S-Ketamine-Induced NMDA Receptor Blockade during Natural Speech Production and Its Implications for Formal Thought Disorder in Schizophrenia: A Pharmaco-fMRI Study.

Structural and functional changes in the lateral temporal language areas have been related to formal thought disorder (FTD) in schizophrenia. Continuous, natural speech production activates the right lateral temporal lobe in schizophrenia, as opposed to the left in healthy subjects. Positive and negative FTD can be elicited in healthy subjects by glutamatergic NMDA blockade with ketamine. It is unclear whether the glutamate system is related to the reversed hemispheric lateralization during speaking in patients. In a double-blind, crossover, placebo-controlled study, 15 healthy, male, right-handed volunteers overtly described 7 pictures for 3 min each while BOLD signal changes were acquired with fMRI. As a measure of linguistic demand, the number of words within 20 s epochs was correlated with BOLD responses. Participants developed S-ketamine-induced psychotic symptoms, particularly positive FTD. Ketamine vs placebo was associated with enhanced neural responses in the right middle and inferior temporal gyri. Similar to a previous fMRI study in schizophrenia patients vs healthy controls applying the same design, S-ketamine reversed functional lateralization during speech production in healthy subjects. Results demonstrate an association between glutamatergic imbalance, dysactivations in lateral temporal brain areas, and FTD symptom formation.

Neural integration of speech and gesture in schizophrenia: evidence for differential processing of metaphoric gestures.

Gestures are an important component of interpersonal communication. Especially, complex multimodal communication is assumed to be disrupted in patients with schizophrenia. In healthy subjects, differential neural integration processes for gestures in the context of concrete [iconic (IC) gestures] and abstract sentence contents [metaphoric (MP) gestures] had been demonstrated. With this study we wanted to investigate neural integration processes for both gesture types in patients with schizophrenia. During functional magnetic resonance imaging-data acquisition, 16 patients with schizophrenia (P) and a healthy control group (C) were shown videos of an actor performing IC and MP gestures and associated sentences. An isolated gesture (G) and isolated sentence condition (S) were included to separate unimodal from bimodal effects at the neural level. During IC conditions (IC > G ∩ IC > S) we found increased activity in the left posterior middle temporal gyrus (pMTG) in both groups. Whereas in the control group the left pMTG and the inferior frontal gyrus (IFG) were activated for the MP conditions (MP > G ∩ MP > S), no significant activation was found for the identical contrast in patients. The interaction of group (P/C) and gesture condition (MP/IC) revealed activation in the bilateral hippocampus, the left middle/superior temporal and IFG. Activation of the pMTG for the IC condition in both groups indicates intact neural integration of IC gestures in schizophrenia. However, failure to activate the left pMTG and IFG for MP co-verbal gestures suggests a disturbed integration of gestures embedded in an abstract sentence context. This study provides new insight into the neural integration of co-verbal gestures in patients with schizophrenia.

Effects of ketamine-induced psychopathological symptoms on continuous overt rhyme fluency.

The N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. Administered to healthy individuals, a subanesthetic dose of the noncompetitive NMDAR antagonist ketamine reproduces several psychopathological symptoms commonly observed in patients with schizophrenia. In a counterbalanced, placebo-controlled, double-blind, within-participants study, fifteen healthy subjects were administered a continuous subanesthetic S-ketamine infusion while cortical activation was measured using functional magnetic resonance imaging. While being scanned, subjects performed an overt word generation task. Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine administration elicited effects on psychopathology, including difficulties in abstract thinking, lack of spontaneity and flow of conversation as well as formal thought disorder. On a behavioral level, verbal fluency performance was unaffected. The PANSS score for formal thought disorder positively correlated with activation measures encompassing the left superior temporal gyrus, the right middle and inferior frontal gyrus and the precuneus. Difficulty in abstract thinking was correlated with pronounced activations in prefrontal as well as in anterior cingulate regions, whereas hyperactivations in the left superior temporal gyrus were found in association with a lack of spontaneity and flow of conversation. In the absence of behavioral impairments during verbal fluency, NMDAR blocking evoked psychopathological symptoms and cortical activations in regions previously reported in schizophrenia patients. The results provide further support for the hypothesis of an NMDAR dysfunction in the pathophysiology of schizophrenia.

Neural correlates of rhyming vs. lexical and semantic fluency.

Rhyming words, as in songs or poems, is a universal feature of human language across all ages. In the present fMRI study a novel overt rhyming task was applied to determine the neural correlates of rhyme production. Fifteen right-handed healthy male volunteers participated in this verbal fluency study. Participants were instructed to overtly articulate as many words as possible either to a given initial letter (LVF) or to a semantic category (SVF). During the rhyming verbal fluency task (RVF), participants had to generate words that rhymed with pseudoword stimuli. On-line overt verbal responses were audiotaped in order to correct the imaging results for the number of generated words. Fewer words were generated in the rhyming compared to both the lexical and the semantic condition. On a neural level, all language tasks activated a language network encompassing the left inferior frontal gyrus, the middle and superior temporal gyri as well as the contralateral right cerebellum. Rhyming verbal fluency compared to both lexical and semantic verbal fluency demonstrated significantly stronger activation of left inferior parietal region. Generating novel rhyme words seems to be mainly mediated by the left inferior parietal lobe, a region previously found to be associated with meta-phonological as well as sub-lexical linguistic processes.

Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency.

The glutamatergic N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction. In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency. Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia.