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Background and Hypothesis Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low. Study Design An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations. Study Results In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians’ belief that patients feel anxious about their hallucinations (β = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (β =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (β = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; PFDRadj < .01). Conclusions Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information.

Background It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH). Design Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls. Results PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups. Conclusions PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification.

The cognitive characterization of Alzheimer's disease risk states, such as amnestic mild cognitive impairment (aMCI) and subjective cognitive decline (SCD), is fundamental for timely diagnosis and interventions. The Face Name Associative Memory Exam (FNAME) is sensitive to early Alzheimer's disease brain changes, and an extended version captures a fuller range of associative memory abilities. We aimed to assess group effects in the extended FNAME in older adults with SCD, aMCI, and older adult controls (CON).Two concurrently created versions of the extended FNAME were used to test three groups of older adults (CON = 35, SCD = 37, aMCI = 31) at twoIn all models, the main effect for group was significant with large effect sizes, driven by a worse performance of aMCI participants. No significant differences were found between SCD and CON. The main effect forThe worse performance of aMCI in the extended FNAME implies an impairment in associative memory abilities beyond recall. The similar performance of CON and SCD might be explained by the recruitment of SCD participants that did not spontaneously seek help for memory decline. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Mild cognitive impairment (MCI) is a stage between expected age-related cognitive decline and dementia.Dementias have been associated with changes in neural oscillations across the frequency spectrum, including the alpha range.Alpha is the most prominent rhythm in human EEG and is best detected during awake resting state (RS). Though severalstudies measured alpha power and synchronization in MCI, findings have not yet been integrated.Objective: To consolidate findings on power and synchronization of alpha oscillations across stages of cognitive decline.Methods: We included studies published until January 2020 that compared power or functional connectivity between 1)people with MCI and cognitively healthy older adults (OA) or people with a neurodegenerative dementia, and 2) people withprogressive and stable MCI. Random-effects meta-analyses were performed when enough data was available.Results: Sixty-eight studies were included in the review. Global RS alpha power was lower in AD than in MCI (ES = –0.30;95% CI = –0.51, –0.10; k = 6), and in MCI than in OA (ES = –1.49; 95% CI = –2.69, –0.29; k = 5). However, the latter metaanalysisshould be interpreted cautiously due to high heterogeneity. The review showed lower RS alpha power in progressivethan in stable MCI, and lower task-related alpha reactivity in MCI than in OA. People with MCI had both lower and higherfunctional connectivity than OA. Publications lacked consistency in MCI diagnosis and EEG measures.Conclusion: Research indicates that RS alpha power decreases with increasing impairment, and could—combined withmeasures from other frequency bands—become a biomarker of early cognitive decline.keywords: Alpha rhythm, brain waves, dementia, electroencephalography, mild cognitive impairment

BackgroundCognition is commonly affected in brain disorders. Non-invasive brain stimulation (NIBS) may have procognitive effects, with high tolerability. This meta-analysis evaluates the efficacy of transcranial magnetic stimulation (TMS) and transcranial Direct Current Stimulation (tDCS) in improving cognition, in schizophrenia, depression, dementia, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis.MethodsA PRISMA systematic search was conducted for randomized controlled trials. Hedges'gwas used to quantify effect sizes (ES) for changes in cognition after TMS/tDCSv.sham. As different cognitive functions may have unequal susceptibility to TMS/tDCS, we separately evaluated the effects on: attention/vigilance, working memory, executive functioning, processing speed, verbal fluency, verbal learning, and social cognition.ResultsWe included 82 studies (n= 2784). For working memory, both TMS (ES = 0.17,p= 0.015) and tDCS (ES = 0.17,p= 0.021) showed small but significant effects. Age positively moderated the effect of TMS. TDCS was superior to sham for attention/vigilance (ES = 0.20,p= 0.020). These significant effects did not differ across the type of brain disorder. Results were not significant for the other five cognitive domains.ConclusionsOur results revealed that both TMS and tDCS elicit a small trans-diagnostic effect on working memory, tDCS also improved attention/vigilance across diagnoses. Effects on the other domains were not significant. Observed ES were small, yet even slight cognitive improvements may facilitate daily functioning. While NIBS can be a well-tolerated treatment, its effects appear domain specific and should be applied only for realistic indications (i.e. to induce a small improvement in working memory or attention).

Auditory-verbal hallucinations (AVH) are a key symptom of schizophrenia. Recent neuroimaging studies examining dynamic functional connectivity suggest that disrupted dynamic interactions between brain networks characterize complex symptoms in mental illness including schizophrenia. Studying dynamic connectivity may be especially relevant for hallucinations, given their fluctuating phenomenology. Indeed, it remains unknown whether AVH in schizophrenia are directly related to altered dynamic connectivity within and between key brain networks involved in auditory perception and language, emotion processing, and top-down control. In this study, we used dynamic connectivity approaches including sliding window and k-means to examine dynamic interactions among brain networks in schizophrenia patients with and without a recent history of AVH. Dynamic brain network analysis revealed that patients with AVH spent less time in a ‘network-antagonistic’ brain state where the default mode network (DMN) and the language network were anti-correlated, and had lower probability to switch into this brain state. Moreover, patients with AVH showed a lower connectivity within the language network and the auditory network, and lower connectivity was observed between the executive control and the language networks in certain dynamic states. Our study provides the first neuroimaging evidence of altered dynamic brain networks for understanding neural mechanisms of AVH in schizophrenia. The findings may inform and further strengthen cognitive models of AVH that aid the development of new coping strategies for patients. Electronic supplementary material The online version of this article (10.1007/s00429-020-02119-1) contains supplementary material, which is available to authorized users.

