Branislava Ćurčić-Blake

Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia

Auditory verbal hallucinations (AVH) in schizophrenia have previously been associated with functional deficiencies in language networks, specifically with functional disconnectivity in fronto-temporal connections in the left hemisphere and in interhemispheric connections between frontal regions. Here, we investigate whether AVH are accompanied by white matter abnormalities in tracts connecting the frontal, parietal and temporal lobes, also engaged during language tasks. We combined diffusion tensor imaging with tract-based spatial statistics and found white matter abnormalities in patients with schizophrenia as compared with healthy controls. The patients showed reduced fractional anisotropy bilaterally: in the anterior thalamic radiation (ATR), body of the corpus callosum (forceps minor), cingulum, temporal part of the superior longitudinal fasciculus (SLF) and a small area in the inferior fronto-occipital fasciculus (IFOF); and in the right hemisphere: in the visual cortex, forceps major, body of the corpus callosum (posterior parts) and inferior parietal cortex. Compared to patients without current hallucinations, patients with hallucinations revealed decreased fractional anisotropy in the left IFOF, uncinate fasciculus, arcuate fasciculus with SLF, corpus callosum (posterior parts–forceps major), cingulate, corticospinal tract and ATR. The severity of hallucinations correlated negatively with white matter integrity in tracts connecting the left frontal lobe with temporal regions (uncinate fasciculus, IFOF, cingulum, arcuate fasciculus anterior and long part and superior long fasciculus frontal part) and in interhemispheric connections (anterior corona radiata). These findings support the hypothesis that hallucinations in schizophrenia are accompanied by a complex pattern of white matter alterations that negatively affect the language, emotion and attention/perception networks.

When Broca Goes Uninformed: Reduced Information Flow to Broca’s Area in Schizophrenia Patients With Auditory Hallucinations

Auditory-verbal hallucinations (AVHs) are frequently associated with activation of the left superior temporal gyrus (including Wernickes area), left inferior frontal gyrus (including Brocas area), and the right hemisphere homologs of both areas. It has been hypothesized that disconnectivity of both interhemispheric transfer and frontal and temporal areas may underlie hallucinations in schizophrenia. We investigated reduced information flow in this circuit for the first time using dynamic causal modeling, which allows for directional inference. A group of healthy subjects and 2 groups of schizophrenia patients-with and without AVH-performed a task requiring inner speech processing during functional brain scanning. We employed connectivity models between left hemispheric speech-processing areas and their right hemispheric homologs. Bayesian model averaging was used to estimate the connectivity strengths and evaluate group differences. Patients with AVH showed significantly reduced connectivity from Wernickes to Brocas area (97% certainty) and a trend toward a reduction in connectivity from homologs of Brocas and Wernickes areas to Brocas area (93% and 94% certainty). The connectivity magnitude in patients without hallucinations was found to be intermediate. Our results point toward a reduced input from temporal to frontal language areas in schizophrenia patients with AVH, suggesting that Brocas activity may be less constrained by perceptual information received from the temporal cortex. In addition, a lack of synchronization between Broca and its homolog may lead to the erroneous interpretation of emotional speech activity from the right hemisphere as coming from an external source.

The arcuate fasciculus in auditory-verbal hallucinations: A meta-analysis of diffusion-tensor-imaging studies

Auditory-verbal hallucinations (AVHs) are associated with an impaired connectivity of large-scale networks. To examine the relationship between white-matter integrity and AVHs, we conducted a meta-analysis of diffusion-tensor-imaging studies that compared patients with schizophrenia and AVHs with matched healthy controls (HCs). Five studies were retained gathering 256 DTI data points, divided into AVHs (n=106) and HCs (n=150). The meta-analysis demonstrated a reduced fractional anisotropy in the left Arcuate Fasciculus (AF) of hallucinators (hg= -0.42; CI[-0.69,-0.16]; p<10(-3)). The current meta-analysis confirmed disruptions of white matter integrity in the left AF bundle of schizophrenia patients with AVHs.

