Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Hyperconnectivity and altered interactions of a nucleus accumbens network in post-stroke depression.

Post-stroke depression is a common complication of stroke. To date, no consistent locus of injury is associated with this complication. Here, we probed network dynamics and structural alterations in post-stroke depression in four functional circuits linked to major depressive disorder and a visual network, which served as a control network. Forty-four participants with recent stroke (mean age = 69.03, standard deviation age = 8.59, age range = 51-86 and gender: female = 10) and 16 healthy volunteers (mean age = 71.53, standard deviation age = 10.62, age range = 51-84 and gender: female = 11) were imaged with 3-Tesla structural, diffusion and resting-state functional MRI. The Geriatric Depression Scale was administered to measure depression severity. Associations between depression severity and functional connectivity were investigated within networks seeded from nucleus accumbens, amygdala, dorsolateral prefrontal cortex and primary visual cortex. In addition, the default mode network was identified by connectivity with medial prefrontal cortex and posterior cingulate cortex. Circuits that exhibited altered activity associated with depression severity were further investigated by extracting within-network volumetric and microstructural measures from structural images. In the stroke group, functional connectivity within the nucleus accumbens-seeded network (left hemisphere: P = 0.001; and right hemisphere: P = 0.004) and default mode network (cluster one: P < 0.001; and cluster two: P < 0.001) correlated positively with depressive symptoms. Normal anticorrelations between these two networks were absent in patients with post-stroke depression. Grey matter volume of the right posterior cingulate cortex (Pearson correlation coefficient = -0.286, P = 0.03), as well as microstructural measures in the posterior cingulate cortex (right: Pearson correlation coefficient = 0.4, P = 0.024; and left: Pearson correlation coefficient = 0.3, P = 0.048), right medial prefrontal cortex (Pearson correlation coefficient = 0.312, P = 0.039) and the medial forebrain bundle (Pearson correlation coefficient = 0.450, P = 0.003), a major projection pathway interconnecting the nucleus accumbens-seeded network and linking to medial prefrontal cortex, were associated with depression severity. Depression after stroke is marked by reduced mutual inhibition between functional circuits involving nucleus accumbens and default mode network as well as volumetric and microstructural changes within these networks. Aberrant network dynamics present in patients with post-stroke depression are therefore likely to be influenced by secondary, pervasive alterations in grey and white matter, remote from the site of injury.

Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke.

Spontaneous recovery of motor and cognitive function occurs in many individuals after stroke. The mechanisms are incompletely understood, but may involve neurotransmitter systems that support neural plasticity, networks that are involved in learning and regions of the brain that are able to flexibly adapt to demand (such as the 'multiple-demand system'). Forty-two patients with first symptomatic ischaemic stroke were enrolled in a longitudinal cohort study of cognitive function after stroke. High-resolution volumetric, diffusion MRI and neuropsychological assessment were performed at a mean of 70 ± 18 days after stroke. Cognitive assessment was repeated 1 year after stroke, using parallel test versions to avoid learning effects, and change scores were computed for long-term episodic, short-term and working memory. Structural MRI features that predicted change in cognitive scores were identified by a two-stage analysis: a discovery phase used whole-brain approaches in a hypothesis-free unbiased way; and an independent focused phase, where measurements were derived from regions identified in the discovery phase, using targeted volumetric measurements or tractography. Evaluation of the cholinergic basal forebrain, based on a validated atlas-based approach, was included given prior evidence of a role in neural plasticity. The status of the fornix, cholinergic basal forebrain and a set of hippocampal subfields were found to predict improvement in long-term memory performance. In contrast to prior expectation, the same pattern was found for short-term and working memory, suggesting that these regions are part of a common infrastructure that supports recovery across cognitive domains. Associations between cholinergic basal forebrain volume and cognitive recovery were found primarily in subregions associated with the nucleus basalis of Meynert, suggesting that it is the cholinergic outflow to the neocortex that enables recovery. Support vector regression models derived from baseline measurements of fornix, cholinergic basal forebrain and hippocampal subfields were able to explain 62% of change in long-term episodic and 41% of change in working memory performance over the subsequent 9 months. The results suggest that the cholinergic system and extended hippocampal network play key roles in cognitive recovery after stroke. Evaluation of these systems early after stroke may inform personalized therapeutic strategies to enhance recovery.

