Jochen Kindler

Resting-state EEG in schizophrenia: auditory verbal hallucinations are related to shortening of specific microstates.

OBJECTIVE Abnormal perceptions and cognitions in schizophrenia might be related to abnormal resting states of the brain. Previous research found that a specific class (class D) of sub-second electroencephalography (EEG) microstates was shortened in schizophrenia. This shortening correlated with positive symptoms. We questioned if this reflected positive psychotic traits or present psychopathology. METHODS Resting-state EEGs of frequently hallucinating patients, indicating on- and offset of hallucinations by button press, were analyzed. Microstate class D duration was related to spontaneous within-subject fluctuations of auditory hallucinations. RESULTS Microstate D was significantly shorter in periods with hallucinations. CONCLUSIONS Microstates of class D resemble topographies associated with error monitoring. Its premature termination may facilitate the misattribution of self-generated inner speech to external sources during hallucinations. SIGNIFICANCE These results suggest that microstate D represents a biological state marker for hallucinatory experiences.

Reduced neuronal activity in language-related regions after transcranial magnetic stimulation therapy for auditory verbal hallucinations.

BACKGROUND Transcranial magnetic stimulation (TMS) is a novel therapeutic approach, used in patients with pharmacoresistant auditory verbal hallucinations (AVH). To investigate the neurobiological effects of TMS on AVH, we measured cerebral blood flow with pseudo-continuous magnetic resonance-arterial spin labeling 20 ± 6 hours before and after TMS treatment. METHODS Thirty patients with schizophrenia or schizoaffective disorder were investigated. Fifteen patients received a 10-day TMS treatment to the left temporoparietal cortex, and 15 received the standard treatment. The stimulation location was chosen according to an individually determined language region determined by a functional magnetic resonance imaging language paradigm, which identified the sensorimotor language area, area Spt (sylvian parietotemporal), as the target region. RESULTS TMS-treated patients showed positive clinical effects, which were indicated by a reduction in AVH scores (p ≤ .001). Cerebral blood flow was significantly decreased in the primary auditory cortex (p ≤ .001), left Brocas area (p ≤ .001), and cingulate gyrus (p ≤ .001). In control subjects, neither positive clinical effects nor cerebral blood flow decreases were detected. The decrease in cerebral blood flow in the primary auditory cortex correlated with the decrease in AVH scores (p ≤ .001). CONCLUSIONS TMS reverses hyperactivity of language regions involved in the emergence of AVH. Area Spt acts as a gateway to the hallucination-generating cerebral network. Successful therapy corresponded to decreased cerebral blood flow in the primary auditory cortex, supporting its crucial role in triggering AVH and contributing to the physical quality of the false perceptions.

Muting the Voice: A Case of Arterial Spin Labeling-Monitored Transcranial Direct Current Stimulation Treatment of Auditory Verbal Hallucinations

To THE EDrroR: In February 2011, a 44-year-oId man with schizophrenia was referred to our hospital for the treatment of auditory verbal hallucinations. He had undergone outpatient treatment with adequate dosages of antipsychotic medications for several months, but he still heard a real-sounding voice that ordered him to commit suicide. We introduced transcranial direct current stimulation (tDCS) as a tiovel therapeutic approach. Cathodal stimulation diminishes cortical excitability at a circumscribed region (1), and Wernickes area has been described as an appropriate target region for cathodal stimulation in previous transcranial magnetic stimulation (TMS) studies (2-4). The anodal electrode was placed over the right supraorbital area. Transcranial direct current stimulation was applied for 15 minutes on 10 consecutive days by using a 1 tnA current and 7 cm X 5 cm electrodes, resulting in a current density of 0.029 mA/cm .̂ The medication doses (5 mg of haloperidol and 20 mg of olanzapine) remained the same 4 weeks before and during the patients intervention. Before and after tDCS, we measured arterial spin labeling, a noninvasive MR technique that provides a direct quantitative measure of cerebral blood flow (CBF). Arterial spin labeling has been successfully used to measure the difference and changes in regional CBF between healthy individuals and schizophrenia patients experiencing formal thought disorders (5). Clinical assessments showed improvements in our patients scores on the Hallucination Change Scale (pre-tDCS score=10; post-tDCS score=4), the Positive and Negative Syndrome Scale (pre-tDCS score=61; post-tDCS score=50), and the Psychotic Symptom Rating Scale (pre-tDCS score=51; post-tDCS score=43). The decrease in regional CBF indicated that the intervention had a specific neurobiological effect (Figure 1). At follow-up investigation 6 weeks after the tDCS intervention, our patients clinical improvement was maintained. To our knowledge, this is the first case report suggesting the clinical and neurobiological efficacy of cathodal tDCS in the treatment of auditory verbal hallucinations in a patient with schizophrenia. Compared to TMS, a rather expensive and laborious technique, tDCS is convenient and inexpensive, and the equipment is highly portable. It could be an attractive treatment option for alleviating long-term hallticinations in the clinical setting. Although the findings are promising, further study of tDCS for this clinical indication is required.