Deep brain stimulation (DBS) provides clinical benefits for several neurological and psy-chiatric conditions. By overcoming the limitations and risks of conventional DBS, trans -cranial temporal interference stimulation (tTIS) has the potential to offer non-invasive stimulation of deep brain regions. However, research that investigates the efficacy of tTIS is limited to animal studies or computer simulations and its capability to modulate neural oscillations in humans has not been demonstrated so far. The method of tTIS is hypoth-esized to elicit its effects via neural entrainment, corresponding to the supposed mecha-nism of action underlying transcranial alternating current stimulation (tACS), another, more established non-invasive brain stimulation technique. Physiological effects of tACS are well established for cortical brain oscillations, but not for deep brain structures. In particular, aftereffects on the power of parieto-occipital alpha oscillations have been shown repeatedly. In a first attempt to test the efficacy of tTIS in the human brain, the current study thus seeks to compare the effects of tTIS to the well-studied aftereffect of tACS in the cortex. To investigate this research question, the current study compared MEG-recorded brain activity during a simple visual change detection task in 34 healthy subjects pre-and post-tTIS. Additionally, the effects of tTIS were contrasted to conventional tACS and a control stimulation. We expected that the parieto-occipital a-power will increase after tTIS and tACS, in contrast to the control stimulation. Overall, no difference between the experimental groups (tTIS, tACS and control stimulation) were found regarding the source-projected increase in a-power. Based on the results of the study two hypothesis can be made: tTIS, tACS and the control stimulation condition don't have an effect on human brain oscillations in the a-band, or, any experimental conditions of the current study can modulate brain oscillations in the a-band. Both hypotheses emphasize the importance of further studies investigating different carrier frequencies, and the comparison to sham stimulation.(c) 2022 Elsevier Ltd. All rights reserved.

Transcranial temporal interference stimulation (tTIS) is a novel non-invasive brain stimulation technique for electrical stimulation of neurons at depth. Deep brain regions are generally small in size, making precise targeting a necessity. The variability of electric fields across individual subjects resulting from the same tTIS montages is unknown so far and may be of major concern for precise tTIS targeting. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across 25 subjects. To this end, the electric fields of different electrode montages consisting of two electrode pairs with different center frequencies were simulated in order to target selected regions-of-interest (ROIs) with tTIS. Moreover, we set out to compare the electric fields of tTIS with the electric fields of conventional tACS. The latter were also based on two electrode pairs, which, however, were driven in phase at a common frequency. Our results showed that the electric field strengths inside the ROIs (left hippocampus, left motor area and thalamus) during tTIS are variable on single subject level. In addition, tTIS stimulates more focally as compared to tACS with much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields inside the ROI were, however, comparable for both methods. Overall, our results emphasize the potential benefits of tTIS for the stimulation of deep targets, over conventional tACS. However, they also indicate a need for individualized stimulation montages to leverage the method to its fullest potential.

N.H. is supported by funding from an International Max Planck Research School (IMPRS) for language sciences fellowship grant, and the work of N.H. and S.C.V. was supported by a Max Planck Research Group (MPRG) awarded to S.C.V. The work of L.V. and A.R. was supported by a Max Planck Research Group (MPRG) awarded to A.R. S.C.V. was also supported by a Human Frontiers Science Program (HFSP) Research grant (grant no. RGP0058/2016) and a UKRI Future Leaders Fellowship (grant no. MR/T021985/1). Comparative animal studies of complex behavioural traits, and their neurobiological underpinnings, can increase our understanding of their evolution, including in humans. Vocal learning, a potential precursor to human speech, is one such trait. Mammalian vocal learning is under-studied: most research has either focused on vocal learning in songbirds or its absence in non-human primates. Here, we focus on a highly promising model species for the neurobiology of vocal learning: grey seals (Halichoerus grypus). We provide a neuroanatomical atlas (based on dissected brain slices and magnetic resonance images), a labelled MRI template, a three-dimensional model with volumetric measurements of brain regions, and histological cortical stainings. Four main features of the grey seal brain stand out: (i) it is relatively big and highly convoluted; (ii) it hosts a relatively large temporal lobe and cerebellum; (iii) the cortex is similar to that of humans in thickness and shows the expected six-layered mammalian structure; (iv) there is expression of FoxP2 present in deeper layers of the cortex; FoxP2 is a gene involved in motor learning, vocal learning, and spoken language. Our results could facilitate future studies targeting the neural and genetic underpinnings of mammalian vocal learning, thus bridging the research gap from songbirds to humans and non-human primates. Our findings are relevant not only to vocal learning research but also to the study of mammalian neurobiology and cognition more in general. Postprint