Transdiagnostic In Vivo Magnetic Resonance Imaging Markers of Neuroinflammation.

Accumulating evidence suggests that inflammation is not limited to archetypal inflammatory diseases such as multiple sclerosis, but instead represents an intrinsic feature of many psychiatric and neurological disorders not typically classified as neuroinflammatory. A growing body of research suggests that neuroinflammation can be observed in early and prodromal stages of these disorders and, under certain circumstances, may lead to tissue damage. Traditional methods to assess neuroinflammation include serum or cerebrospinal fluid markers and positron emission tomography. These methods require invasive procedures or radiation exposure and lack the exquisite spatial resolution of magnetic resonance imaging (MRI). There is, therefore, an increasing interest in noninvasive neuroimaging tools to evaluate neuroinflammation reliably and with high specificity. While MRI does not provide information at a cellular level, it facilitates the characterization of several biophysical tissue properties that are closely linked to neuroinflammatory processes. The purpose of this review is to evaluate the potential of MRI as a noninvasive, accessible, and cost-effective technology to image neuroinflammation across neurological and psychiatric disorders. We provide an overview of current and developing MRI methods used to study different aspects of neuroinflammation and weigh their strengths and shortcomings. Novel MRI contrast agents are increasingly able to target inflammatory processes directly, therefore offering a high degree of specificity, particularly if used in conjunction with multitissue, biophysical diffusion MRI compartment models. The capability of these methods to characterize several aspects of the neuroinflammatory milieu will likely push MRI to the forefront of neuroimaging modalities used to characterize neuroinflammation transdiagnostically.

Microstructural changes in the reward system are associated with post-stroke depression.

BACKGROUND: Studies of lesion location have been unsuccessful in identifying mappings between single brain regions and post-stroke depression (PSD). Based on studies implicating the reward system in major depressive disorder without stroke, we investigated structural correlates within this system and their associations with PSD. METHODS: The study enrolled 16 healthy controls, 12 stroke patients with PSD and 34 stroke patients free of PSD. Participants underwent 3T structural and diffusion MRI. Graph theoretical measures were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between groups. Structural correlates specific to the reward system were examined from grey matter volumes and by reconstructing its main white matter pathways, namely the medial forebrain bundle and cingulum connections, using deterministic tractography. Fractional anisotropy (FA) was derived as a measure of microstructural organization, and extracellular free-water (FW) as a possible proxy of neuroinflammation. RESULTS: Subnetworks of decreased FA-weighted and increased FW-weighted connectivity were observed in patients with PSD relative to healthy controls. These networks subsumed the majority of regions constituting the reward system. Within the reward system, FA and FW of major connection pathways and grey matter volume were collectively predictive of PSD, explaining 37.8% of the variance in depression severity. CONCLUSIONS: PSD is associated with grey matter volume loss, reduced FA and increased extracellular FW in the reward system, similar to features observed in major depression without stroke. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke.

Auditory white matter pathways are associated with effective connectivity of auditory prediction errors within a fronto-temporal network.

Auditory prediction errors, i.e. the mismatch between predicted, forthcoming auditory sensations and actual sensory input, trigger the detection of surprising auditory events in the environment. Auditory mismatches engage a hierarchical functional network of cortical sources, which are also interconnected by auditory white matter pathways. Hence it is plausible that these structural and functional networks are quantitatively related. The present study set out to investigate whether structural connectivity of auditory white matter pathways enables the effective connectivity underpinning auditory mismatch responses. Participants (N = 89) underwent diffusion weighted magnetic resonance imaging (MRI) and electroencephalographic (EEG) recordings. Anatomically-constrained tractography was used to extract auditory white matter pathways, namely the bilateral arcuate fasciculi, inferior fronto-occipital fasciculi (IFOF), and the auditory interhemispheric pathway, from which Apparent Fibre Density (AFD) was calculated. EEG data were recorded in the same participants during a stochastic oddball paradigm, which was used to elicit auditory prediction error responses. Dynamic causal modelling was used to investigate the effective connectivity underlying auditory mismatch responses generated in brain regions interconnected by the above mentioned auditory white matter pathways. Our results showed that brain areas interconnected by all auditory white matter pathways best explained the dynamics of auditory mismatch responses. Furthermore, AFD in the right arcuate fasciculus was significantly associated with the effective connectivity between the cortical regions that lie within it. Taken together, these findings indicate that auditory prediction errors recruit a fronto-temporal network of brain regions that are effectively and structurally connected by auditory white matter pathways.

White matter connectivity reductions in the pre-clinical continuum of psychosis: A connectome study.

Widespread white matter connectivity disruptions have commonly been reported in schizophrenia. However, it is questionable whether structural connectivity decline is specifically associated with schizophrenia or whether it extends along a continuum of psychosis into the healthy population. Elucidating brain structure changes associated with psychotic-like experiences in healthy individuals is insofar important as it is a necessary first step towards our understanding of brain pathology preceding florid psychosis. High resolution, multishell diffusion-weighted magnetic resonance images (MRI) were acquired from 89 healthy individuals. Whole-brain white matter fibre tracking was performed to quantify the strength of white matter connections. Network-based statistics were applied to white matter connections in a regression model in order to test for a linear relationship between streamline count and psychotic-like experiences. A significant subnetwork was identified whereby streamline count declined with increasing psychotic-like experiences. This network of structural connectivity reductions affected all cortical lobes, subcortical structures and the cerebellum and spanned along prominent association and commissural white matter pathways. A widespread network of linearly declining connectivity strength with increasing number of psychotic-like experiences was identified in healthy individuals. This finding is in line with white matter connectivity reductions reported from early to chronic stages of schizophrenia and might therefore aid the development of tools to identify individuals at risk of transitioning to psychosis.

Prediction of Speech Sounds Is Facilitated by a Functional Fronto-Temporal Network.

Predictive coding postulates that the brain continually predicts forthcoming sensory events based on past experiences in order to process sensory information and respond to unexpected events in a fast and efficient manner. Predictive coding models in the context of overt speech are believed to operate along auditory white matter pathways such as the arcuate fasciculus and the frontal aslant. The aim of this study was to investigate whether brain regions that are structurally connected via these white matter pathways are also effectively engaged when listening to externally-generated, temporally-predicable speech sounds. Using Electroencephalography (EEG) and Dynamic Causal Modeling (DCM) we investigated network models that are structurally connected via the arcuate fasciculus from primary auditory cortex to Wernicke's and via Geschwind's territory to Broca's area. Connections between Broca's and supplementary motor area, which are structurally connected by the frontal aslant, were also included. The results revealed that bilateral areas interconnected by indirect and direct pathways of the arcuate fasciculus, in addition to regions interconnected by the frontal aslant best explain the EEG responses to speech that is externally-generated but temporally predictable. These findings indicate that structurally connected brain regions involved in the production and processing of auditory stimuli are also effectively connected.

Childhood adversity associated with white matter alteration in the corpus callosum, corona radiata, and uncinate fasciculus of psychiatrically healthy adults.

Diffusion tensor imaging studies report childhood adversity (CA) is associated with reduced fractional anisotropy (FA) in multiple white matter tracts in adults. Reduced FA may result from changes in tissue, suggesting myelin/axonal damage, and/or from increased levels of extracellular free-water, suggesting atrophy or neuroinflammation. Free-water imaging can separately identify FA in tissue (FAT) and the fractional volume of free-water (FW). We tested whether CA was associated with altered FA, FAT, and FW in seven white matter regions of interest (ROI), in which FA changes had been previously linked to CA (corona radiata, corpus callosum, fornix, cingulum bundle: hippocampal projection, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus). Tract-based spatial statistics were performed in 147 psychiatrically healthy adults who had completed a self-report questionnaire on CA primarily stemming from parental maltreatment. ROI were extracted according to the protocol provided by the ENIGMA-DTI working group. Analyses were performed both treating CA as a continuous and a categorical variable. CA was associated with reduced FA in all ROI (although categorical analyses failed to find an association in the fornix). In contrast, CA was only associated with reduced FAT in the corona radiata, corpus callosum, and uncinate fasciculus (with the continuous measure of CA finding evidence of a negative relation between CA and FAT in the fornix). There was no association between CA on FW in any ROI. These results provide preliminary evidence that childhood adversity is associated with changes to the microstructure of white matter itself in adulthood. However, these results should be treated with caution until they can be replicated by future studies which address the limitations of the present study.

Deficits in Cortical Suppression During Vocalization are Associated With Structural Abnormalities in the Arcuate Fasciculus in Early Illness Schizophrenia and Clinical High Risk for Psychosis.

