Edith J. Liemburg

Auditory Hallucinations in Schizophrenia Are Associated with Reduced Functional Connectivity of the Temporo-Parietal Area

BACKGROUND Schizophrenia has been conceptualized as a disorder of integration of neural activity across distributed networks. However, the relationship between specific symptom dimensions and patterns of functional connectivity remains unclear. The current study aimed to investigate the relationship between auditory-verbal hallucinations (AVH), a particularly prevalent and clinically relevant symptom in schizophrenia, and functional connectivity of the temporo-parietal junction (TPJ). METHODS Resting state functional magnetic resonance imaging scans were obtained from 27 schizophrenia patients with AVH and 27 matched control subjects. We calculated correlations reflecting functional connectivity between a priori defined regions-of-interest and the bilateral TPJ seed regions, comprising the neural network involved in inner speech processes and AVH. RESULTS Compared with healthy control subjects, schizophrenia patients showed reduced functional connectivity between left TPJ and the right homotope of Broca. Within the patient group, more severe AVH were associated with reduced neural coupling between left TPJ and bilateral anterior cingulate as well as the bilateral amygdala. CONCLUSIONS In schizophrenia patients with chronic hallucinations, the left TPJ-a critical node in the speech perception/AVH network-shows reduced functional connectivity with brain areas involved in the attribution of agency, self-referent processing, and attentional control.

Two subdomains of negative symptoms in psychotic disorders: Established and confirmed in two large cohorts

Negative symptoms of schizophrenia are normally grouped into a single category. However, the diversity of such symptoms suggests that they are actually made up of more than one dimension. The DSM-V proposes two negative symptom domains, namely expressive deficits and avolition/asociality. We investigated whether the negative symptoms do indeed have two dimensions. An exploratory factor analysis was carried out based on interviews with the PANSS (664 patients). We restricted our analysis to items that had been described as negative symptoms in previous factor analyses. The symptom structure was then tested for stability by performing a confirmatory factor analysis on PANSS interviews from a separate cohort (2172 patients). Exploratory factor analysis yielded a two-factor structure of negative symptoms. The first factor consisted of PANSS items Flat affect, Poor rapport, Lack of spontaneity, Mannerisms and posturing, Motor retardation, and Avolition. The second factor consisted of Emotional withdrawal, Passive/apathetic social withdrawal, and Active social avoidance. The first factor could be related to expressive deficits, reflecting a loss of initiative, and the second factor to social amotivation, related to community interaction. This factor structure supports the DSM-V classification and may be relevant for pathophysiology and treatment of schizophrenia and other psychotic disorders.

Brain Networks Subserving Emotion Regulation and Adaptation after Mild Traumatic Brain Injury

The majority of patients with traumatic brain injury (TBI) sustain a mild injury (mTBI). One out of 4 patients experiences persistent complaints, despite their often normal neuropsychological test results and the absence of structural brain damage on conventional neuroimaging. Susceptibility to develop persistent complaints is thought to be affected by interindividual differences in adaptation, which can also be influenced by preinjury psychological factors. Coping is a key construct of adaptation and refers to strategies to deal with new situations and serious life events. An important element of coping is the ability to regulate emotions and stress. The prefrontal cortex is a crucial area in this regulation process, given that it exerts a top-down influence on the amygdala and other subcortical structures involved in emotion processing. However, little is known about the role of the prefrontal cortex and associated brain networks in emotion regulation and adaptation post-mTBI. Especially, the influence of prefrontal dysfunction on development of persistent postconcussive complaints is poorly understood. In this article, we aim to integrate findings from functional and structural MRI studies on this topic. Alterations within the default mode, executive and salience network have been found in relation to complaints post-mTBI. Dysfunction of the medial prefrontal cortex may impair network dynamics for emotion regulation and adaptation post-mTBI, resulting in persistent post-concussive complaints.