Abnormal function and connectivity of the fronto-parietal network (FPN) have been documented in patients with schizophrenia, but studies are correlational. We applied repetitive transcranial magnetic stimulation (rTMS) to the dorso-lateral prefrontal cortex (DLPFC) and observed causal connectivity to the inferior parietal lobe (IPL). We hypothesized that patients with schizophrenia would have lower activation and slower reaction in the IPL following DLPFC stimulation. Thirteen patients with schizophrenia (SZ) and fourteen healthy controls subjects (HC) underwent rTMS at 10 Hz to the right DLPFC. Simultaneously, we measured brain activation in the IPL, represented as oxygenized hemoglobin (HbO) levels, using functional near-infrared spectroscopy (fNIRS). rTMS consisted of 20 trains of impulses at 10 Hz for 3 seconds, and 60 seconds waiting time. Using NIRSLab software, GLM was applied to estimate both hemodynamic response function (HRF) and its derivative. Following TMS to the DLPFC, SZ showed a smaller decrease in HbO levels in the bilateral IPL than HC (p = 0.05). Timecourse analysis revealed an immediate decrease in parietal HbO levels in HC, but not in SZ. This difference was significant (at a threshold level of p ≤ 0.05, with Bonferroni correction) for several time segments and channels in both rights and left IPL. Our findings suggest abnormal fronto-temporal connectivity in patients with schizophrenia, beyond a mere decrease or slowing of information processing. This is in line with the hypothesis of reduced fronto-parietal inhibition in schizophrenia.

Background: Impaired clinical and cognitive insight are prevalent in schizophrenia and relate to poorer outcome. Good insight has been suggested to depend on social cognitive and metacognitive abilities requiring global integration of brain signals. Impaired insight has been related to numerous focal gray matter (GM) abnormalities distributed across the brain suggesting dysconnectivity at the global level. In this study, we test whether global integration deficiencies reflected in gray matter network connectivity underlie individual variations in insight.Methods: We used graph theory to examine whether individual GM-network metrics relate to insight in patients with a psychotic disorder (n = 114). Clinical insight was measured with the Schedule for the Assessment of Insight & ndash;Expanded and item G12 of the Positive and Negative Syndrome Scale, and cognitive insight with the Beck Cognitive Insight Scale. Individual GM-similarity networks were created from GM-segmentations of T1weighted MRI-scans. Graph metrics were calculated using the Brain Connectivity Toolbox.Results: Networks of schizophrenia patients with poorer clinical insight showed less segregation (i.e. clustering coefficient) into specialized subnetworks at the global level. Schizophrenia patients with poorer cognitive insight showed both less segregation and higher connectedness (i.e. lower path length) of their brain networks, making their network topology more & ldquo;random & rdquo;.Conclusions: Our findings suggest less segregated processing of information in patients with poorer cognitive and clinical insight, in addition to higher connectedness in patients with poorer cognitive insight. The ability to take a critical perspective on one & rsquo;s symptoms (clinical insight) or views (cognitive insight) might depend especially on segregated specialized processing within distinct subnetworks.

Introduction: The memory impairment that is characteristic of amnestic mild cognitive impairment (aMCI) is often accompanied by difficulties in executive functioning, including planning. Though planning deficits in aMCI are well documented, their neural correlates are largely unknown, and have not yet been investigated with functional magnetic resonance imaging (fMRI).Objectives: The aim of this study was to: (1) identify differences in brain activity and connectivity during planning between people with aMCI and cognitively healthy older adults, and (2) find whether planning-related activity and connectivity are associated with cognitive performance and symptoms of apathy.Methods: Twenty-five people with aMCI and 15 cognitively healthy older adults performed a visuospatial planning task (Tower of London; ToL) during fMRI. Task-related brain activation, spatial maps of task-related independent components, and seed-to-voxel functional connectivity were compared between the two groups and regressed against measures of executive functions (Trail Making Test difference score, TMT B-A; Digit Symbol Substitution Test, DSST), delayed recall (Rey Auditory Verbal Learning Test), and apathy (Apathy Evaluation Scale).Results: People with aMCI scored lower on task-switching (TMT B-A), working memory (DSST), and planning (ToL). During planning, people with aMCI had less activation in the bilateral anterior calcarine sulcus/cuneus, the bilateral temporal cortices, the left precentral gyrus, the thalamus, and the right cerebellum. Across all participants, higher planning-related activity in the supplementary motor area, the retrosplenial cortex and surrounding areas, and the right temporal cortex was related to better delayed recall. There were no betweengroup differences in functional connectivity, nor were there any associations between connectivity and cognition. We also did not find any associations between brain activity or connectivity and apathy.Conclusion: Impaired planning in people with aMCI appears to be accompanied by lower activation in a diffuse cortico-thalamic network. Across all participants, higher planning-related activity in parieto-occipital, temporal, and frontal areas was related to better memory performance. The results point to the relevance of planning deficits for understanding aMCI and extend its clinical and neurobiological signature.

Purpose: White matter (WM) degeneration of the visual pathways in primary open-angle glaucoma (POAG) is well documented, but its exact pathophysiology remains unclear. To date, glaucomatous WM degeneration has been exclusively studied using diffusion tensor imaging (DTI) only. However, DTI measures lack direct biological interpretation, and the approach itself suffers from multiple technical limitations. Fixel-based analysis (FBA) is a novel framework for studying WM degeneration, overcoming DTI's technical limitations and providing biologically meaningful metrics. FBA measures fiber density (FD), representing early microstructural changes, and fiber-bundle cross section (FC), representing late macrostructural changes. In this study, we use FBA to study glaucomatous degeneration of the pregeniculate optic tracts (OTs) and postgeniculate optic radiation (ORs) in POAG.Methods: This was a cross-sectional case-control study with 12 POAG patients and 16 controls. Multi-shell diffusion-weighted images were acquired. FBA was used to produce a population template, and probabilistic tractography was used to track the OTs and ORs in template space. Finally, FD and FC of the tracts of interest were compared between the two groups.Results: Compared with the controls, the OTs of the patients exhibited a significant (familywise error corrected P Conclusions: FBA provides sensitive measures to assess WM changes in glaucoma. Our findings suggest that the OTs of glaucoma patients exhibit signs of more advanced WM degeneration compared with the ORs. This potentially implicates anterograde trans-synaptic propagation as the primary cause of glaucomatous spread along the visual pathways.

