Andre Richter

NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI

BACKGROUND Based on animal data, NMDA receptor hypofunction has been suggested as a model for positive symptoms in schizophrenia. NMDA receptor hypofunction affects several corticolimbic brain regions, of which the posterior cingulate seems to be the most sensitive. However, empirical support for a crucial role of posterior cingulate NMDA hypofunction in the pathophysiology of positive symptoms is still missing in humans. We therefore conducted an fMRI study using the NMDA antagonist ketamine in healthy human subjects during episodic memory retrieval, which is supposed to activate the posterior cingulate. METHODS We investigated 16 healthy subjects which were assigned to either placebo (n = 7; saline) or ketamine (n = 9; 0.6 mg/kg/h) group in a double-blind study design. All subjects received their infusion while performing an episodic memory retrieval task in the scanner. Immediately after the fMRI session, psychopathological effects of ketamine were measured using the Altered States of Consciousness Questionnaire. RESULTS The placebo group showed BOLD signal increases in the posterior and anterior cingulate during retrieval. Signal increases were significantly lower in the ketamine group. Lower signal increases in the posterior cingulate correlated significantly with positive (i.e. psychosis-like) symptoms induced by ketamine. CONCLUSION The present study for the first time demonstrates a relationship between NMDA receptors, posterior cingulate and positive (i.e. psychosis-like) symptoms in humans. Confirming findings from animal studies, it supports the hypothesis of a pathophysiological role of NMDA receptor hypofunction in the posterior cingulate in schizophrenia.

GABA-ergic Modulation of Prefrontal Spatio-temporal Activation Pattern during Emotional Processing: A Combined fMRI/MEG Study with Placebo and Lorazepam

Various prefrontal cortical regions have been shown to be activated during emotional stimulation, whereas neurochemical mechanisms underlying emotional processing in the prefrontal cortex remain unclear. We therefore investigated the influence of the GABA-A potentiator lorazepam on prefrontal cortical emotionalmotor spatio-temporal activation pattern in a combined functional magnetic resonance imaging/magnetoencephalography study. Lorazepam led to the reversal in orbito-frontal activation pattern, a shift of the early magnetic field dipole from the orbito-frontal to medial prefrontal cortex, and alterations in premotor/motor cortical function during negative and positive emotional stimulation. It is concluded that negative emotional processing in the orbito-frontal cortex may be modulated either directly or indirectly by GABA-A receptors. Such a modulation of orbito-frontal cortical emotional function by lorazepam has to be distinguished from its effects on cortical motor function as being independent from the kind of processing either emotional or nonemotional.

Lorazepam modulates orbitofrontal signal changes during emotional processing in catatonia

Catatonia is a psychomotor syndrome characterized by concomitant emotional, behavioural and motor symptoms. In many cases clinical symptoms disappear almost immediately with administration of lorazepam, which acts on GABAA receptors.

Sustained cognitive impairments after clinical recovery of severe depression.

Abstract Neuropsychological impairment is prominent in patients with depression, but it is unclear whether deficits persist after clinical response. This study aimed to investigate neuropsychological functions in the course of the illness. Depressive patients were investigated in the acute state and after clinical response using an extensive neuropsychological test battery. After clinical response, there was only a partial improvement in learning and memory and there were no changes regarding working memory, executive functions, and attention. Transient impairments in visual learning and memory suggest a depression-related state effect. The continuing deficits in attention, working memory, and executive function might be considered a trait marker.

Essentials of psychoanalytic process and change: how can we investigate the neural effects of psychodynamic psychotherapy in individualized neuro-imaging?

The paper focuses on the essentials of psychoanalytic process and change and the question of how the neural correlates and mechanisms of psychodynamic psychotherapy can be investigated. The psychoanalytic approach aims at enabling the patient to “remember, repeat, and work through” concerning explicit memory. Moreover, the relationship between analyst and patient establishes a new affective configuration which enables a reconstruction of the implicit memory. If psychic change can be achieved it corresponds to neuronal transformation. Individualized neuro-imaging requires controlling and measuring of variables that must be defined. Two main methodological problems can be distinguished: the design problem addresses the issue of how to account for functionally related variables in an experimentally independent way. The translation problem raises the question of how to bridge the gaps between different levels of the concepts presupposed in individualized neuro-imaging (e.g., the personal level of the therapist and the client, the neural level of the brain). An overview of individualized paradigms, which have been used until now is given, including Operationalized Psychodynamic Diagnosis (OPD-2) and the Maladaptive Interpersonal Patterns Q-Start (MIPQS). The development of a new paradigm that will be used in fMRI experiments, the “Interpersonal Relationship Picture Set” (IRPS), is described. Further perspectives and limitations of this new approach concerning the design and the translation problem are discussed.