Reduced Connectivity in the Self-Processing Network of Schizophrenia Patients with Poor Insight

Lack of insight (unawareness of illness) is a common and clinically relevant feature of schizophrenia. Reduced levels of self-referential processing have been proposed as a mechanism underlying poor insight. The default mode network (DMN) has been implicated as a key node in the circuit for self-referential processing. We hypothesized that during resting state the DMN network would show decreased connectivity in schizophrenia patients with poor insight compared to patients with good insight. Patients with schizophrenia were recruited from mental health care centers in the north of the Netherlands and categorized in groups having good insight (n = 25) or poor insight (n = 19). All subjects underwent a resting state fMRI scan. A healthy control group (n = 30) was used as a reference. Functional connectivity of the anterior and posterior part of the DMN, identified using Independent Component Analysis, was compared between groups. Patients with poor insight showed lower connectivity of the ACC within the anterior DMN component and precuneus within the posterior DMN component compared to patients with good insight. Connectivity between the anterior and posterior part of the DMN was lower in patients than controls, and qualitatively different between the good and poor insight patient groups. As predicted, subjects with poor insight in psychosis showed decreased connectivity in DMN regions implicated in self-referential processing, although this concerned only part of the network. This finding is compatible with theories implying a role of reduced self-referential processing as a mechanism contributing to poor insight.

Interaction of language, auditory and memory brain networks in auditory verbal hallucinations

&NA; Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. However, reconciliation of these theories with experimental evidence is missing. We review 50 studies investigating functional (EEG and fMRI) and anatomic (diffusion tensor imaging) connectivity in these networks, and explore the evidence supporting abnormal connectivity in these networks associated with AVH. We distinguish between functional connectivity during an actual hallucination experience (symptom capture) and functional connectivity during either the resting state or a task comparing individuals who hallucinate with those who do not (symptom association studies). Symptom capture studies clearly reveal a pattern of increased coupling among the auditory, language and striatal regions. Anatomical and symptom association functional studies suggest that the interhemispheric connectivity between posterior auditory regions may depend on the phase of illness, with increases in non‐psychotic individuals and first episode patients and decreases in chronic patients. Leading hypotheses involving concepts as unstable memories, source monitoring, top‐down attention, and hybrid models of hallucinations are supported in part by the published connectivity data, although several caveats and inconsistencies remain. Specifically, possible changes in fronto‐temporal connectivity are still under debate. Precise hypotheses concerning the directionality of connections deduced from current theoretical approaches should be tested using experimental approaches that allow for discrimination of competing hypotheses. HighlightsThe language, auditory and memory/limbic networks are of particular relevance for auditory verbal hallucinations.An increased interaction among the auditory‐language and striatal brain regions occurs while patients hallucinate.Fronto‐temporal connections are often altered in AVH individuals, but there is no consensus regarding increase or decrease.Connections of the interhemispheric auditory pathway are stronger for first episode patients, but they are weaker in chronic patients.The majority of studies support hybrid AVH hypotheses in which all three networks and the striatal network are involved.

Abnormal connectivity between attentional, language and auditory networks in schizophrenia

Brain circuits involved in language processing have been suggested to be compromised in patients with schizophrenia. This does not only include regions subserving language production and perception, but also auditory processing and attention. We investigated resting state network connectivity of auditory, language and attention networks of patients with schizophrenia and hypothesized that patients would show reduced connectivity. Patients with schizophrenia (n = 45) and healthy controls (n = 30) underwent a resting state fMRI scan. Independent components analysis was used to identify networks of the auditory cortex, left inferior frontal language regions and the anterior cingulate region, associated with attention. The time courses of the components where correlated with each other, the correlations were transformed by a Fishers Z transformation, and compared between groups. In patients with schizophrenia, we observed decreased connectivity between the auditory and language networks. Conversely, patients showed increased connectivity between the attention and language network compared to controls. There was no relationship with severity of symptoms such as auditory hallucinations. The decreased connectivity between auditory and language processing areas observed in schizophrenia patients is consistent with earlier research and may underlie language processing difficulties. Altered anterior cingulate connectivity in patients may be a correlate of habitual suppression of unintended speech, or of excessive attention to internally generated speech. This altered connectivity pattern appears to be present independent of symptom severity, and may be suggestive of a trait, rather than a state characteristic.