BACKGROUND: Neuromodulation is nowadays investigated as a promising method for pain relief. Research indicates that a single 30-minute stimulation with transcranial pulsed electromagnetic fields (tPEMF) can induce analgesic effects. However, it is unknown whether tPEMF can induce analgesia in neuropathic pain patients.OBJECTIVE: To evaluate the effect of tPEMF on spontaneous pain and heat pain in neuropathic pain patients.METHODS: This study had a randomized double-blind crossover design. Twenty neuropathic pain patients received 30-minutes of tPEMF and 30-minutes sham stimulation. Primary outcomes were pain intensity, pain aversion and heat pain. Secondary outcomes included affect, cognition, and motor function, to investigate safety, tolerability and putative working mechanisms of tPEMF. Outcomes were assessed before, during and after stimulation.RESULTS: No differences in analgesic affects between tPEMF and sham stimulation were found for pain intensity, pain aversion or heat pain. No differences between tPEMF and sham stimulation were observed for affect, motor, and cognitive outcomes.CONCLUSION: A single 30-minute tPEMF stimulation did not induce analgesic effects in neuropathic pain patients, compared to sham. Further study is needed to determine whether prolonged stimulation is necessary for analgesic effects.

Background A fundamental challenge for many people with severe mental illness (SMI) is how to deal with cognitive impairments. Cognitive impairments are common in this population and limit daily functioning. Moreover, neural plasticity in people with SMI appears to be reduced, a factor that might hinder newly learned cognitive skills to sustain. The objective of this pilot trial is to investigate the effects of cognitive remediation (CR) on cognitive and daily functioning in people dependent on residential settings. In addition, transcranial direct current stimulation (tDCS) is used to promote neural plasticity. It is expected that the addition of tDCS can enhance learning and will result in longer-lasting improvements in cognitive and daily functioning. Methods This is a pragmatic, triple-blinded, randomized, sham-controlled, pilot trial following a non-concurrent multiple baseline design with the participants serving as their own control. We will compare (1) CR to treatment as usual, (2) active/sham tDCS+CR to treatment as usual, and (3) active tDCS+CR to sham tDCS+CR. Clinical relevance, feasibility, and acceptability of the use of CR and tDCS will be evaluated. We will recruit 26 service users aged 18 years or older, with a SMI and dependent on residential facilities. After a 16-week waiting period (treatment as usual), which will serve as a within-subject control condition, participants will be randomized to 16 weeks of twice weekly CR combined with active (N = 13) or sham tDCS (N = 13). Cognitive, functional, and clinical outcome assessments will be performed at baseline, after the control (waiting) period, directly after treatment, and 6-months post-treatment. Discussion The addition of cognitive interventions to treatment as usual may lead to long-lasting improvements in the cognitive and daily functioning of service users dependent on residential facilities. This pilot trial will evaluate whether CR on its own or in combination with tDCS can be a clinically relevant addition to further enhance recovery. In case the results indicate that cognitive performance can be improved with CR, and whether or not tDCS will lead to additional improvement, this pilot trial will be extended to a large randomized multicenter study. Trial registration Dutch Trial Registry NL7954. Prospectively registered on August 12, 2019.

Highlights • In aMCI, apathy severity was associated with lower FA in widespread WM pathways. • WM aberrations are related to apathy severity after controlling for depression. • Disruptions related to apathy severity are not limited to frontal-subcortical area., Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer’s Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p

The degree to which glaucoma has effects beyond the eye –in the brain– is unclear. We investigated white matter microstructure (WMM) alterations in 37 tracts of patients with glaucoma, monocular blindness and controls. We used reproducible methods and the advanced cloud computing platform brainlife.io. White matter tracts were subdivided into seven categories ranging from primarily involved in vision (the visual white matter) to primarily involved in cognition and motor control. WMM in both glaucoma and monocular blind subjects was lower than controls in the visual white matter, suggesting neurodegenerative mechanisms due to reduced sensory inputs. In glaucoma participants WMM differences from controls decreased outside the visual white matter. A test-retest validation approach was used to validate these results. The pattern of results was different in monocular blind participants, where WMM properties increased outside the visual white matter as compared to controls. The pattern of results suggests that whereas in the blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the brain plasticity effects that in other patient groups follow visual loss.

The degree to which glaucoma has effects in the brain beyond the eye and the visual pathways is unclear. To clarify this, we investigated white matter microstructure (WMM) in 37 tracts of patients with glaucoma, monocular blindness, and controls. We used brainlife.io for reproducibility. White matter tracts were subdivided into seven categories ranging from those primarily involved in vision (the visual white matter) to those primarily involved in cognition and motor control. In the vision tracts, WMM was decreased as measured by fractional anisotropy in both glaucoma and monocular blind subjects compared to controls, suggesting neurodegeneration due to reduced sensory inputs. A test–retest approach was used to validate these results. The pattern of results was different in monocular blind subjects, where WMM properties increased outside the visual white matter as compared to controls. This pattern of results suggests that whereas in the monocular blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the reorganization as seen in other patient groups following visual loss.

