Lena K. L. Oestreich

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 (Cohens 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.

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.

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.

Sensory prediction errors in the continuum of psychosis

Sensory prediction errors are fundamental brain responses that signal a violation of expectation in either the internal or external sensory environment, and are therefore crucial for survival and adaptive behaviour. Patients with schizophrenia show deficits in these internal and external sensory prediction errors, which can be measured using electroencephalography (EEG) components such as N1 and mismatch negativity (MMN), respectively. New evidence suggests that these deficits in sensory prediction errors are more widely distributed on a continuum of psychosis, whereas psychotic experiences exist to varying degrees throughout the general population. In this paper, we review recent findings in sensory prediction errors in the auditory domain across the continuum of psychosis, and discuss these in light of the predictive coding hypothesis.

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.

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.

Structural connectivity facilitates functional connectivity of auditory prediction error generation within a fronto-temporal network

Auditory prediction errors, i.e. the mismatch between predicted and actual auditory input, are generated by a hierarchical functional network of cortical sources. This network is also interconnected by auditory white matter pathways. Hence it would be reasonable to assume that these structural and functional networks are quantitatively related, which is what the present study set out to investigate. Specifically, whether structural connectivity of auditory white matter pathways enables effective connectivity of auditory prediction error generation. Eighty-nine participants underwent diffusion weighted magnetic resonance imaging. Anatomically-constrained tractography was used to extract auditory white matter pathways, namely the bilateral arcuate fasciculus, the inferior occipito-frontal fasciculi (IOFF), and the auditory interhemispheric pathway, from which Apparent Fibre Density (AFD) was calculated. The same participants also underwent a stochastic oddball paradigm, which was used to elicit prediction error responses, while undergoing electroencephalographic recordings. Dynamic causal modelling (DCM) was used to investigate the effective connectivity of auditory prediction error generation in brain regions interconnected by the above mentioned auditory white matter pathways. Brain areas interconnected by all auditory white matter pathways best explained the dynamics of auditory prediction error responses. Furthermore, AFD in the right IOFF and right arcuate fasciculus significantly predicted the effective connectivity parameters underlying auditory prediction error generation. In conclusion, the generation of auditory prediction errors within an effectively connected, fronto-temporal network was found to be facilitated by the structural connectivity of auditory white matter pathways. These findings build upon the notion that structural connectivity facilitates dynamic interactions within brain regions that are effectively connected. Significance statement The brain continuously generates and updates hypotheses that predict forthcoming sensory input. Within the auditory domain, it has repeatedly been reported that these predictions about the auditory environment are facilitated by specific functional cortical connections. These functionally connected brain regions are also structurally connected via auditory white matter pathways. For the first time, this study provides quantitative evidence for a structural basis along which this functional network of auditory prediction error generation operates. This finding provides evidence for the notion that the functional connectivity of dynamically interacting brain areas is facilitated by structural connectivity amongst these brain areas.

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.