Gender characteristics of cerebral hemodynamics during complex cognitive functioning.

Functional Transcranial Doppler sonography (fTCD) has been applied to assess peak mean cerebral blood flow velocity (MFV) with a high temporal resolution during cognitive activation. Yet, little attention has been devoted to gender-related alterations of MFV, including spectral analysis. In healthy subjects, fTCD was used to investigate a series of cerebral hemodynamic parameters in the middle cerebral arteries (MCA) during the Trail Making Tests (TMT), a means of selective attention and complex cognitive functioning. In females, there was a frequency peak at 0.375 Hz in both MCA, and we observed a dynamic shift in hemispheric dominance during that condition. Further, after the start phase, there was an MFV decline during complex functioning for the entire sample. These novel results suggest condition-specific features of cerebral hemodynamics in females, and it adds to the notion that gender is a fundamental confounder of brain physiology.

Subsyndromal delirium in the intensive care setting: Phenomenological characteristics and discrimination of subsyndromal delirium versus no and full-syndromal delirium

OBJECTIVE Similar to delirium, its subsyndromal form has been recognized as the cause of diverse adverse outcomes. Nonetheless, the nature of this subsyndromal delirium remains vastly understudied. Therefore, in the following, we evaluate the phenomenological characteristics of this syndrome versus no and full-syndromal delirium. METHOD In this prospective cohort study, we evaluated the Delirium Rating Scale-Revised, 1998 (DRS-R-98) versus the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnostic criteria and examined the diagnosis of delirium with respect to phenomenological distinctions in the intensive care setting. RESULTS Out of 289 patients, 36 with subsyndromal delirium versus 86 with full-syndromal and 167 without delirium were identified. Agreement with respect to the DSM-IV-TR diagnosis of delirium was perfect. The most common subtype in those with subsyndromal delirium was hypoactive, in contrast to mixed subtype in those with full-syndromal delirium versus no motor alterations in those without delirium. By presence and severity of delirium symptoms, subsyndromal delirium was intermediate. The ability of the DRS-R-98 items to discriminate between either form of delirium was substantial. Between subsyndromal and no delirium, the cognitive domain and sleep-wake cycle were more impaired and allowed a distinction with no delirium. Further, between full- and subsyndromal delirium, the prevalence and severity of individual DRS-R-98 items were greater. Although the differences between these two forms of delirium was substantial, the items were not very specific, indicating that the phenomenology of subsyndromal delirium is closer to full-syndromal delirium. SIGNIFICANCE OF RESULTS Phenomenologically, subsyndromal delirium was found to be distinct from and intermediate between no delirium and full-syndromal delirium. Moreover, the greater proximity to full-syndromal delirium indicated that subsyndromal delirium represents an identifiable subform of full-syndromal delirium.

Delirium in the intensive care setting and the Richmond Agitation and Sedation Scale (RASS): Drowsiness increases the risk and is subthreshold for delirium

INTRODUCTION Sedation is a core concept in the intensive care setting, however, the impact of sedation on delirium has not yet been studied to date. METHODS In this prospective cohort study, 225 patients with Richmond Agitation and Sedation (RASS) scores of -1 - drowsiness and 0 - alert- and calmness were assessed with the Delirium Rating Scale-Revised 1998 (DRS-R-98) and DSM-IV-TR-determined diagnosis of delirium assessing drowsiness versus alertness. RESULTS By itself, drowsiness increased the odds for developing delirium eightfold (OR 7.88 p<0.001) and rates of delirium were 68.2 and 21.4%, respectively. Further, in the drowsy patient, delirium was more severe. In the presence of drowsiness, delirium was characterized by sleep-wake cycle disturbances and language abnormalities. These two features, in addition to psychomotor retardation, allowed the correct classification of delirium at RASS-1. The same features, in addition to thought abnormalities and the impairment in the cognitive domain, orientation, attention, short- and long-term memory representing the core domains of delirium, or the temporal onset were very sensitive towards delirium, however lacked specificity. Conversely, delusions, perceptual abnormalities and lability of affect representing the non-core domain were very specific for delirium in the drowsy, however, not very sensitive. In the absence of delirium, drowsiness caused attentional impairment and language abnormalities. CONCLUSION Drowsiness increased the odds for developing delirium eightfold and caused more severe delirium, which was characterized by sleep-wake cycle and language abnormalities. Further, drowsiness by itself caused attentional impairment and language abnormalities, thus, with its disturbance in consciousness was subthreshold for delirium.