In this sentence reading study, we used event-related potentials (ERPs) to investigate the processing mechanism of article-noun gender disagreement in two kinds of nouns in Italian. The first are nouns with syntactic gender (il treno(M) 'train' la sedia(F) 'chair') for which the processing and repair of gender disagreement entails only one repair option, namely for the article (morphosyntactic repair). The second kind are nouns with semantic gender (il bambino(M) 'boy', la bambina(F) 'girl'). Here, there are two options for processing and repairing gender mismatch: repairing the article (morphosyntactic repair) or repairing the noun (both morphosyntactic and semantic repair). Both classes of nouns elicited the LAN, indicating that gender disagreement is always registered at the morphosyntactic level. In addition, the P600 was elicited in both conditions, but was larger for semantic gender, reflecting a more complex repair for this class of nouns.

Purpose of review The association between hallucinations and sensory loss, especially vision- and hearing-impairment, has been firmly established over the past years. The deafferentation theory, a decrease of the threshold for activation in the brain and the consequential imbalance between excitatory and inhibitory brain networks, is hypothesized to underly this relationship. Here we review the studies investigating this theory with a focus on the most recent literature to better understand the contribution of sensory loss to hallucinations. Recent findings A large cross-sectional study has recently confirmed the relationship between auditory impairment and deafferentation. However, the underlying mechanisms of deafferentation are still under debate, with hyperexcitability and deviations in bottom-up and top-down processes being the most likely explanations. Social isolation following sensory impairment increases the risk for hallucinations. Better knowledge and awareness about the contribution of deafferentation and loneliness would benefit diagnosis and treatment of hallucinations. Summary Studies imply activity in higher order areas, corresponding to the functional mapping of sensory system, and a general state of higher excitability as neurobiological explanation. Auditory deafferentation, tinnitus and other auditory hallucinations, likely lie on a continuum. Social isolation mediates psychotic symptoms in sensory-impaired individuals. Currently, there is no standard treatment for deafferentation hallucinations.

BACKGROUND: Cognitive insight is defined as the ability to reflect upon oneself (i.e. self-reflectiveness), and to not be overly confident of one's own (incorrect) beliefs (i.e. self-certainty). These abilities are impaired in several disorders, while they are essential for the evaluation and regulation of one's behavior. We hypothesized that cognitive insight is a dynamic process, and therefore examined how it relates to temporal dynamics of resting state functional connectivity (FC) and underlying structural network characteristics in 58 healthy individuals.METHODS: Cognitive insight was measured with the Beck Cognitive Insight Scale. FC characteristics were calculated after obtaining four FC states with leading eigenvector dynamics analysis. Gray matter (GM) and DTI connectomes were based on GM similarity and probabilistic tractography. Structural graph characteristics, such as path length, clustering coefficient, and small-world coefficient, were calculated with the Brain Connectivity Toolbox. FC and structural graph characteristics were correlated with cognitive insight.RESULTS: Individuals with lower cognitive insight switched more and spent less time in a globally synchronized state. Additionally, individuals with lower self-reflectiveness spent more time in, had a higher probability of, and had a higher chance of switching to a state entailing default mode network (DMN) areas. With lower self-reflectiveness, DTI-connectomes were segregated less (i.e. lower global clustering coefficient) with lower embeddedness of the left angular gyrus specifically (i.e. lower local clustering coefficient).CONCLUSIONS: Our results suggest less stable functional and structural networks in individuals with poorer cognitive insight, specifically self-reflectiveness. An overly present DMN appears to play a key role in poorer self-reflectiveness.

In the past years, ample interest in brain abnormalities related to clinical and cognitive insight in psychosis has contributed several neuroimaging studies to the literature. In the current study, published findings on the neural substrates of clinical and cognitive insight in psychosis are integrated by performing a systematic review and meta-analysis. Coordinate-based meta-analyses were performed with the parametric coordinate-based meta-analysis approach, non-coordinate based meta-analyses were conducted with the metafor package in R. Papers that could not be included in the meta-analyses were systematically reviewed. Thirty-seven studies were retrieved, of which 21 studies were included in meta-analyses. Poorer clinical insight was related to smaller whole brain gray and white matter volume and gray matter volume of the frontal gyri. Cognitive insight was predominantly positively associated with structure and function of the hippocampus and ventrolateral prefrontal cortex. Impaired clinical insight is not associated with abnormalities of isolated brain regions, but with spatially diffuse global and frontal abnormalities suggesting it might rely on a range of cognitive and self-evaluative processes. Cognitive insight is associated with specific areas and appears to rely more on retrieving and integrating self-related information.

