrast gain at follow-up. Conclusions The study provides evidence for a state-dependent modulation of retinal contrast gain in patients with major depression. Reduced contrast gain normalised after therapy. A PERG-based contrast gain could serve as a state marker of depression.

Background: Everyday language relates depressed mood to visual phenomena. Previous studies point to a reduced sensitivity of subjective contrast perception in depressed patients. One way to assess visual contrast perception in an objective way at the level of the retina is to measure the pattern electroretinogram (PERG). To find an objective correlate of reduced contrast perception, we measured the PERG in healthy control subjects and unmedicated and medicated patients with depression.Methods: Forty patients with a diagnosis of major depression (20 with and 20 without medication) and 40 matched healthy subjects were studied. Visual PERGs were recorded from both eyes.Results: Unmedicated and medicated depressed patients displayed dramatically lower retinal contrast gain. We found a strong and significant correlation between contrast gain and severity of depression. This marker distinguishes most patients on a single-case basis from control subjects. A receiver operating characteristic analysis revealed a specificity of 92.5% and a sensitivity of 77.5% for classifying the participants correctly.Conclusions: Because PERG recording does not depend on subjective ratings, this marker may be an objective correlate of depression in human beings. If replicated, PERG may be helpful in further animal and human research in depression.

Objectives. The last decade has seen an increasing interest in the method of magnet resonance spectroscopy (MRS) since this is the only research tool that allows a non-invasive in vivo assessment of neurochemical aspects of ADHD without employing ionising radiation. In this paper we review published MRS results with respect to childhood, adolescence and adult ADHD. Method. We searched the Medline (Pub Med) database using the key words ADHD, attention-deficit/hyperactivity disorder, magnet resonance spectroscopy, MRS and spectroscopy. Citations of identified articles were also searched for relevant studies. Meta-analyses were performed for the measured metabolites and regions of assessment. Results. Sixteen studies could be identified that used MRS to investigate the neurobiology of ADHD. Two regions could be identified as the focus of spectroscopic investigations - the frontal lobe including anterior cingulate cortex and parts of prefrontal cortex and the basal ganglia, mostly striatum, alongside the fronto-striato-thalamo-frontal circuits. As for metabolites, in the majority of studies the ratios to creatine and not absolute concentrations of metabolites were estimated. Choline compounds, N-acetyl-aspartate and glutamate/glutamine (to creatine ratios) could be identified as being altered in several studies in ADHD. The meta-analysis showed increased choline compounds in several researched regions. Discussion. MRS is a promising tool for the non-invasive in vivo assessment of the cerebral neurochemistry in ADHD. More regions of interest (ROI) like amygdala, hippocampus, thalamus and cerebellum should be assessed in future studies. Further methodological improvements of MRS are desirable in order to assess the absolute metabolite concentration of several ROIs at the same time. Such developments will open novel perspectives in spectroscopic investigations of ADHD.