Altered resting state connectivity of the default mode network in alexithymia

Alexithymia is a trait characterized by a diminished capacity to describe and distinguish emotions and to fantasize; it is associated with reduced introspection and problems in emotion processing. The default mode network (DMN) is a network of brain areas that is normally active during rest and involved in emotion processing and self-referential mental activity, including introspection. We hypothesized that connectivity of the DMN might be altered in alexithymia. Twenty alexithymic and 18 non-alexithymic healthy volunteers underwent a resting state fMRI scan. Independent component analysis was used to identify the DMN. Differences in connectivity strength were compared between groups. Within the DMN, alexithymic participants showed lower connectivity within areas of the DMN (medial frontal and temporal areas) as compared to non-alexithymic participants. In contrast, connectivity in the high-alexithymic participants was higher for the sensorimotor cortex, occipital areas and right lateral frontal cortex than in the low-alexithymic participants. These results suggest a diminished connectivity within the DMN of alexithymic participants, in brain areas that may also be involved in emotional awareness and self-referential processing. On the other hand, alexithymia was associated with stronger functional connections of the DMN with brain areas involved in sensory input and control of emotion.

Variation of the gene coding for DARPP-32 (PPP1R1B) and brain connectivity during associative emotional learning

Associative emotional learning, which is important for the social emotional functioning of individuals and is often impaired in psychiatric illnesses, is in part mediated by dopamine and glutamate pathways in the brain. The protein DARPP-32 is involved in the regulation of dopaminergic and glutaminergic signaling. Consequently, it has been suggested that the haplotypic variants of the gene PPP1R1B that encodes DARPP-32 are associated with working memory and emotion processing. We hypothesized that PPP1R1B should have a significant influence on the network of brain regions involved in associative emotional learning that are rich in DARPP-32, namely the striatum, prefrontal cortex (comprising the medial frontal gyrus and inferior frontal gyrus (IFG)), amygdala and parahippocampal gyrus (PHG). Dynamic causal models were applied to functional MRI data to investigate how brain connectivity during an associative emotional learning task is affected by different single-nucleotide polymorphisms (SNPs) of PPP1R1B: rs879606, rs907094 and rs3764352. Compared to heterozygotes, homozygotes with GTA alleles displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli. We have also elucidated the directionality of these genetic influences. Our data suggest that homozygotes with GTA alleles involve stronger functional connections between brain areas in order to maintain activation of these regions. Homozygotes might engage a greater degree of motivational learning and integration of information to perform the emotional learning task correctly. We conclude that PPP1R1B is associated with the neural network involved in associative emotional learning.

Bidirectional Information Flow in Frontoamygdalar Circuits in Humans: A Dynamic Causal Modeling Study of Emotional Associative Learning

Everyday language is replete with descriptions of emotional events that people have experienced and wish to share with others. Such descriptions presumably rely on pairings of affective words and visual information (such as events and pictures) that have been learnt throughout ones development. To study this kind of affective language learning in the brain, we used functional neuroimaging during associative learning of emotional words and pictures. Brain imaging revealed increased activation of both primary emotional areas such as the amygdala and of higher cognitive areas such as the inferior frontal gyrus (IFG) and medial frontal gyrus. The dynamic causal modeling with Bayesian model selection suggested that the IFG first receives the input and that the connections are bidirectional, suggesting that during such emotional picture-word pair learning, the frontal cortex drives the amygdala activation. Specifically, the interaction between the frontal regions and the amygdala was enhanced by active learning involving both negative and positive emotional stimuli as compared with neutral stimuli. This circuit (especially for negative stimuli) converges with emotion regulation circuits. The enhancement in the connectivity might be responsible for the emotional memory effect in this type of learning.

Altered frontal-amygdala effective connectivity during effortful emotion regulation in bipolar disorder

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).