OBJECTIVES Sufficient prefrontal top-down control of limbic affective areas, especially the amygdala, is essential for successful effortful emotion regulation (ER). Difficulties in effortful ER have been seen in patients with bipolar disorder (BD), which could be suggestive of a disturbed prefrontal-amygdala regulation circuit. The aim of this study was to investigate whether BD patients show abnormal effective connectivity from the prefrontal areas to the amygdala during effortful ER (reappraisal). METHODS Forty participants (23 BD patients and 17 healthy controls [HC]) performed an ER task during functional magnetic resonance imaging. Using dynamic causal modeling, we investigated effective connectivity from the dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) to the amygdala, as well as connectivity between the DLPFC and VLPFC during reappraisal. RESULTS Both BD patients and HC showed decreased negative affect ratings following reappraisal compared to attending negative pictures (P

Purpose Glutamatergic models of psychosis propose that dysfunction of N -methyl- d -aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate + glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy ( 1 H MRS) to calculate their association with AVH. Methods Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8 mm 3 voxel placed in the left lateral prefrontal region, belonging to both the cingulum and forceps minor. Patients with lifetime AVH (AVH group; n = 45) and patients without lifetime AVH were compared (NoAVH group; n = 22) to control participants. Results Levels of Glx were significantly different between the groups (F(2,94) = 5.27, p = 0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group ( p = 0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH ( p = 0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale). Conclusion The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

Insight is impaired in most patients with psychosis and has been associated with poorer prognosis. The exact neural basis of impaired insight is still unknown, but it may involve disrupted prefrontal neural connectivity. Numerous studies have indeed found white matter (WM) abnormalities in psychosis. The association between prefrontal WM abnormalities and insight has not been studied yet by means of proton magnetic resonance spectroscopy (H-1-MRS). H-1-MRS can be used to measure N-acetylaspartate (NAA), which is considered to be a marker of neuronal integrity. We measured insight with the Birchwood Insight Scale (BIS) as well as item G12 of the Positive and Negative Syndrome Scale (PANSS) in 88 patients with psychosis. Prefrontal WM concentrations of NAA and ratios of NAA to creatine (Cr) were assessed with H-1-MRS. Nonparametric partial correlational analyses were conducted between NAA concentrations and insight controlling for illness duration, standardized antipsychotic dose, symptom scores, voxel grey matter content and voxel cerebrospinal fluid content. We found a significant correlation between reduced NAA/Cr ratios and poorer insight as measured with the BIS, which remained significant after additional correction for full width at half maximum, signal/noise and age. This is the first study reporting a relationship between lower prefrontal concentrations of a marker of neuronal integrity and impaired insight, providing further evidence that prefrontal pathology may play an important role in impaired insight in psychosis. This may be explained by the involvement of the prefrontal cortex in several executive and metacognitive functions, such as cognitive flexibility and perspective taking. (C) 2016 Elsevier B.V. All rights reserved.

Background One of the most prominent deficits in schizophrenia is impairment in executive function. This impairment is associated to aberrant function of the dorso-lateral prefrontal cortex (DLPFC)(Weinberger et al. 1986) and the fronto-parietal network (FPN) (Deserno et al. 2012). The FPN is involved in cognitive control (Seeley et al. 2007, Zanto & Gazzaley 2013). While correlations of activation of DLPFC and inferior parietal lobe (IPL) are well documented, fMRI based techniques cannot determine causal relationships of interactions between brain regions. We used Transcranial magnetic stimulation (TMS), which directly affects the stimulated brain region and connected brain areas (Valchev et al 2015) and therefore can be used to investigate causal interactions between brain regions. TMS stimulation to the DLPFC at 10 Hz may cause either putative increase or decrease of activation in the in the IPL, depending on whether connections are inhibitory or excitatory (Curtin et al 2019). We hypothesised that patients with schizophrenia would have slower reaction in IPL as a consequence of DLPFC stimulation. Methods Thirteen patients and fourteen healthy controls (HC) underwent transcranial magnetic stimulation (TMS) to the right DLPFC. TMS consisted of 20 trains of impulses at 10 Hz for 3 seconds, and 60 seconds waiting time. Simultaneously, we measured brain activation IPL using functional near infrared spectroscopy (fNIRS). Diagnostic category was confirmed using MINI plus interview. The severity of symptoms was assessed using the positive and negative syndrome scale (PANSS). We estimated levels of Oxygenised haemoglobin (HbO) using NIRSLab software. GLM was applied using both hemodynamic response function (HRF) and it’s derivative. T-test was used, with FDR correction, to compare time segments of HbO following TMS stimulation. Results There was no difference in age and gender between the groups. The two groups differed in education (t(2,25)= 2,584, p=0.016). GLM revealed decreased levels of HbO in HC in bilateral IPL following the TMS to the DLPFC (p_bonferroni=0.05). However, when patients were compared to HC higher levels of HbO were observed (p=0.05). However, no difference in derivative of HRF was observed. In addition, there was a significant difference in time courses between patients and HC following TMS stimulation. Namely, while there was an immediate decrease in parietal HbO levels in HC, in SZ first an increase, followed by a decrease was observed. This was significant (at a threshold level of pFDR=0.05) for several time segments and channels in both right and left IPL. Discussion We observed differences in activation of bilateral IPL as a consequence of DLPFC stimulation in patients with schizophrenia. Namely, there was an initial increase in HbO levels, as opposite to HC who had an immediate decrease in HbO level. This indicates opposite function of information processing from the frontal to parietal lobe in schizophrenia patients. This is in line with the idea of impaired fronto-parietal inhibition in schizophrenia which has been proposed to underlie impairments in schizophrenia such as lack of cognitive control.