Self-generated speech produces a smaller N1 amplitude in the auditory-evoked potential than externally generated speech; this phenomenon is known as N1-suppression. Schizophrenia patients show less N1-suppression than healthy controls. This failure to self-suppress may underlie patients' characteristic tendency to misattribute self-generated thoughts and actions to external sources. While the cause of N1-suppression deficits to speech in schizophrenia remains unclear, structural damage to the arcuate fasciculus is a candidate, due to its ostensible role in transmitting the efference copy of the motor plan to speak. Fifty-one patients with early illness schizophrenia (ESZ), 40 individuals at clinical high-risk for psychosis (CHR), and 59 healthy control (HC) participants underwent an electroencephalogram while they spoke and then listened to a recording of their speech. N1-suppression to the spoken sounds was calculated. Participants also underwent a diffusion-tensor imaging (DTI) scan, from which the arcuate fasciculus and pyramidal tract were extracted with deterministic tractography. ESZ patients exhibited significantly less N1-suppression to self-generated speech than HC participants, with CHR participants exhibiting intermediate levels. ESZ patients also exhibited structural abnormalities in the arcuate fasciculus-specifically, reduced fractional anisotropy and increased radial diffusivity-relative to both HC and CHR. There were no between-group differences in the structural integrity of the pyramidal tract. Finally, level of N1-suppression was linearly related to the structural integrity of the arcuate fasciculus, but not the pyramidal tract, across groups. These results suggest that the self-suppression deficits to willed speech consistently observed in schizophrenia patients may be caused, at least in part, by structural damage to the arcuate fasciculus.

Characterizing white matter changes in chronic schizophrenia: A free-water imaging multi-site study.

Diffusion tensor imaging (DTI) studies in chronic schizophrenia have found widespread but often inconsistent patterns of white matter abnormalities. These studies have typically used the conventional measure of fractional anisotropy, which can be contaminated by extracellular free-water. A recent free-water imaging study reported reduced free-water corrected fractional anisotropy (FAT) in chronic schizophrenia across several brain regions, but limited changes in the extracellular volume. The present study set out to validate these findings in a substantially larger sample. Tract-based spatial statistics (TBSS) was performed in 188 healthy controls and 281 chronic schizophrenia patients. Forty-two regions of interest (ROIs), as well as average whole-brain FAT and FW were extracted from free-water corrected diffusion tensor maps. Compared to healthy controls, reduced FAT was found in the chronic schizophrenia group in the anterior limb of the internal capsule bilaterally, the posterior thalamic radiation bilaterally, as well as the genu and body of the corpus callosum. While a significant main effect of group was observed for FW, none of the follow-up contrasts survived correction for multiple comparisons. The observed FAT reductions in the absence of extracellular FW changes, in a large, multi-site sample of chronic schizophrenia patients, validate the pattern of findings reported by a previous, smaller free-water imaging study of a similar sample. The limited number of regions in which FAT was reduced in the schizophrenia group suggests that actual white matter tissue degeneration in chronic schizophrenia, independent of extracellular FW, might be more localized than suggested previously.

Abnormal white matter microstructure and increased extracellular free-water in the cingulum bundle associated with delusions in chronic schizophrenia.

BACKGROUND: There is growing evidence to suggest that delusions associated with schizophrenia arise from altered structural brain connectivity. The present study investigated whether structural changes in three major fasciculi that interconnect the limbic system - the cingulum bundle, uncinate fasciculus and fornix - are associated with delusions in chronic schizophrenia patients. METHODS: Free-water corrected Diffusion Tensor Imaging was used to investigate the association between delusions and both microstructural changes within these three fasciculi and extracellular changes in the surrounding free-water. Clinical data and diffusion MRI scans were obtained from 28 healthy controls and 86 schizophrenia patients, of whom 34 had present state delusions, 35 had a lifetime history but currently remitted delusions, and 17 had never experienced delusions. RESULTS: While present state and remitted delusions were found to be associated with reduced free-water corrected fractional anisotropy (FAT) and increased free-water corrected radial diffusivity (RDT) in the cingulum bundle bilaterally, extracellular free-water (FW) in the left cingulum bundle was found to be specifically associated with present state delusions in chronic schizophrenia. No changes were observed in the remaining tracts. CONCLUSIONS: These findings suggest that state and trait delusions in chronic schizophrenia are associated with microstructural processes, such as myelin abnormalities (as indicated by decreased FAT and increased RDT) in the cingulum bundle and that state delusions are additionally associated with extracellular processes such as neuroinflammation or atrophy (as indicated by increased FW) in the left cingulum bundle.

Self-initiated actions result in suppressed auditory but amplified visual evoked components in healthy participants.

Self-suppression refers to the phenomenon that sensations initiated by our own movements are typically less salient, and elicit an attenuated neural response, compared to sensations resulting from changes in the external world. Evidence for self-suppression is provided by previous ERP studies in the auditory modality, which have found that healthy participants typically exhibit a reduced auditory N1 component when auditory stimuli are self-initiated as opposed to externally initiated. However, the literature investigating self-suppression in the visual modality is sparse, with mixed findings and experimental protocols. An EEG study was conducted to expand our understanding of self-suppression across different sensory modalities. Healthy participants experienced either an auditory (tone) or visual (pattern-reversal) stimulus following a willed button press (self-initiated), a random interval (externally initiated, unpredictable onset), or a visual countdown (externally initiated, predictable onset-to match the intrinsic predictability of self-initiated stimuli), while EEG was continuously recorded. Reduced N1 amplitudes for self- versus externally initiated tones indicated that self-suppression occurred in the auditory domain. In contrast, the visual N145 component was amplified for self- versus externally initiated pattern reversals. Externally initiated conditions did not differ as a function of their predictability. These findings highlight a difference in sensory processing of self-initiated stimuli across modalities, and may have implications for clinical disorders that are ostensibly associated with abnormal self-suppression.

Cortical Suppression to Delayed Self-Initiated Auditory Stimuli in Schizotypy: Neurophysiological Evidence for a Continuum of Psychosis.

Schizophrenia patients have been shown to exhibit subnormal levels of electrophysiological suppression to self-initiated, button press elicited sounds. These self-suppression deficits have been shown to improve following the imposition of a subsecond delay between the button press and the evoked sound. The current study aimed to investigate whether nonclinical individuals who scored highly on the personality dimension of schizotypy would exhibit similar patterns of self-suppression abnormalities to those exhibited in schizophrenia. Thirty-nine nonclinical individuals scoring above the median (High Schizotypy) and 41 individuals scoring below the median (Low Schizotypy) on the Schizotypal Personality Questionnaire (SPQ) underwent electroencephalographic recording. The amplitude of the N1-component was calculated while participants (1) listened to tones initiated by a willed button press and played back with varying delay periods between the button press and the tone (Active conditions) and (2) passively listened to a series of tones (Listen condition). N1-suppression was calculated by subtracting the amplitude of the N1-component of the auditory evoked potential in the Active condition from that of the Listen condition, while controlling for the activity evoked by the button press per se. The Low Schizotypy group exhibited significantly higher levels of N1-suppression to undelayed tones compared to the High Schizotypy group. Furthermore, while N1-suppression was found to decrease linearly with increasing delays between the button press and the tone in the Low Schizotypy group, this was not the case in the High Schizotypy group. The findings of this study suggest that nonclinical, highly schizotypal individuals exhibit subnormal levels of N1-suppression to undelayed self-initiated tones and an abnormal pattern of N1-suppression to delayed self-initiated tones. To the extent that these results are similar to those previously reported in patients with schizophrenia, these findings provide support for the existence of a neurophysiological "continuum of psychosis".

Decreased integrity of the fronto-temporal fibers of the left inferior occipito-frontal fasciculus associated with auditory verbal hallucinations in schizophrenia.

Auditory verbal hallucinations (AVH) have been proposed to result from altered connectivity between frontal speech production regions and temporal speech perception regions. Whilst the dorsal language pathway, serviced by the arcuate fasciculus, has been extensively studied in relation to AVH, the ventral language pathway, serviced by the inferior occipito-frontal fasciculus (IOFF) has been rarely studied in relation to AVH. This study examined whether structural changes in anatomically defined subregions of the IOFF were associated with AVH in patients with schizophrenia. Diffusion tensor imaging scans and clinical data were obtained from the Australian Schizophrenia Research Bank for 113 schizophrenia patients, of whom 39 had lifetime experience of AVH (18 had current AVH, 21 had remitted AVH), 74 had no lifetime experience of AVH, and 40 healthy controls. Schizophrenia patients with a lifetime experience of AVH exhibited reduced fractional anisotropy (FA) in the fronto-temporal fibers of the left IOFF compared to both healthy controls and schizophrenia patients without AVH. In contrast, structural abnormalities in the temporal and occipital regions of the IOFF were observed bilaterally in both patient groups, relative to the healthy controls. These results suggest that while changes in the structural integrity of the bilateral IOFF are associated with schizophrenia per se, integrity reductions in the fronto-temporal fibers of the left IOFF may be specifically associated with AVH.