Functional connectivity of the temporo-parietal region in schizophrenia: Effects of rTMS treatment of auditory hallucinations

Auditory-verbal hallucinations are a hallmark symptom of schizophrenia. In recent years, repetitive transcranial magnetic stimulation (rTMS) targeting speech perception areas has been advanced as a potential treatment of medication-resistant hallucinations. However, the underlying neural processes remain unclear. This study aimed to assess whether 1 Hz rTMS treatment would affect functional connectivity of the temporo-parietal junction (TPJ). Resting state fMRI scans were obtained from 18 patients with schizophrenia. Patients were assessed before and after a 6 day treatment with 1 Hz rTMS to the left TPJ, or placebo treatment with sham rTMS to the same location. We assessed functional connectivity between a priori defined regions-of-interest (ROIs) comprising the putative AVH network and the bilateral TPJ seed regions, targeted with rTMS. Symptom improvement following rTMS treatment was observed in the left rTMS group, whereas no change at occurred in the placebo group. Although no corresponding changes were observed in the functional connections previously found to be associated with AVH severity, an increase in connectivity between the left TPJ and the right insula was observed in group receiving rTMS to the left TPJ. The placebo group conversely showed a decrease in connectivity between the left TPJ and left anterior cingulate. We conclude that application of 1 Hz rTMS to the left TPJ region may affect functional connectivity of the targeted region. However, the relationship between these functional changes during the resting state and the rate of clinical improvement needs further clarification.

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.

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.

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.

Estimating Dopamine D-2 Receptor Occupancy for Doses of 8 Antipsychotics: A Meta-Analysis A Reply

Rationale: Dose equivalents based on dopamine D2 receptor occupancy can be used to compare antipsychotics on D2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. Objectives: To model the relationship between dose and D2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data. Methods: We conducted a meta-analysis on published D2 receptor occupancy data (positron emission tomography and single-photon emission computed tomography) in patients with schizophrenia treated with antipsychotics. A nonlinear mixed effects model estimated the median D2 receptor occupancy for a given antipsychotic dose. Heterogeneity between studies was investigated by incorporating study as a random effect in the model, in addition to patient- and study-specific explanatory variables. Results: Included were 51 studies, describing 606 patients (mean T SD age, 32.2 T10.8 years; 25.7% female). The models described the doseoccupancy relationship with narrow confidence bands around the therapeutic dose range. Maximum occupancy (95% confidence interval [CI]) was estimated for haloperidol (91.9%; 95% CI, 86.1Y97.8), risperidone (92.4%; 95% CI, 81.8Y100), olanzapine (96.5%; 95% CI, 85.8Y100), clozapine (61.7%; 95% CI, 49.2Y74.2), quetiapine (49.1%; 95% CI, 18.7Y79.6), aripiprazole (86.9%; 95% CI, 78.2Y95.7), ziprasidone (82.9%; 95% CI, 44.9Y100), and amisulpride (85.0%; 95% CI, 68.5Y100). Interindividual differences explained most of the variability in occupancy values, besides significant heterogeneity between studies. Conclusions: Dose-occupancy functions estimated the median level of dopamine D2 receptor occupancy for 8 frequently prescribed antipsychotics in patients with schizophrenia. These dose equivalents can be

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.

Antipsychotic medication and prefrontal cortex activation: a review of neuroimaging findings.

Decreased prefrontal activation (hypofrontality) in schizophrenia is thought to underlie negative symptoms and cognitive impairments, and may contribute to poor social outcome. Hypofrontality does not always improve during treatment with antipsychotics. We hypothesized that antipsychotics, which share antagonism at dopamine receptors, with a relatively low dopamine receptor affinity and high serotonin receptor affinity may have a sparing effect on prefrontal function compared to strong dopamine receptor antagonists. We systematically investigated the relation between serotonin and dopamine antagonism of antipsychotics and prefrontal functioning by reviewing neuroimaging studies. The weight of the evidence was consistent with our hypothesis that antipsychotics with low dopaminergic receptor affinity and moderate to high serotonergic affinity were associated with higher activation of the prefrontal cortex. However, clozapine, a weak dopamine and strong serotonin antagonist, was associated with decrease in prefrontal activation. Future studies should further elucidate the link between prefrontal activation and negative symptoms using prospective designs and advanced neuroimaging techniques, which may ultimately benefit the development of treatments for disabling negative symptoms.