Background Auditory verbal hallucinations (AVH) are often seen as a hallmark of schizophrenia, but can also occur in the general healthy population. While AVH in non-clinical populations might offer an opportunity to study them in isolation, it remains debatable whether the mechanisms underlying AVH are the same in clinical and non-clinical populations. For example, non-clinical populations are reported to attribute lower emotional valence to their AVH. Such differences in phenomenology are hypothesized to arise from differences on the neurobiological level. With the current study, we employ a data-driven approach to define brain networks involved in AVH in clinical and non-clinical subjects, and test whether dynamic differences in network connectivity exist between these groups. Methods Functional magnetic resonance imaging data of 21 non-psychotic individuals and 21 matched psychotic patients with frequent AVH were obtained. During scanning, subjects manually indicated the on- and offset of their AVH. Using independent component (IC) analysis, the data were split into 72 statistically independent spatial maps and their time courses. These time courses were regressed with the AVH time courses. With a one sample t-test on the beta weights, we selected those ICs that related to AVH in both groups for further dynamic functional network connectivity analysis. To identify functional connectivity states, k-means clustering was implemented on correlation matrices acquired using sliding windows. Group differences between these states were determined with two-sample t-tests. Results Both groups experienced AVH during scanning, with a mean number of 24.71 AVH episodes in the clinical and 17.14 episodes in the non-clinical group. We identified seven ICs with time courses significantly related to the occurrence of AVH in both groups. The auditory, sensorimotor, and posterior salience network were positively related to AVH occurrence. The ventral default mode network (DMN), anterior salience network and a network consisting of (para-)hippocampal areas were negatively related to AVH. While in general, networks related to AVH were similar in both groups, a significant difference between the two groups was found in the mean dwell time in states characterized by varying connectivity between these networks. Psychotic patients spent more time in a state of low connectivity (r < 0.055) between all AVH-related networks. Non-psychotic patients dwelled longer in a different state, where some weak correlations between networks were present (.15 > r ≥ .10). Specifically, networks positively related to AVH showed small negative correlations with each other, and a small negative relationship with the DMN. At the same time, the anterior salience network displayed a small positive relationship with the sensorimotor, auditory and posterior salience networks. Discussion Our findings suggest that similar brain networks underlie AVH in non-psychotic and psychotic individuals, but that the groups differ in terms of connectivity between those networks. Among the involved networks are those typically associated with AVH in psychotic patients, such as the DMN and auditory network. During the experience of AVH, psychotic individuals are more likely to show a state defined by segregation of the AVH-related networks. On the contrary, during AVH non-psychotic individuals are in a state defined by more connectivity between the networks. This suggests that a distinction between clinical and non-clinical AVH may have its neurobiological basis in the extend of disruption of involved network connectivity.

BACKGROUND: Clinical insight is impaired in the majority of individuals with schizophrenia (Dam, 2006) and is associated with poorer outcome (Lincoln et al., 2007). Impaired insight cannot be pinpointed to abnormalities of isolated brain areas, as earlier studies on cortical structure and insight found abnormalities in a distributed network of brain regions (Pijnenborg et al., in prep). Getting a better understanding of the neural substrate of impaired insight might help in finding better treatment options to improve insight. Typically, brains are characterized by small-world topology, reflected by a balance between information segregation (i.e. short distances between nodes) and integration (i.e. high clustering of nodes). Several studies have shown less characteristics of small-world topology in patients with schizophrenia. In this study, we used tools of graph theory to investigate whether there are less characteristics of small-world topology of individual structural networks in patients with a psychotic disorder compared to healthy individuals, and whether this is related to interindividual differences in insight. METHODS: T1-weighted images of 114 patients with a psychotic disorder (76% males; mean age=33.67, SD=10.86) and 54 healthy controls (63% males; mean age=35.11, SD=10.76) were acquired with a 3T Philips Intera MRI-scanner. Clinical insight was measured with item G12 of the PANSS (Kay et al., 1987). In a subsample of 62 patients, clinical insight was also measured with the Schedule of Assessment of Insight – Expanded (SAI-E; Kemp & David, 1997), and cognitive insight with the Beck Cognitive Insight Scale (BCIS; Beck et al., 2004). Brain images were segmented using SPM12. Individual gray matter similarity networks were created from gray matter segmentations using a previously described method (Tijms et al., 2012). We calculated the following graph metrics: path length, clustering coefficient, betweenness centrality, lambda (i.e. normalized path length), gamma (i.e. normalized clustering coefficient) and small-world property (i.e. gamma/lambda) using the Brain Connectivity Toolbox.8 Differences in graph metrics between patients and healthy individuals were investigated with ANCOVA’s. The associations between insight and graph metrics were calculated with partial correlations. Education and total gray matter were entered as covariates in all analyses. RESULTS: We found significantly lower clustering coefficient (F(1,165)=17.90, pFDR

Purpose: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma.Methods: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage.Results: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p Conclusions: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.

Impaired insight into illness, associated with worse treatment outcome, is common in schizophrenia. Insight has been related to the self‐reflective processing, centred on the medial frontal cortex. We hypothesized that anatomical and functional routes to and from the ventromedial prefrontal cortex (vmPFC) would differ in patients according to their degree of impaired insight. Forty‐five schizophrenia patients and 19 healthy subjects performed a self‐reflection task during fMRI, and underwent diffusion tensor imaging. Using dynamic causal modelling we observed increased effective connectivity from the posterior cingulate cortex (PCC), inferior parietal lobule (IPL), and dorsal mPFC (dmPFC) towards the vmPFC with poorer insight and decrease from vmPFC to the IPL. Stronger connectivity from the PCC to vmPFC during judgment of traits related to self was associated with poorer insight. We found small‐scale significant changes in white matter integrity associated with clinical insight. Self‐reflection may be influenced by synaptic changes that lead to the observed alterations in functional connectivity accompanied by the small‐scale but measurable alterations in anatomical connections. Our findings may point to a neural compensatory response to an impairment of connectivity between self‐processing regions. Similarly, the observed hyper‐connectivity might be a primary deficit linked to inefficiency in the component cognitive processes that lead to impaired insight. We suggest that the stronger cognitive demands placed on patients with poor insight is reflected in increased effective connectivity during the task in this study. Hum Brain Mapp 36:4859–4868, 2015. © 2015 Wiley Periodicals, Inc.

