Data-Driven Analysis of Functional Connectivity Reveals a Potential Auditory Verbal Hallucination Network.

Schizophrenia is a severe global health problem, with over half of such patients experiencing auditory verbal hallucinations (AVHs). A better understanding of the neural correlates differentiating patients experiencing AVHs from patients not experiencing AVHs and healthy controls may identify targets that lead to better treatment strategies for AVHs. Employing 2 data-driven, voxel-based measure of functional connectivity, we studied 46 patients with schizophrenia or schizoaffective disorder (28 experiencing AVHs and 18 not experiencing AVHs).

Studying hallucinations within the NIMH RDoC framework.

We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of functioning. We start with a description of the objectives of the RDoC project and its domains and constructs. Because the RDoC initiative asks investigators to study phenomena across the wellness spectrum and different diagnoses, we address whether hallucinations experienced in nonclinical populations are the same as those experienced by people with psychotic diagnoses, and whether hallucinations studied in one clinical group can inform our understanding of the same phenomenon in another.

Transcranial magnetic stimulation of Wernicke's and Right homologous sites to curtail "voices": a randomized trial.

Background: Auditory/verbal hallucinations (AVHs) are accompanied by activation in Wernicke's and right homologous regions. Efficacy in curtailing AVHs via 1-Hz repetitive magnetic stimulation (rTMS) targeting a site in each region ("W" and "rW") was therefore studied.

Methods: Patients with schizophrenia and AVHs (N = 83) were randomly allocated to double-masked rTMS versus sham stimulation, with blocks of five sessions given to W and rW in random order, followed by five sessions to the site yielding greater improvement.

Bursting as a source of non-linear determinism in the firing patterns of nigral dopamine neurons.

Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single-spikes and phasic bursts that encode information for certain types of reward-related learning and behavior. Non-linear dynamical analysis has previously demonstrated the presence of a non-linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non-linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non-linear determinism in the firing patterns of DA neurons.

Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond.

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies.

Functional connectivity studies of patients with auditory verbal hallucinations.

Functional connectivity (FC) studies of brain mechanisms leading to auditory verbal hallucinations (AVHs) utilizing functional magnetic resonance imaging (fMRI) data are reviewed. Initial FC studies utilized fMRI data collected during performance of various tasks, which suggested frontotemporal disconnection and/or source-monitoring disturbances. Later FC studies have utilized resting (no-task) fMRI data.

Time course of regional brain activity accompanying auditory verbal hallucinations in schizophrenia.

Background: The pathophysiology of auditory verbal hallucinations remains poorly understood.

Aims: To characterise the time course of regional brain activity leading to auditory verbal hallucinations.

Method: During functional magnetic resonance imaging, 11 patients with schizophrenia or schizoaffective disorder signalled auditory verbal hallucination events by pressing a button.

Using computational patients to evaluate illness mechanisms in schizophrenia.

Background: Various malfunctions involving working memory, semantics, prediction error, and dopamine neuromodulation have been hypothesized to cause disorganized speech and delusions in schizophrenia. Computational models may provide insights into why some mechanisms are unlikely, suggest alternative mechanisms, and tie together explanations of seemingly disparate symptoms and experimental findings.

Methods: Eight corresponding illness mechanisms were simulated in DISCERN, an artificial neural network model of narrative understanding and recall.

Elevated functional connectivity along a corticostriatal loop and the mechanism of auditory/verbal hallucinations in patients with schizophrenia.

Background: Higher levels of inter-region functional coordination can facilitate emergence of neural activity as conscious percepts. We consequently tested the hypothesis that auditory/verbal hallucinations (AVHs) arise from elevated functional coordination within a speech processing network.

Methods: Functional coordination was indexed with functional connectivity (FC) computed from functional magnetic resonance imaging data.

When it's time for a change: failures to track context in schizophrenia.

Introduction: Reduction of P300 event-related potential amplitude in schizophrenia is perhaps the most replicated biological reflection of the illness. P300 is typically elicited by infrequent deviant events that are imbedded in a series of identical frequent standard events. Deviants have features that explicitly distinguish them from standards, whereas standards can be distinguished from each other based on their local sequential probabilities within the stimulus series.

Revisiting Arieti's "listening attitude" and hallucinated voices.

Silvano Arieti proposed that auditory/verbal hallucinations (AVHs) are triggered by momentary states of heightened auditory attention that he identified as a "listening attitude." Studies and clinical observations by our group support this view. Patients enrolled in our repetitive transcranial magnetic stimulation trials, if experiencing a significant curtailment of these hallucinations, often report an episodic sense that their voices are still occurring even if they no longer can be heard, suggesting episodic states of heightened auditory expectancy.

Neurophysiological Distinction between Schizophrenia and Schizoaffective Disorder.

