Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention.

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Neural mechanisms of mismatch negativity dysfunction in schizophrenia.

Schizophrenia is associated with cognitive deficits that reflect impaired cortical information processing. Mismatch negativity (MMN) indexes pre-attentive information processing dysfunction at the level of primary auditory cortex. This study investigates mechanisms underlying MMN impairments in schizophrenia using event-related potential, event-related spectral decomposition (ERSP) and resting state functional connectivity (rsfcMRI) approaches. For this study, MMN data to frequency, intensity and duration-deviants were analyzed from 69 schizophrenia patients and 38 healthy controls. rsfcMRI was obtained from a subsample of 38 patients and 23 controls. As expected, schizophrenia patients showed highly significant, large effect size (P=0.0004, d=1.0) deficits in MMN generation across deviant types. In ERSP analyses, responses to deviants occurred primarily the theta (4-7 Hz) frequency range consistent with distributed corticocortical processing, whereas responses to standards occurred primarily in alpha (8-12 Hz) range consistent with known frequencies of thalamocortical activation. Independent deficits in schizophrenia were observed in both the theta response to deviants (P=0.021) and the alpha-response to standards (P=0.003). At the single-trial level, differential patterns of response were observed for frequency vs duration/intensity deviants, along with At the network level, MMN deficits engaged canonical somatomotor, ventral attention and default networks, with a differential pattern of engagement across deviant types (P<0.0001). Findings indicate that deficits in thalamocortical, as well as corticocortical, connectivity contribute to auditory dysfunction in schizophrenia. In addition, differences in ERSP and rsfcMRI profiles across deviant types suggest potential differential engagement of underlying generator mechanisms.

Imaging glutamate in schizophrenia: review of findings and implications for drug discovery.

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

The 5% difference: early sensory processing predicts sarcasm perception in schizophrenia and schizo-affective disorder.

BACKGROUND: Intact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia. METHOD: Auditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory performance. RESULTS: Patients showed large effect-size deficits across auditory measures. Sarcasm deficits correlated significantly with general functioning and impaired pitch processing both across groups and within the patient group alone. Patients also showed reduced sensitivity to alterations in mean pitch and variability. For patients, sarcasm discrimination correlated exclusively with the level of rsFC within primary auditory regions whereas for controls, correlations were observed exclusively within core-mentalizing regions (the right posterior superior temporal gyrus, anterior superior temporal sulcus and insula, and left posterior medial temporal gyrus). CONCLUSIONS: These findings confirm the contribution of auditory deficits to theory of mind (ToM) impairments in schizophrenia, and demonstrate that FC within auditory, but not core-mentalizing, regions is rate limiting with respect to sarcasm detection in schizophrenia.

Amusia and protolanguage impairments in schizophrenia.

BACKGROUND: Both language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed. METHOD: Musical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition. RESULTS: Highly significant deficits were seen between patients and controls across auditory tasks (p < 0.001). Moreover, significant differences were seen in AER between the amusia and intact music-perceiving groups, which remained significant after controlling for group status and education. Correlations with AER were specific to the melody domain, and correlations between protolanguage (melody domain) and language were independent of overall cognition. DISCUSSION: This is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia.

Early experience with the use of anti-inhibitor coagulant complex to treat bleeding in hemophiliacs with inhibitors to factor VIII.

Early clinical experience with anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors is described. Sixty patients with a total of 120 bleeding episodes were studied. Satisfactory responses were obtained in 86.6% of bleeding episodes. Efficacy was slightly better in open bleeding than in closed bleeding. Higher doses were significantly better than lower doses in treating open bleeding. The incidence of adverse reactions was low. The results reported support the safety and efficacy of anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors.

PROPLEX vs. PROPLEX SX: a controlled double blind study of the effectiveness in treating acute hemarthroses in hemophilia A patients with inhibitors to factor VIII.

A blinded randomized multicenter trial of two non-activated prothrombin complex concentrates was carried out to determine the clinical effectivity in the treatment of acute hemarthrosis in hemophiliac patients with inhibitors. The one product was prepared via DEAE Sephadex chromatography, while the second was fractionated via various precipitation procedures including polyethylene glycol. Equivalence of the two products was established with less than 15% difference in efficacy rates.

Morphine and codeine are endogenous components of human cerebrospinal fluid.