Background Cognitive deficits are commonly observed in people diagnosed with schizophrenia and have been found to be more predictive of future daily and community functioning than the severity of clinical symptoms (e.g., hallucinations and delusions). Cognitive remediation (CR) is a psychological treatment developed to improve cognitive functioning and thereby daily functioning. Despite the effectivity of CR programs, reduced neuroplasticity in brain networks underlying the cognitive tasks may impede the effectiveness of these treatment programs. Increasing the neuroplasticity in these networks by the use of non-invasive brain stimulation (NIBS) like transcranial direct current stimulation or transcranial magnetic stimulation might boost the effect of CR. In a systematic review, we will address the question whether the combination of non-invasive brain stimulation and cognitive remediation may be a promising treatment strategy. We will apply a transdiagnostic perspective in order to determine the potential benefit of combining CR and NIBS in general, and not specific to a diagnostic category. Methods A systematic review of literature was conducted by searching PsycINFO, Pubmed, Web of Science, and Medline databases for combined treatments of CR and NIBS. Included studies were assessed for cognitive, clinical and functional outcomes. Results 64 studies were identified, with 40 studies including clinical populations (e.g., schizophrenia, Alzheimer’s disease, HIV, MS). The cognitive outcomes showed mixed results. Most effects were found on complex attention and executive functioning. In these domains about 38% of the studies found an added positive treatment effect for combining interventions, in comparison to single interventions (i.e. CR, NIBS, or CR+sham-stimulation). Functional outcome measures were included in ten of the 40 studies with clinical populations. Eight studies found a positive trend towards greater improvements in daily functioning when CR and NIBS were combined. Discussion So far, findings indicate promising effects of combining CR and NIBS on cognitive functioning and daily functioning in healthy and various clinical populations. There is a lot of variety between studies (e.g., duration of treatment, number of total sessions, number of weekly sessions, cognitive domains targeted) which may explain the mixed results. Especially, the design of the CR varied widely. Strategy-use and targeting meta-cognition, which were identified as effective elements of CR as a stand-alone treatment were not included in many combined CR+NIBS designs. Future studies have to elucidate whether the combining CR (including strategy-use and meta-cognition) and NIBS has an additive effect on cognitive and/or daily functioning compared to non-combined treatment. Moreover, future studies should evaluate whether beneficial effects from the experimental studies translate into long-term improvement in activities of daily life.

Background: Insight is impaired in the majority of schizophrenia patients. The exact neural correlates of impaired insight remain unclear. We assume that the ability to regulate emotions contributes to having good clinical insight, as patients should be able to regulate their emotional state in such a way that they can adapt adequately in order to cope with impaired functioning and negative stigma associated with a diagnosis of schizophrenia. Numerous studies have shown emotional dysregulation in schizophrenia. We investigated the association between insight and brain activation and connectivity during emotion regulation. Methods: Brain activation during emotion regulation was measured with functional MRI in 30 individuals with schizophrenia. Two emotion regulation strategies were examined: cognitive reappraisal and expressive suppression. Clinical insight was measured with the Schedule for the Assessment of Insight – Expanded, and cognitive insight was measured with the Beck Cognitive Insight Scale. Whole brain random effects multiple regression analyses were conducted to assess the relation between brain activation during emotion regulation and insight. Generalized psychophysiological interaction (gPPI) was used to investigate the relation between task-related connectivity and insight. Results: No significant associations were found between insight and neural correlates of cognitive reappraisal. For clinical insight and suppression, significant positive associations were found between symptom relabeling and activation in the left striatum, thalamus and insula, right insula and caudate, right pre- and postcentral gyrus, left superior occipital gyrus and cuneus and right middle and superior occipital gyrus and cuneus. Furthermore, reduced clinical insight was associated with more connectivity between midline medial frontal gyrus and right middle occipital gyrus. For cognitive insight and suppression, significant positive associations were found between self-reflectiveness and activation in pre- and postcentral gyrus and left middle cingulate gyrus. Conclusions: Our results suggest an association between the capacity to relabel symptoms and activation of brain systems involved in cognitive-emotional control and visual processing of negative stimuli. Furthermore, poorer self-reflectiveness may be associated with brain systems subserving control and execution. Keywords: Insight, Cognitive reappraisal, Expressive suppression, fMRI, gPPI, Emotion regulation

Abnormalities in brain connectivity are associated with hallucinations. Several networks including sensory and resting-state networks have been pointed out as crucial in various hallucination modalities. Here we review the literature on brain connectivity relevant to auditory verbal and visual hallucinations with an emphasis on the most recent studies. Most recent literature investigates this issue in first-episode patients who are mainly medication naive. This enables the investigation of “true” abnormalities in brain connections, how they change with medication, and how they develop with illness progression. The literature that includes neural correlates of hallucinations in mood disorder is deficient. Both visual and auditory verbal hallucinations are associated with abnormal connections of perception areas, specific to that particular hallucination modality.