Static and Dynamic Characteristics of Cerebral Blood Flow During the Resting State in Schizophrenia

BACKGROUND The cerebral network that is active during rest and is deactivated during goal-oriented activity is called the default mode network (DMN). It appears to be involved in self-referential mental activity. Atypical functional connectivity in the DMN has been observed in schizophrenia. One hypothesis suggests that pathologically increased DMN connectivity in schizophrenia is linked with a main symptom of psychosis, namely, misattribution of thoughts. METHODS A resting-state pseudocontinuous arterial spin labeling (ASL) study was conducted to measure absolute cerebral blood flow (CBF) in 34 schizophrenia patients and 27 healthy controls. Using independent component analysis (ICA), the DMN was extracted from ASL data. Mean CBF and DMN connectivity were compared between groups using a 2-sample t test. RESULTS Schizophrenia patients showed decreased mean CBF in the frontal and temporal regions (P < .001). ICA demonstrated significantly increased DMN connectivity in the precuneus (x/y/z = -16/-64/38) in patients than in controls (P < .001). CBF was not elevated in the respective regions. DMN connectivity in the precuneus was significantly correlated with the Positive and Negative Syndrome Scale scores (P < .01). CONCLUSIONS In schizophrenia patients, the posterior hub--which is considered the strongest part of the DMN--showed increased DMN connectivity. We hypothesize that this increase hinders the deactivation of the DMN and, thus, the translation of cognitive processes from an internal to an external focus. This might explain symptoms related to defective self-monitoring, such as auditory verbal hallucinations or ego disturbances.

Cerebral blood flow identifies responders to transcranial magnetic stimulation in auditory verbal hallucinations

Auditory hallucinations comprise a critical domain of psychopathology in schizophrenia. Repetitive transcranial magnetic stimulation (TMS) has shown promise as an intervention with both positive and negative reports. The aim of this study was to test resting-brain perfusion before treatment as a possible biological marker of response to repetitive TMS. Twenty-four medicated patients underwent resting-brain perfusion magnetic resonance imaging with arterial spin labeling (ASL) before 10 days of repetitive TMS treatment. Response was defined as a reduction in the hallucination change scale of at least 50%. Responders (n=9) were robustly differentiated from nonresponders (n=15) to repetitive TMS by the higher regional cerebral blood flow (CBF) in the left superior temporal gyrus (STG) (P<0.05, corrected) before treatment. Resting-brain perfusion in the left STG predicted the response to repetitive TMS in this study sample, suggesting this parameter as a possible bio-marker of response in patients with schizophrenia and auditory hallucinations. Being noninvasive and relatively easy to use, resting perfusion measurement before treatment might be a clinically relevant way to identify possible responders and nonresponders to repetitive TMS.

Theta burst transcranial magnetic stimulation for the treatment of auditory verbal hallucinations: Results of a randomized controlled study

One Hertz (1 Hz) repetitive transcranial magnetic stimulation (rTMS) is an effective therapy for auditory verbal hallucinations (AVH). Theta burst protocols (TBS) show longer after-effects. This single-blind, randomized controlled study compared continuous TBS with 1Hz rTMS in a 10-day treatment. Patients were diagnosed with schizophrenia or schizoaffective disorder. TBS demonstrated equal clinical effects compared to 1Hz TMS.

Theta Burst Stimulation Over the Right Broca's Homologue Induces Improvement of Naming in Aphasic Patients

Background and Purpose— Improvements of language production in aphasic patients have been reported following repeated 1-Hz transcranial magnetic stimulation over the nondamaged right hemisphere. Most studies examined aphasic patients in the chronic phase. The effect of transcranial magnetic stimulation application in acute or subacute patients has not been systematically studied. We aimed to evaluate whether continuous theta burst stimulation, an inhibitory protocol with a shorter application time than the common 1-Hz protocol, is able to improve naming performance in aphasic patients in different poststroke phases. Methods— Eighteen right-handed aphasic patients performed a picture naming task and a language independent alertness test before and after the application of theta burst stimulation over the intact right Brocas homologue localized by the 10–20 electroencephalogram system in a randomized, sham-controlled, crossover trial. Results— We found that naming performance was significantly better, and naming latency was significantly shorter, after theta burst stimulation than after the sham intervention. Patients who responded best were in the subacute phase after stroke. Conclusions— This setting with the short theta burst stimulation application time and the simple stimulation localization procedure is suitable for clinical purposes.

Symptom Dimensions of the Psychotic Symptom Rating Scales in Psychosis: A Multisite Study

The Psychotic Symptom Rating Scales (PSYRATS) is an instrument designed to quantify the severity of delusions and hallucinations and is typically used in research studies and clinical settings focusing on people with psychosis and schizophrenia. It is comprised of the auditory hallucinations (AHS) and delusions subscales (DS), but these subscales do not necessarily reflect the psychological constructs causing intercorrelation between clusters of scale items. Identification of these constructs is important in some clinical and research contexts because item clustering may be caused by underlying etiological processes of interest. Previous attempts to identify these constructs have produced conflicting results. In this study, we compiled PSYRATS data from 12 sites in 7 countries, comprising 711 participants for AHS and 520 for DS. We compared previously proposed and novel models of underlying constructs using structural equation modeling. For the AHS, a novel 4-dimensional model provided the best fit, with latent variables labeled Distress (negative content, distress, and control), Frequency (frequency, duration, and disruption), Attribution (location and origin of voices), and Loudness (loudness item only). For the DS, a 2-dimensional solution was confirmed, with latent variables labeled Distress (amount/intensity) and Frequency (preoccupation, conviction, and disruption). The within-AHS and within-DS dimension intercorrelations were higher than those between subscales, with the exception of the AHS and DS Distress dimensions, which produced a correlation that approached the range of the within-scale correlations. Recommendations are provided for integrating these underlying constructs into research and clinical applications of the PSYRATS.

Repeated measurements of cerebral blood flow in the left superior temporal gyrus reveal tonic hyperactivity in patients with auditory verbal hallucinations: a possible trait marker

Background: The left superior temporal gyrus (STG) has been suggested to play a key role in auditory verbal hallucinations (AVH) in patients with schizophrenia. Methods: Eleven medicated subjects with schizophrenia and medication-resistant AVH and 19 healthy controls underwent perfusion magnetic resonance (MR) imaging with arterial spin labeling (ASL). Three additional repeated measurements were conducted in the patients. Patients underwent a treatment with transcranial magnetic stimulation (TMS) between the first 2 measurements. The main outcome measure was the pooled cerebral blood flow (CBF), which consisted of the regional CBF measurement in the left STG and the global CBF measurement in the whole brain. Results: Regional CBF in the left STG in patients was significantly higher compared to controls (p < 0.0001) and to the global CBF in patients (p < 0.004) at baseline. Regional CBF in the left STG remained significantly increased compared to the global CBF in patients across time (p < 0.0007), and it remained increased in patients after TMS compared to the baseline CBF in controls (p < 0.0001). After TMS, PANSS (p = 0.003) and PSYRATS (p = 0.01) scores decreased significantly in patients. Conclusions: This study demonstrated tonically increased regional CBF in the left STG in patients with schizophrenia and auditory hallucinations despite a decrease in symptoms after TMS. These findings were consistent with what has previously been termed a trait marker of AVH in schizophrenia.

Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.