Orbitofrontal Cortical Dysfunction and “Sensori-motor Regression”: A Combined Study of fMRI and Personal Constructs in Catatonia

Objective A close relationship between subjective experience and neurophysiological mechanisms could provide a new foundation for neurobiological correlates underlying psychodynamic processes in neuropsychiatric diseases. Pursuing a novel methodological approach by combining both techniques we investigated catatonia a psychomotor syndrome with uncontrollable anxieties and akinesia i.e., “immobilization by anxieties” which, psychodynamically, can be characterized as a “sensori-motor regression” reflecting a basic somatic defense mechanism. However psychological and physiological mechanisms of generation of such “sensori-motor regression” in catatonia remain unclear. We therefore investigated in a combined study operationalized subjective psychological characteristics using Repertory-Grid Technique as well as prefrontal cortical activation pattern during emotional-motor stimulation using functional magnetic resonance imaging (fMRI). Method We investigated 18 catatonic patients with an underlying affective or schizoaffective psychosis and compared them with age, sex, diagnosis, and medication matched non-catatonic psychiatric controls (n = 69), and healthy controls (n = 32). Subjective operationalized psychological characteristics were investigated using the Repertory Grid Technique (GRID) for personal constructs of the “self” in an acute and a post-acute state. In addition 10 catatonic patients, 10 psychiatric controls and 10 healthy controls underwent emotional stimulation with motor reaction during functional magnetic resonance imaging (fMRI). Results Subjective operationalized psychological characteristics of both the acute and post-acute state could be characterized by significant lack of social contact, decreased self-esteem, and reduced emotional arousal compared to non-catatonic psychiatric and healthy controls. fMRI revealed significant dysfunctional activation patterns in orbitofrontal cortex and alterations in medial prefrontal and premotor cortex during negative emotional stimulation which correlated significantly (p = 0.0082–0.042) with affective, behavioral, and motor alterations in catatonia as well as with the GRID dimensions of self-esteem, emotional arousal, and social contact. Conclusions Subjective operationalized psychological characteristics demonstrate the central importance of lack of emotional control as well as of alterations in interactions between emotional, social, and motor functions in catatonia. Orbitofrontal cortical dysfunction and related alterations in medial prefrontal and premotor cortical activity may account for lack of emotional control with consecutive “sensori-motor regression” as an “immobilization by anxieties” in catatonia. In general one may conclude that orbitofrontal cortical dysfunction may be closely related with regression to somatic defense mechanisms as paradigmatically observed in catatonia.

One look is worth a thousand words: New picture stimuli of interpersonal situations

ABSTRACT This paper introduces a picture system that can be used in functional imaging experiments exploring interpersonal relations. This is important for psychotherapy research to understand the neural basis of psychological treatment effects. Pictures have many advantages for the design of functional imaging experiments, but no picture system illustrating interpersonal behavior patterns is, to date, available. We therefore developed, on the basis of a validated card-sorting test, the Interpersonal Relations Picture System. In summary, 43 pictures with 2 or more stick figures in different social situations and 9 control pictures were composed. To test the relation between each picture and the appropriate description, two successive online surveys, including 1058 and 675 individuals respectively, were conducted. Using two question types, the grade expressiveness of each picture was assessed. In total, 24 pictures and 6 control pictures met our criteria for sufficient strength and consistency with the appropriate description. Both measures are correlated with each other in all pictures illustrating interpersonal behavior, but not in the control pictures. Relations to other stimulus types and the applicability of the new picture system in functional neuroimaging methods are discussed. It is concluded that the new system will be helpful in studying the profound effect of relational change in psychotherapy.