We have examined cerebrospinal fluid (CSF) from twelve patients who were not on any medication and found them to contain both morphine and codeine in concentrations of 2 to 339 fmol/ml. These are comparable to the concentration of opioid peptides in spinal fluid. Both morphine and codeine are present mainly in conjugated form from which the free alkaloids can be released by acid hydrolysis.

Impasses in psychoanalysis: overcoming resistance in situations of stalemate.

Many impasses occur in treatment when the patient fears that analysis will repeat frightening or disappointing experiences. These stalemates result from the patient's conviction that the analyst has confirmed a preexisting belief that is central to the patient's primary conflict. Frequently, this belief involves an unacceptable or frightening self- or object representation. At these times, intense resistance and strong negative transference/countertransference reactions may develop. Impasses are differentiated from these strong negative reactions only by virtue of the fact that they remain unanalyzed. The factors that create these negative states can best be understood in instances where the potential impasse is resolved. When impasses persist, most often patients leave treatment. Under these circumstances, we can try retrospectively to understand what has gone wrong, but without the patient's confirmation, our conclusions must remain speculative. Four cases illustrate varying degrees of analysis and resolution of resistance and transference/countertransference binds.

The analyst's style and its impact on the analytic process: overcoming a patient-analyst stalemate.

Analysts have characteristic styles in working with their patients. At times of crisis or stalemate, an alteration in style may facilitate the progress of the treatment. To illustrate the impeding effects of an analytic style at a particular phase of analysis, I describe a stalemate in the analysis of a severely self-critical patient. Recognition of the limiting effects of style on the treatment became apparent in a countertransference enactment, influenced by the patient-analyst match. Self-analysis and alteration in the characteristic style of the analyst resolved the stalemate and enabled the analytic work to progress.

The role of the preconscious in psychoanalysis.

The analytic process inevitably involves the interdigitation of the intrapsychic structures of both patient and analyst. This interplay is expressed in transference-countertransference interactions. Drawing a dichotomy between intrapsychic and interpersonal factors as central agents of psychic change is a faulty construction. Affective, behavioral interchanges between patient and analyst reflect their individual intrapsychic organizations and their interplay, which influence the form and nature of psychological change. The safer both patient and analyst feel in relation to each other, the more freely will they relax their customary cognitive controls and permit the emergence of preconscious responses. Preconscious resonance between patient and analyst is likely to facilitate the lifting of repressive barriers and the emergence of unconscious material in both participants. The integration and reworking of old conflicts then becomes possible. The role of the preconscious in facilitating the analytic process is illustrated. Creative use of preconscious processes requires the analyst's self-discipline to preserve the analytic role and keep the treatment safe for both participants.

A different perspective on the therapeutic process: the impact of the patient on the analyst.

The therapeutic process is considered from the perspective of its impact on the analyst. Analysts undertake self-scrutiny, focusing on transference and countertransference reactions, in order to facilitate the treatment of their patients. However, this self-reflection also serves to continue and enhance the analysts own personal understanding. In the course of analyzing patients, an interactional process develops in which many of the therapeutic aspects of analysis affect the analyst as well as the patient. A clinical example is offered to illustrate this process.

Brief communication: a comparison of the place of dreams in institute curricula between 1980-1981 and 1998-1999.

The analysis of dreams was central in demonstrating Freud's theory of mind and the power of unconscious forces. Many analysts informally comment that dreams no longer seem to hold the same centrality they had for analysts who were trained prior to the 1980s. This paper presents a brief study assessing whether there has been a change in the teaching of dreams in psychoanalytic institutes. Comparison of theoretical and clinical courses on dreams in 1980-1981 and 1998-1999 indicates that the actual number of hours devoted to teaching dreams has in fact decreased. However, there are indications that a renewal of interest in dreams may now be occurring, at least in some institutes. The relationship between views on the role of dreams and perspectives on psychoanalysis itself is discussed.

Followup of psychoanalysis five to ten years after termination: II. Development of the self-analytic function.

Thirteen of seventeen patients in followup interviews five to ten years after the termination of analysis reported the development or refinement of a self-analytic capacity. According to the accounts of these patients, there did not appear to be a direct relation between the attainment of a self-analytic function and the extent of resolution of the transference neurosis or the maintenance of therapeutic gains after treatment.

Followup of psychoanalysis five to ten years after termination: III. The relation between the resolution of the transference and the patient-analyst match.

