disrupted relationship with memory performance and potential implications for delusions

Recent concepts have highlighted the role of the hippocampus and adjacent medial temporal lobe (MTL) in positive symptoms like delusions in schizophrenia. In healthy individuals, the MTL is critically involved in the detection and encoding of novel information. Here, we aimed to investigate whether dysfunctional novelty processing by the MTL might constitute a potential neural mechanism contributing to the pathophysiology of delusions, using functional magnetic resonance imaging (fMRI) in 16 unmedicated patients with paranoid schizophrenia and 20 age-matched healthy controls. All patients experienced positive symptoms at time of participation. Participants performed a visual target detection task with complex scene stimuli in which novel and familiar rare stimuli were presented randomly intermixed with a standard and a target picture. Presentation of novel relative to familiar images was associated with hippocampal activation in both patients and healthy controls, but only healthy controls showed a positive relationship between novelty- related hippocampal activation and recognition memory performance after 24 h. Patients, but not controls, showed a robust neural response in the orbitofrontal cortex (OFC) during presentation of novel stimuli. Functional connectivity analysis in the patients further revealed a novelty-related increase of functional connectivity of both the hippocampus and the OFC with the rostral anterior cingulate cortex (rACC) and the ventral striatum (VS). Notably, delusions correlated positively with the difference of the functional connectivity of the hippocampus vs. the OFC with the rACC. Taken together, our results suggest that alterations of fronto-limbic novelty processing may contribute to the pathophysiology of delusions in patients with acute psychosis

Separating Fusion from Rivalry

Visual fusion is the process in which differing but compatible binocular information is transformed into a unified percept. Even though this is at the basis of binocular vision, the underlying neural processes are, as yet, poorly understood. In our study we therefore aimed to investigate neural correlates of visual fusion. To this end, we presented binocularly compatible, fusible (BF),and incompatible, rivaling (BR) stimuli, as well as an intermediate stimulus type containing both binocularly fusible and monocular, incompatible elements (BFR). Comparing BFR stimuli with BF and BR stimuli, respectively, we were able to disentangle brain responses associated with either visual fusion or rivalry. By means of functional magnetic resonance imaging, we measured brain responses to these stimulus classes in the visual cortex, and investigated them in detail at various retinal eccentricities. Compared with BF stimuli, the response to BFR stimuli was elevated in visual cortical areas V1 and V2, but not in V3 and V4 - implying that the response to monocular stimulus features decreased from V1 to V4. Compared to BR stimuli, the response to BFR stimuli decreased with increasing eccentricity, specifically within V3 and V4. Taken together, it seems that although the processing of exclusively monocular information decreases from V1 to V4, the processing of binocularly fused information increases from earlier to later visual areas. Our findings suggest the presence of an inhibitory neural mechanism which, depending on the presence of fusion, acts differently on the processing of monocular information

Emotional experience in patients with clinically isolated syndrome and early multiple sclerosis

Background and purpose: Evidence suggests that there are changes in the processing of emotional information (EP) in people with multiple sclerosis (MS). It is unclear which functional domains of EP are affected, whether these changes are secondary to other MS-related neuropsychological or psychiatric symptoms and if EP changes are present in early MS. The aim of the study was to investigate EP in patients with early MS (clinically isolated syndrome and early relapsing/remitting MS) and healthy controls (HCs). Methods: A total of 29 patients without neuropsychological or psychiatric deficits and 29 matched HCs were presented with pictures from the International Affective Picture System with negative, positive or neutral content. Participants rated the induced emotion regarding valence and arousal using nine-level Likert scales. A speeded recognition test assessed memory for the emotional stimuli and for the emotional modulation of response time. A subgroup of participants was tested during a magnetic resonance imaging (MRI) session. Results: Patients in the MRI subgroup rated the experience induced by pictures with positive or negative emotional content significantly more weakly than HCs. Further, these patients were significantly less aroused when watching the pictures from the International Affective Picture System. There were no effects in the non-MRI subgroup or effects on emotional memory or response times. Conclusions: Emotional processing changes may be present in early MS in the form of flattened emotional experience on both the valence and arousal dimensions. These changes do not appear to be secondary to neuropsychological or psychiatric deficits. The fact that emotional flattening was only found in the MRI setting suggests that EP changes may be unmasked within stressful environments and points to the potential yet underestimated impact of the MRI setting on behavioral outcomes

Neural correlates of RDoC-specific cognitive processes in a high-functional autistic patient: a statistically validated case report

The level of functioning of individuals with autism spectrum disorder (ASD) varies widely. To better understand the neurobiological mechanism associated with high-functioning ASD, we studied the rare case of a female patient with an exceptional professional career in the highly competitive academic field of Mathematics. According to the Research Domain Criteria (RDoC) approach, which proposes to describe the basic dimensions of functioning by integrating different levels of information, we conducted four fMRI experiments targeting the (1) social processes domain (Theory of mind (ToM) and face matching), (2) positive valence domain (reward processing), and (3) cognitive domain (N-back). Patient's data were compared to data of 14 healthy controls (HC). Additionally, we assessed the subjective experience of our case during the experiments. The patient showed increased response times during face matching and achieved a higher total gain in the Reward task, whereas her performance in N-back and ToM was similar to HC. Her brain function differed mainly in the positive valence and cognitive domains. During reward processing, she showed reduced activity in a left-hemispheric frontal network and cortical midline structures but increased connectivity within this network. During the working memory task patients' brain activity and connectivity in left-hemispheric temporo-frontal regions were elevated. In the ToM task, activity in posterior cingulate cortex and temporo-parietal junction was reduced. We suggest that the high level of functioning in our patient is rather related to the effects in brain connectivity than to local cortical information processing and that subjective report provides a fruitful framework for interpretation

Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.Peer Reviewe

Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing

Bupropion for the treatment of apathy in Huntington's disease:A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial

OBJECTIVE:To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS:In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS:At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION:Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION:ClinicalTrials.gov 01914965

Reduced Gray to White Matter Tissue Intensity Contrast in Schizophrenia

BACKGROUND: While numerous structural magnetic resonance imaging (MRI) studies revealed changes of brain volume or density, cortical thickness and fibre integrity in schizophrenia, the effect of tissue alterations on the contrast properties of neural structures has so far remained mostly unexplored. METHODS: Whole brain high-resolution MRI at 3 Tesla was used to investigate tissue contrast and cortical thickness in patients with schizophrenia and healthy controls. RESULTS: Patients showed significantly decreased gray to white matter contrast in large portions throughout the cortical mantle with preponderance in inferior, middle, superior and medial temporal areas as well as in lateral and medial frontal regions. The extent of these intensity contrast changes exceeded the extent of cortical thinning. Further, contrast changes remained significant after controlling for cortical thickness measurements. CONCLUSIONS: Our findings clearly emphasize the presence of schizophrenia related brain tissue changes that alter the imaging properties of brain structures. Intensity contrast measurements might not only serve as a highly sensitive metric but also as a potential indicator of a distinct pathological process that might be independent from volume or thickness alterations