Subnormal sensory attenuation to self-generated speech in schizotypy: Electrophysiological evidence for a 'continuum of psychosis'.

BACKGROUND: A 'continuum of psychosis' refers to the concept that psychotic-like experiences occur to certain extents in the healthy population and to more severe extents in individuals with psychotic disorders. If this concept is valid, neurophysiological abnormalities exhibited by patients with schizophrenia should also be present, to some degree, in non-clinical individuals who score highly on the personality dimension of schizotypy. Patients with schizophrenia have consistently been shown to exhibit electrophysiological suppression abnormalities to self-generated speech. The present study aimed to investigate whether these electrophysiological suppression abnormalities were also present in non-clinical individuals who scored highly on schizotypy. METHODS: Thirty-seven non-clinical individuals scoring High (above median) and 37 individuals scoring Low (below median) on the Schizotypal Personality Questionnaire (SPQ; a commonly used schizotypy scale) underwent electroencephalographic (EEG) recording. The amplitude of the N1 component of the auditory-evoked potential was measured while participants (a) vocalized simple syllables (Talk condition), (b) passively listened to a recording of these vocalizations (Listen condition) and (c) listened to a recording of the vocalizations while simultaneously watching a video depicting the sound-wave of the forthcoming vocalizations, allowing them to be temporally predicted (Cued Listen condition). RESULTS: The Low Schizotypy group exhibited significantly reduced N1-amplitude in the Talk condition relative to both the Listen and Cued Listen conditions; that is, they exhibited significant N1-suppression. The High Schizotypy group exhibited significantly lower levels of N1-suppression compared to the Low Schizotypy group. Furthermore, while the Cued Listen condition induced significantly lower N1-amplitudes compared to the Listen condition in the Low Schizotypy group, this was not the case for the High Schizotypy group. CONCLUSIONS: The results suggest that non-clinical, highly schizotypal individuals exhibit subnormal levels of N1-suppression to self-generated speech, similar to the N1-suppression abnormalities which have previously been reported in patients with schizophrenia. This finding provides empirical support for the existence of a neurophysiological 'continuum of psychosis'.

Reduced integrity of the left arcuate fasciculus is specifically associated with auditory verbal hallucinations in schizophrenia.

BACKGROUND: Schizophrenia patients with auditory verbal hallucinations (AVH) have reduced structural integrity in the left arcuate fasciculus (AFL) compared to healthy controls. However, it is neither known whether these changes are specific to AVH, as opposed to hallucinations or schizophrenia per se, nor how radial and/or axial diffusivity are altered. This study aimed to test the hypothesis that reductions to the structural integrity of the AFL are specifically associated with AVH in schizophrenia. METHOD: Diffusion tensor imaging scans and clinical data were obtained from the Australian Schizophrenia Research Bank for 39 schizophrenia patients with lifetime AVH (18 current, 21 remitted), 74 schizophrenia patients with no lifetime AVH (40 with lifetime hallucinations in other modalities, 34 no lifetime hallucinations) and 40 healthy controls. RESULTS: Fractional anisotropy was significantly reduced in the AFL of patients with lifetime AVH compared to both healthy controls (Cohen's d=1.24) and patients without lifetime AVH (d=.72), including compared to the specific subsets of patients without AVH who either had hallucinations in other modalities (d=.69) or no history of any hallucinations (d=.73). Radial, but not axial, diffusivity was significantly increased in patients with lifetime AVH compared to both healthy controls (d=.89) and patients without lifetime AVH (d=.39). Evidence was found for a non-linear relation between fractional anisotropy in the AFL and state AVH. CONCLUSION: Reduced integrity of the AFL is specifically associated with AVH, as opposed to schizophrenia in general or hallucinations in other modalities. Increased radial diffusivity suggests dysmyelination or demyelination of the AFL may play a role in AVH.