As part of a long-term followup study of the outcome of psychoanalysis, we examined the relation between the extent of resolution of the transference at termination and the characteristics of the patient-analyst match. For twelve of the seventeen patients interviewed five to ten years after termination of psychoanalysis, the researchers found that the patient-analyst match played a role in the outcome of the analysis. Illustrations of the influence of the match in cases where the transference was resolved and those where it was not are presented.

Followup of psychoanalysis five to ten years after termination: I. Stability of change.

Seven out of 17 patients interviewed in a long-term followup of psychoanalysis showed either improvement in psychological functioning or a retention of psychological gains they had made during the course of psychoanalysis. Six patients deteriorated in their psychological functioning, but their gains were restored with subsequent treatment. Four patients deteriorated in psychological functioning without restoration, whether or not treatment was reentered. Neither analysts' assessments at the time of termination nor patients' assessments of themselves or assessments based on psychological tests one year after termination predicted which patients would improve or retain psychological change. No causal generalizations about factors related to psychological change can be made from these data. Different factors in interaction are suggested to account for the stability and instability of psychological change.

Changes in the level and quality of object relations in psychoanalysis: followup of a longitudinal, prospective study.

As part of a prospective, longitudinal study of suitability for and outcome of psychoanalysis, 22 patients were evaluated for changes in the level and quality of their object relations. These patients had been accepted for supervised analysis with candidates in training by senior analysts who had diagnosed them as neurotic. The majority of these patients reported difficulties in relationships as at least one of their reasons for originally seeking psychoanalytic treatment. Prior to beginning analysis, each patient was given a battery of psychological tests. One year after the termination of analysis, the test battery was readministered and a followup interview was conducted separately with each patient and analyst. Ratings of change based on patient and analyst interviews and comparisons of psychological tests before and after treatment all showed statistically significant improvement in the level and quality of object relations for this patient group. The results of this study support what is often observed in clinical practice, that psychoanalysis has a positive effect on the level and quality of a patient's object relations.

The role of reality testing in psychoanalysis: followup of 22 cases.

As part of a prospective, longitudinal study of psychoanalytic outcome, 22 patients were evaluated for changes in their level of reality testing. These patients had been accepted for supervised psychoanalysis with candidates in training by senior analysts who had diagnosed them as neurotic. Psychological tests given prior to the beginning of analysis indicated, however, that more than one third of our sample demonstrated serious distortions in their perceptions of reality. When psychological tests administered one year after the completion of analysis were compared with these pretreatment tests, no significant improvement was found in the level of reality testing for the group as a whole. However, when excluding two patients who had suffered major traumas in the year following psychoanalysis, significant improvement in reality testing was found for the remaining 20 patients. Post-treatment interviews with the treating analysts revealed that in the course of analysis itself, approximately one third of these patients showed some disturbance in reality testing; only three of these patients showed significant improvement in the level of their reality testing during treatment. These findings suggest that while patients may not present clinically with evidence of impaired reality testing, such evidence may be available in psychological testing, and may become apparent in the course of the treatment.

Affect availability, tolerance, complexity, and modulation in psychoanalysis: followup of a longitudinal, prospective study.

Evaluation of 22 patients in supervised psychoanalysis showed that affect availability and tolerance changed in a positive direction during the course of psychoanalysis. In this study, we have defined criteria of change that can be clinically observed. The changes observed were present one year following the completion of psychoanalysis. Ratings of analysts' and patients' interviews, and ratings of psychological tests all revealed that patients had derived "therapeutic benefit" in relation to affect experience and management. Discriminations were made among changes in affect modulation, which reflected both loosening and tightening of controls, changes in affect availability, changes in experience of painful affects, and changes in experience of affect complexity. Analysts' interviews and psychological test data reflected notable changes in affect modulation in the direction of increased control, while patients' interviews more often reflected changes in the direction of increased expressiveness.

The patient-analyst match and the outcome of psychoanalysis: a pilot study.

This paper presents a pilot study in which we explore the possibility that the match between analyst and analysand is a factor of central importance in the analytic situation. It is an attempt to look at the issue of match across a large number of patients. The data we used were not collected for studying this topic; thus, the study has serious limitations. Nevertheless, certain patterns emerged which support our thesis that patient-analyst match plays a significant role in the outcome of psychoanalysis. We present this work as a first step in developing concepts and methods which will be pursued in a more systematic and rigorous fashion in a later study.