Schizoaffective disorder (SA) is distinguished from schizophrenia (SZ) based on the presence of prominent mood symptoms over the illness course. Despite this clinical distinction, SA and SZ patients are often combined in research studies, in part because data supporting a distinct pathophysiological boundary between the disorders are lacking. Indeed, few studies have addressed whether neurobiological abnormalities associated with SZ, such as the widely replicated reduction and delay of the P300 event-related potential (ERP), are also present in SA.

Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia.

Current treatments for psychiatric disorders were developed with the aim of providing symptomatic relief rather than reversing underlying abnormalities in neuroplasticity or neurodevelopment that might contribute to psychiatric disorders. This review considers the possibility that psychiatric treatments might be developed that target neuroplasticity deficits or that manipulate neuroplasticity in novel ways. These treatments might not provide direct symptomatic relief.

Time course of regional brain activation associated with onset of auditory/verbal hallucinations.

The time course of brain activation prior to onset of auditory/verbal hallucinations was characterised using functional magnetic resonance imaging in six dextral patients with schizophrenia. Composite maps of pre-hallucination periods revealed activation in the left anterior insula and in the right middle temporal gyrus, partially replicating two previous case reports, as well as deactivation in the anterior cingulate and parahippocampal gyri. These findings may reflect brain events that trigger or increase vulnerability to auditory/verbal hallucinations.

Impairment of working memory maintenance and response in schizophrenia: functional magnetic resonance imaging evidence.

Background: Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases.

Methods: Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load.

The dependence of P300 amplitude on gamma synchrony breaks down in schizophrenia.

Introduction: Auditory P300 amplitude reduction in schizophrenia is canonical and may be explained by poor synchronization or reduced power of the underlying neural activity. We asked if patients have reduced synchrony and power, and whether together with P300 amplitude, they make unique or overlapping contributions to the discrimination between patients and controls. We also asked whether people who have large P300s have higher power and greater synchrony of neural activity, and if the relationships between P300 and power and synchrony are different in patients and healthy controls.

Auditory/Verbal hallucinations, speech perception neurocircuitry, and the social deafferentation hypothesis.

Auditory/verbal hallucinations (AVHs) are comprised of spoken conversational speech seeming to arise from specific, nonself speakers. One hertz repetitive transcranial magnetic stimulation (rTMS) reduces excitability in the brain region stimulated. Studies utilizing 1-Hz rTMS delivered to the left temporoparietal cortex, a brain area critical to speech perception, have demonstrated statistically significant improvements in AVHs relative to sham simulation.

Extracting spurious messages from noise and risk of schizophrenia-spectrum disorders in a prodromal population.

Atendency to extract spurious, message-like meaning from meaningless noise was assessed as a risk factor leading to schizophrenia-spectrum disorders by assessing word length of speech illusions elicited by multispeaker babble in 43 people with prodromal symptoms. These individuals were randomised to olanzapine v. placebo groups during year 1 followed by no pharmacological treatment for those with no disorder conversion during year 2.

A social deafferentation hypothesis for induction of active schizophrenia.

The "social brain" of humans reflects widespread neural resources dedicated to understanding the conversational language, emotionality, states of mind, and intentions of other persons. A social deafferentation (SDA) hypothesis for induction of active schizophrenia is proposed. Analogous to hallucinations produced by sensory deafferentation, such as phantom limb, the SDA hypothesis assumes that high levels of social withdrawal/isolation in vulnerable individuals prompt social cognition programs to produce spurious social meaning in the form of complex, emotionally compelling hallucinations and delusions representing other persons or agents.

Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation.

Functional magnetic resonance imaging and repetitive transcranial magnetic stimulation (rTMS) were used to explore the pathophysiology of auditory/verbal hallucinations (AVHs). Sixteen patients with schizophrenia-spectrum disorder were studied with continuous or near continuous AVHs. For patients with intermittent hallucinations (N = 8), blood oxygenation level-dependent (BOLD) activation maps comparing hallucination and nonhallucination periods were generated.

Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

Objective: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia.

Method: This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period.

Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample.

Background: Auditory hallucinations are often resistant to treatment and can produce significant distress and behavioral difficulties. A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal repetitive transcranial magnetic stimulation (rTMS) compared to sham stimulation. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention.

Simulated apoptosis/neurogenesis regulates learning and memory capabilities of adaptive neural networks.

Characterization of neuronal death and neurogenesis in the adult brain of birds, humans, and other mammals raises the possibility that neuronal turnover represents a special form of neuroplasticity associated with stress responses, cognition, and the pathophysiology and treatment of psychiatric disorders. Multilayer neural network models capable of learning alphabetic character representations via incremental synaptic connection strength changes were used to assess additional learning and memory effects incurred by simulation of coordinated apoptotic and neurogenic events in the middle layer. Using a consistent incremental learning capability across all neurons and experimental conditions, increasing the number of middle layer neurons undergoing turnover increased network learning capacity for new information, and increased forgetting of old information.

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior.