Retinal dysfunction of contrast processing in major depression also apparent in cortical activity.

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.

Neuropsychological and cerebral morphometric aspects of negative symptoms in schizophrenia: negative symptomatology is associated with specific mnestic deficits in schizophrenic patients.

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.

Freiburg Questionnaire of linguistic pragmatics (FQLP): psychometric properties based on a psychiatric sample.

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.

Effect of antidepressive therapy on retinal contrast processing in depressive disorder.

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.

Replication of Reduced Pattern Electroretinogram Amplitudes in Depression With Improved Recording Parameters.

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.

Normalization of increased retinal background noise after ADHD treatment: A neuronal correlate.

Inattention, distractibility, and problems inhibiting irrelevant information impose a large disease burden in attention deficit 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. Despite the high impact of ADHD, the pathophysiology and the mechanism of treatment action remains poorly understood. 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-naïve adults with ADHD before and after treatment with methylphenidate and in 21 control subjects. Background noise was identified 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 µV) compared to controls (Mdn = 0.062 µV; z = -2.79, p = 0.016, r = -0.44). The noise in the ADHD group decreased significantly at follow-up after treatment with methylphenidate (Mdn = 0.069 µV, 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.

Hippocampus and amygdala morphology in adults with attention-deficit hyperactivity disorder.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) in adulthood is a serious health problem with a prevalence of up to 4%. Limbic structures have been implicated in the genesis of ADHD; it has been suggested that they mediate mood and cognitive disturbances in affected individuals. Recently, a large study involving children and adolescents with ADHD reported bilateral enlargement of the hippocampus and indirect evidence of amygdala volume loss in this patient sample. We sought to test the hypothesis that, like in pediatric patients, there might be hippocampus and amygdala volume abnormalities in adult patients with ADHD. METHODS: We studied 27 adult patients with ADHD and 27 group-matched healthy volunteers using a 1.5 T magnetic resonance imaging scanner. We manually obtained morphometric measurements of the regions mentioned. RESULTS: In contrast to previous findings in children and adolescents, we found no significant differences in hippocampus and amygdala volumes among adults with and without the disorder. CONCLUSION: Findings of hippocampus enlargement and amygdala volume loss are not very stable across different samples of patients with ADHD. Contradictory findings may be related to the different locations of alterations along the complex circuits responsible for the different symptoms of ADHD. Further studies involving larger samples of adult patients with ADHD and using multimodal designs are needed.

Looking into the brain through the retinal ganglion cells in psychiatric disorders: A review of evidences.

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.

Aripiprazole in patients with Tourette syndrome.

The treatment of the Gilles de la Tourette syndrome (GTS) is often challenging. One reason for this is the high neuropsychiatric cormorbidity in terms of ADHD or obsessive-compulsive symptoms. Dopaminergic modulation e.g. with antidopaminergic medication is an important part of the medical therapy aimed at motor and vocal tics. We report recent experiences with treatment with aripiprazole, a novel antipsychotic agent, which not only improved motor and vocal tics but also ameliorated some behavioural symptoms of the GTS cluster. Furthermore, we discuss possible pharmacological mechanisms for the observed effects.

[Well Educated Unemployed--On Education, Employment and Comorbidities in Adults with High-Functioning Autism Spectrum Disorders in Germany]. / Überdurchschnittlich ausgebildete Arbeitslose--Bildung, Beschäftigungsverhältnisse und Komorbiditäten bei Erwachsenen mit hochfunktionalem Autismus in Deutschland.

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.

Increased Prevalence of Intermittent Rhythmic Delta or Theta Activity (IRDA/IRTA) in the Electroencephalograms (EEGs) of Patients with Borderline Personality Disorder.

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.

Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study.

BACKGROUND: Glutamatergic dysfunction has been implicated in the pathophysiology of schizophrenia. However, so far there is limited direct evidence of altered in vivo glutamate concentrations in the brains of patients with schizophrenia. To test the hypothesis that altered glutamatergic neurotransmission might play a role in the pathogenesis of schizophrenia, we measured glutamate and glutamine concentrations in the prefrontal cortex and the hippocampus of patients with chronic schizophrenia using high-field magnetic resonance spectroscopy. METHODS: Twenty-one patients with schizophrenia and 32 healthy volunteers were examined clinically and by means of short echo time single voxel magnetic resonance spectroscopy of the dorsolateral prefrontal cortex and the hippocampus. Absolute concentrations of neurometabolites were calculated. RESULTS: Absolute concentrations of glutamate were significantly higher in the prefrontal cortex and the hippocampus in the patient group. Factorial analysis of variance (ANOVA) revealed no significant interactions between duration of schizophrenia, number of hospitalizations, or type of antipsychotic medication and glutamate concentrations. Increased prefrontal glutamate concentrations were associated with poorer global mental functioning. CONCLUSIONS: This is the first study that reports increased levels of glutamate in prefrontal and limbic areas in patients with schizophrenia. Our data support the hypothesis of glutamatergic dysfunction in schizophrenia.

Normal Visual Acuity and Electrophysiological Contrast Gain in Adults with High-Functioning Autism Spectrum Disorder.

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.

Elevated background noise in adult attention deficit hyperactivity disorder is associated with inattention.

BACKGROUND: Inattention 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. METHODS: The 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. RESULTS: Noise 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). CONCLUSIONS: The 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.

Normal Neurochemistry in the Prefrontal and Cerebellar Brain of Adults with Attention-Deficit Hyperactivity Disorder.

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.

Retinal contrast transfer functions in adults with and without ADHD.

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.

Seeing gray when feeling blue? Depression can be measured in the eye of the diseased.

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.

Vision in depressive disorder.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. Furthermore, dopaminergic neurotransmission plays an important role in the physiology of visual contrast sensitivity (CS). To test the hypothesis that altered dopaminergic neurotransmission plays a role in major depression we measured contrast sensitivity in patients with major depression and in healthy control subjects. METHODS: Twenty-eight patients diagnosed with major depressive disorder were compared to 21 age-matched control subjects on their ability to detect a Gabor target with slightly elevated luminance contrast embedded in seven equi-contrast distracters. RESULTS: Contrast discrimination thresholds were significantly elevated in unmedicated and medicated patients with major depression compared to control subjects, at all pedestal contrast levels tested. CONCLUSIONS: Contrast discrimination performance is reduced in depressive patients and might reflect a state of altered dopaminergic neurotransmission.

Spectroscopic findings in attention-deficit/hyperactivity disorder: review and meta-analysis.

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.