Ralph E. Hoffman

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.

Symptom assessment in schizophrenic prodromal states.

Individuals who develop schizophrenia often suffer long standing deficits. All too often available treatments remain palliative and do not improve the long-term course of illness. The neurobiological deficits associated with the onset of schizophrenia may be most active and damaging in the early stages of this life long illness, a fact which has shifted the focus of research and clinical work toward the early or prodromal stages of this disorder. Results from limited studies suggest that early intervention may lead to a better prognosis. Early interventions that could delay or prevent the onset of psychotic illnesses have obvious public health implications and rely on being able to identify true prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale of Prodromal Symptoms are assessment instruments developed for operationally defining diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

Verbal hallucinations and language production processes in schizophrenia

How is it that many schizophrenics identify certain instances of verbal imagery as hallucinatory? Most investigators have assumed that alterations in sensory features of imagery explain this. This approach, however, has not yielded a definitive picture of the nature of verbal hallucinations. An alternative perspective suggests itself if one allows the possibility that the nonself quality of hallucinations is inferred on the basis of the experience of unintendedness that accompanies imagery production. Information-processing models of “intentional” cognitive processes call for abstract planning representations that are linked to goals and beliefs. Unintended actions - and imagery - can reflect planning disruptions whereby cognitive products do not cohere with concurrent goals. A model of schizophrenic speech disorganization is presented that postulates a disturbance of discourse planning. Insofar as verbal imagery can be viewed as inwardly directed speech, a consequence of such planning disturbances could be the production of unintended imagery. This link between the outward disorganization of schizophrenic speech and unintended verbal imagery is statistically supported by comparing the speech behavior of hallucinating and nonhallucinating schizophrenics. Studies of “borderline” hallucinations during normal, “goal-less” relaxation and drowsiness suggest that experiential unintendedness leads to a nonpathological variant of hallucinatory otherness that is correctable upon emerging from such passive cognitive states. This contrasts with the schizophrenic case, where nonconcordance with cognitive goals reinforces the unintendedness of verbal images and sustains the conviction of an external source. This model compares favorably with earlier models of verbal hallucinations and provides further evidence for a language production disorder in many schizophrenics. Short Abstract : How is it that many schizophrenics identify certain instances of verbal imagery as hallucinatory? This paper proposes that the critical feature identifying hallucinations is the experience of unintendedness. This experience is nonpathological during passive conscious states but pathological if occurring during goal-directed cognitive processing. A model of schizophrenic speech disorganization is presented that postulates a disturbance of discourse planning that specifies communicative intentions. These alterations could generate unintended verbal imagery as well. Statistical data are offered to support the model, and relevant empirical studies are reviewed.

Transcranial magnetic stimulation and auditory hallucinations in schizophrenia

12 patients with schizophrenia and auditory hallucinations received 1 Hz transcranial magnetic stimulation of left temporoparietial cortex. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation.

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression

BACKGROUND Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

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.

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.

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.

Apprehending schizophrenic discourse: A structural analysis of the Listener's task

Abstract Characterizing aberrances specific to schizophrenic utterances, either purely in experiential terms or simply as features intrinsic to the language material itself, has demonstrated important limitations. Consequently, a model of listener interaction with text was pursued whereby constituent statements of discourse are organized on interpretation into hierarchal structures (or “bases”) according to their mutual presupposition relationships. “Coherence” was taken as the experiential signifier of a text base realization whose geometry conforms to a set of five conditions that collectively define “strong hierarchy” (SH). Violations of particular axioms yielded a typology of textual incoherence, referred to collectively as “non-strong-hierarchal” (NSH) discourse. In the experimental portion of the paper, determination of NSH discourse was found to classify speech samples randomly selected from a psychiatric population into schizophrenic and nonschizophrenic groups with a high degree of accurracy. Clinician responses to these same samples were studied. Classificatory accuracy of individual descriptive indices of “thought disorder” was found to be poor. Discriminant analyses for individual clinicians improved classificatory accuracy considerably. The two clinicians who retrospectively could be turned into the most powerful discriminators for schizophrenia also demonstrated the higher canonical correlations with the discourse analysis. These data suggest that clinician competence to a certain extent is modeled by the discourse analysis. The implications of these findings in terms of what is in the mind of the schizophrenic speaker were discussed, and a program for future research in this area was outlined.

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 Wernickes region delineated according to activation detected during AVHs in a prior study. RESULTS Wernickes-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, Wernickes-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 Wernickes 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.