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. To test this hypothesis, we investigated the dimension complexity of inter-spike interval data recorded in vivo from bursting and non-bursting DA neurons in the chloral hydrate-anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non-linear determinism in their firing patterns, whereas non-bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter-burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane-anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate-anesthetized rats. These results strongly indicate that bursting activity is the main source of low-dimensional, non-linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons.

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. To control for effects of motor behaviour, regional activity associated with hallucination events was scaled against corresponding activity arising from random button-presses produced by 10 patients who did not experience hallucinations. RESULTS: Immediately prior to the hallucinations, motor-adjusted activity in the left inferior frontal gyrus was significantly greater than corresponding activity in the right inferior frontal gyrus. In contrast, motor-adjusted activity in a right posterior temporal region overshadowed corresponding activity in the left homologous temporal region. Robustly elevated motor-adjusted activity in the left temporal region associated with auditory verbal hallucinations was also detected, but only subsequent to hallucination events. At the earliest time shift studied, the correlation between left inferior frontal gyrus and right temporal activity was significantly higher for the hallucination group compared with non-hallucinating patients. CONCLUSIONS: Findings suggest that heightened functional coupling between the left inferior frontal gyrus and right temporal regions leads to coactivation in these speech processing regions that is hallucinogenic. Delayed left temporal activation may reflect impaired corollary discharge contributing to source misattribution of resulting verbal images.

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). Twenty healthy controls matched for age, gender, ethnicity, education level, handedness, and estimated verbal intelligence were included for comparison. The intrinsic connectivity distribution (ICD) was used to model each voxel's connectivity to the rest of the brain using a Weibull distribution. To investigate lateralization of connectivity, we used cross-hemisphere ICD, a method that separates the contribution of each hemisphere to interrogate connectivity laterality. Patients with AVHs compared with patients without AVHs exhibited significantly decreased whole-brain connectivity in the medial prefrontal cortex and posterior cingulate cortex, less lateralized connectivity in left putamen, and more lateralized connectivity in left interior frontal gyrus. Correlations with Auditory Hallucination Rating Scale (AHRS) and post hoc seed connectivity analyses revealed significantly altered network connectivity. Using the results from all analyses comparing the patient groups and correlations with AHRS, we identified a potential AVH network, consisting of 25 nodes, showing substantial overlap with the default mode network and language processing networks. This network as a whole, instead of individual nodes, may represent actionable targets for interventions.

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.

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. METHODS: We recorded EEG data from 22 controls and 21 patients with schizophrenia (DSM-IV) while they performed an auditory target detection task. We used wavelet analyses of the single trial data to estimate total power and synchrony of delta, theta, alpha, beta, and gamma activity in a 50ms window around the peak of the P300 to the target. We measured P300 amplitude from the average of the single trials, in a 50ms window around its peak. RESULTS AND CONCLUSIONS: P300 amplitude and delta and theta synchrony were reduced in patients; delta power and synchrony better distinguished between groups than P300 amplitude. In healthy controls, but not patients, gamma synchrony predicted P300 amplitude. In patients, P300 and gamma synchrony are affected by independent factors; the relationship between them is attenuated by an additional pathophysiological process.

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. Arguments against the SDA hypothesis are discussed, and predictions deriving from the hypothesis are offered.

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. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores. RESULTS: During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24). CONCLUSIONS: A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

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. METHODS: Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. RESULTS: Hallucination Change Score was more improved for rTMS relative to sham stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008). There was no evidence of neurocognitive impairment associated with rTMS. CONCLUSIONS: Left temporoparietal 1-hertz rTMS warrants further study as an intervention for auditory hallucinations. Data suggest that this intervention selectively alters neurobiological factors determining frequency of these hallucinations.

Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations.

BACKGROUND: Neuroimaging studies suggest that auditory hallucinations (AHs) of speech arise, at least in part, from activation of brain areas underlying speech perception. One-hertz repetitive transcranial magnetic stimulation (rTMS) produces sustained reductions in cortical activation. Recent results of 4-day administration of 1-Hz rTMS to left temporoparietal cortex were superior to those of sham stimulation in reducing AHs. We sought to determine if a more extended trial of rTMS could significantly reduce AHs that were resistant to antipsychotic medication. METHODS: Twenty-four patients with schizophrenia or schizoaffective disorder and medication-resistant AHs were randomly allocated to receive rTMS or sham stimulation for 9 days at 90% of motor threshold. Patients receiving sham stimulation were subsequently offered an open-label trial of rTMS. Neuropsychological assessments were administered at baseline and during and following each arm of the trial. RESULTS: Auditory hallucinations were robustly improved with rTMS relative to sham stimulation. Frequency and attentional salience were the 2 aspects of hallucinatory experience that showed greatest improvement. Duration of putative treatment effects ranged widely, with 52% of patients maintaining improvement for at least 15 weeks. Repetitive transcranial magnetic stimulation was well tolerated, without evidence of neuropsychological impairment. CONCLUSIONS: These data suggest that the mechanism of AHs involves activation of the left temporoparietal cortex. One-hertz rTMS deserves additional study as a possible treatment for this syndrome.

Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders.

OBJECTIVE: Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity. METHOD: Studies assessing effects of "slow" rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue. RESULTS: Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects. CONCLUSIONS: Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.

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. Simulations also showed that specific patterns of neural turnover based on individual neuronal connection characteristics, or the temporal-spatial pattern of neurons chosen for turnover during new learning impacts new learning performance. These simulations predict that apoptotic and neurogenic events could act together to produce specific learning and memory effects beyond those provided by ongoing mechanisms of connection plasticity in neuronal populations. Regulation of rates as well as patterns of neuronal turnover may serve an important function in tuning the informatic properties of plastic networks according to novel informational demands. Analogous regulation in the hippocampus may provide for adaptive cognitive and emotional responses to novel and stressful contexts, or operate suboptimally as a basis for psychiatric disorders. The implications of these elementary simulations for future biological and neural modeling research on apoptosis and neurogenesis are discussed.

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. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression.

Stimulation parameters seem to strongly influence the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment-resistant depressed patients. The most effective and safest parameters are yet to be defined. Moreover, systematic follow-up data available to document the duration of the therapeutic effects remain sparse. Twenty-one treatment-resistant depressed patients were randomized to either active rTMS (N=12) or to sham (N=9) treatment in a double-blind design. Patients were kept on their medications. Sub-motor-threshold (MT) stimulation (80% MT) was delivered for 10 consecutive work days (20 Hz, 2-s trains, 20 trains). Subjects meeting pre-set criteria for responding were entered into a follow-up phase for up to 5 months. Utilizing the above stimulation parameters, we found no significant difference between groups. Six patients in the active group and one subject in the sham group met criteria for the follow-up phase. The period of time before subjects met criteria for relapse was highly variable ranging from 2 to 20 weeks. Sub-threshold rTMS stimulation for 2 weeks is not significantly superior to sham treatment for treatment-resistant depressed patients. The duration of the therapeutic effects of rTMS delivered to the left prefrontal cortex using the above-described parameters is highly variable.

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. We then discuss the phenomenology of hallucinations and how different RDoC domains might be relevant to their study. We end with a discussion of various challenges and potential next steps to advance the application of the RDoC approach to this area of research.

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. The primary outcome measure was the Hallucination Change Score (HCS). Hallucination frequency, total auditory hallucination rating scale score, and clinical global improvement were secondary outcome measures. Attentional salience of AVHs and neuropsychological measures of laterality were studied as predictors of site-specific response. RESULTS: After 15 sessions, rTMS produced significant improvements relative to sham stimulation for hallucination frequency and clinical global improvement but not for HCS. After limiting analyses to patients whose motor threshold was detected consistently: 1) endpoint HCS demonstrated significantly greater improvement for rTMS compared with sham stimulation; 2) for high-salience AVHs, rTMS to rW after the first five sessions yielded significantly improved HCS scores relative to sham stimulation, whereas for low salience AVHs, rTMS to W produced this finding. Nondominant motor impairment correlated positively with hallucination improvement following rW rTMS. CONCLUSIONS: One-hertz rTMS per our site-optimization protocol produced some clinical benefit in patients with persistent AVHs as a group, especially when motor threshold was consistently detected. Level of hallucination salience may usefully guide selection of W versus rW as intervention sites.

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. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future 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. These studies have produced a mixed picture of disconnection and hyperconnectivity involving different pathways associated with AVHs. Results of our most recent FC study of AVHs are reviewed in detail. This study suggests that the core mechanism producing AVHs involves not a single pathway, but a more complex functional loop. Components of this loop include Wernicke's area and its right homologue, the left inferior frontal cortex, and the putamen. It is noteworthy that the putamen appears to play a critical role in the generation of spontaneous language, and in determining whether auditory stimuli are registered consciously as percepts. Excessive functional coordination linking this region with the Wernicke's seed region in patients with schizophrenia could, therefore, generate an overabundance of potentially conscious language representations. In our model, intact FC in the other two legs of corticostriatal loop (Wernicke's with left IFG, and left IFG with putamen) appeared to allow hyperconnectivity linking the putamen and Wernicke's area (common to schizophrenia overall) to be expressed as conscious hallucinations of speech. Recommendations for future studies are discussed, including inclusion of multiple methodologies applied to the same subjects in order to compare and contrast different mechanistic hypotheses, utilizing EEG to better parse time-course of neural synchronization leading to AVHs, and ascertaining experiential subtypes of AVHs that may reflect distinct mechanisms.

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. Thirty-two patients with schizophrenia reporting AVHs, 24 similarly diagnosed patients without hallucinations, and 23 healthy control subjects were studied. FC was seeded from a bilateral Wernicke's region delineated according to activation detected during AVHs in a prior study. RESULTS: Wernicke's-seeded FC with Brodmann area 45/46 of the left inferior frontal gyrus (IFG) was significantly greater for hallucinating patients compared with nonhallucinating patients but not compared with healthy control subjects. In contrast, Wernicke's-seeded FC with a large subcortical region that included the thalamus, midbrain, and putamen was significantly greater for the combined patient group compared with healthy control subjects after false discovery rate correction, but not when comparing the two patient groups. Within that subcortical domain, the putamen demonstrated significantly greater FC relative to a secondary left IFG seed region when hallucinators were compared with nonhallucinating patients. A follow-up analysis found that FC summed along a loop linking the Wernicke's and IFG seed regions and the putamen was robustly greater for hallucinating patients compared with nonhallucinating patients and healthy control subjects. CONCLUSIONS: These findings suggest that higher levels of functional coordination intrinsic to a corticostriatal loop comprise a causal factor leading to AVHs in schizophrenia.

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. For this study, DISCERN learned sets of autobiographical and impersonal crime stories with associated emotion coding. In addition, 20 healthy control subjects and 37 patients with schizophrenia or schizoaffective disorder matched for age, gender, and parental education were studied using a delayed story recall task. A goodness-of-fit analysis was performed to determine the mechanism best reproducing narrative breakdown profiles generated by healthy control subjects and patients with schizophrenia. Evidence of delusion-like narratives was sought in simulations best matching the narrative breakdown profile of patients. RESULTS: All mechanisms were equivalent in matching the narrative breakdown profile of healthy control subjects. However, exaggerated prediction-error signaling during consolidation of episodic memories, termed hyperlearning, was statistically superior to other mechanisms in matching the narrative breakdown profile of patients. These simulations also systematically confused autobiographical agents with impersonal crime story agents to model fixed, self-referential delusions. CONCLUSIONS: Findings suggest that exaggerated prediction-error signaling in schizophrenia intermingles and corrupts narrative memories when incorporated into long-term storage, thereby disrupting narrative language and producing fixed delusional narratives. If further validated by clinical studies, these computational patients could provide a platform for developing and testing novel treatments.