Formal Thought Disorder In Schizophrenia Research Articles

Clinical and neuroimaging aspects of formal thought disorder in schizophrenia: a brief narrative review

Aim. To analyze current sources regarding the clinical and neuroimaging aspects of formal thought disorder (FTD) in patients with schizophrenia to create an up-to-date pathogenetic model of its main forms. Materials and methods. English-language publications in the Medline database (PubMed) were analyzed for this review. We analyzed only structural magnetic resonance imaging (MRI) studies in which a clear clinical assessment of FTD in schizophrenia is provided and the neuroimaging protocol meets generally accepted standards (as in the ENIGMA Schizophrenia Working Group). For the clinical division of FTD, positive and negative FTD were distinguished according to the positive and negative syndrome scale (PANSS). Results. From a clinical point of view, FTD includes at least 30 phenomena. For clinical and neuroimaging studies, division into positive and negative FTD is used according to the PANSS. Positive FTD is manifested by the disorganization of thinking processes and exhibits mainly in violations of its purposeful sequence. Negative FTD is manifested by violations of the abstract-symbolic way of thinking, lack of spontaneity, and stereotyping. According to morphometric MRI data, atrophic changes in brain regions related to neuronal networks of cognition and impulse control (prefrontal and anterior cingulate cortex), emotional processing (amygdala), abstract thinking, and imagination (lateral occipital cortex) are important for the development of both forms of FTD. Negative FTD is mainly associated with damage to the prefronto-cingulate circles, which are the anatomical and functional substrates of executive functions. A unique feature of positive FTD is atrophy of the structures of the left temporal lobe, which leads to language disorders at the semantic level. Using the method of virtual histology, it was established that both forms of FTD are associated with bilateral changes in astrocytes and dendritic spines in the involved anatomical regions. A positive FTD is also associated with pathological changes in microglia in two hemispheres, while with a negative FTD, microglial damages are present only in the right hemisphere. Conclusions. Positive FTD in schizophrenia is mainly associated with atrophic (astroglial-microglial) processes of cognitive control networks, negative – with the atrophy of networks of semantic processing of verbal information. In both forms, networks of emotional processing, abstract thinking, and imagination are involved. Treatment strategies for FTD should include effects on astroglial and microglial dysfunction.

Linguistic Creativity and Formal Thought Disorder in Schizophrenia

Linguistic Creativity and Formal Thought Disorder in Schizophrenia

Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Brain Structural Network Connectivity of Formal Thought Disorder Dimensions in Affective and Psychotic Disorders

BackgroundThe psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders. MethodsUsing FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology. ResultsThree psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ. ConclusionsWe demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research.

Neurobiological substrates of the positive formal thought disorder in schizophrenia revealed by seed connectome-based predictive modeling

Formal thought disorder (FTD) is a core symptom cluster of schizophrenia, but its neurobiological substrates remain poorly understood. Here we collected resting-state fMRI data from 276 subjects at seven sites and employed machine-learning to investigate the neurobiological correlates of FTD along positive and negative symptom dimensions in schizophrenia. Three a priori, meta-analytically defined FTD-related brain regions were used as seeds to generate whole-brain resting-state functional connectivity (rsFC) maps, which were then compared between schizophrenia patients and controls. A repeated cross-validation procedure was realized within the patient group to identify clusters whose rsFC patterns to the seeds were repeatedly observed as significantly associated with specific FTD dimensions. These repeatedly identified clusters (i.e., robust clusters) were functionally characterized and the rsFC patterns were used for predictive modeling to investigate predictive capacities for individual FTD dimensional-scores. Compared with controls, differential rsFC was found in patients in fronto-temporo-thalamic regions. Our cross-validation procedure revealed significant clusters only when assessing the seed-to-whole-brain rsFC patterns associated with positive-FTD. RsFC patterns of three fronto-temporal clusters, associated with higher-order cognitive processes (e.g., executive functions), specifically predicted individual positive-FTD scores (p = 0.005), but not other positive symptoms, and the PANSS general psychopathology subscale (p > 0.05). The prediction of positive-FTD was moreover generalized to an independent dataset (p = 0.013). Our study has identified neurobiological correlates of positive FTD in schizophrenia in a network associated with higher-order cognitive functions, suggesting a dysexecutive contribution to FTD in schizophrenia. We regard our findings as robust, as they allow a prediction of individual-level symptom severity.

Brain functional correlates of formal thought disorder in schizophrenia: examining the frontal/dysexecutive hypothesis.

One hypothesis proposed to underlie formal thought disorder (FTD), the incoherent speech is seen in some patients with schizophrenia, is that it reflects impairment in frontal/executive function. While this proposal has received support in neuropsychological studies, it has been relatively little tested using functional imaging. This study aimed to examine brain activations associated with FTD, and its two main factor-analytically derived subsyndromes, during the performance of a working memory task. Seventy patients with schizophrenia showing a full range of FTD scores and 70 matched healthy controls underwent fMRI during the performance of the 2-back version of the n-back task. Whole-brain corrected, voxel-based correlations with FTD scores were examined in the patient group. During 2-back performance the patients showed clusters of significant inverse correlation with FTD scores in the inferior frontal cortex and dorsolateral prefrontal cortex bilaterally, the left temporal cortex and subcortically in the basal ganglia and thalamus. Further analysis revealed that these correlations reflected an association only with 'alogia' (poverty of speech, poverty of content of speech and perseveration) and not with the 'fluent disorganization' component of FTD. This study provides functional imaging support for the view that FTD in schizophrenia may involve impaired executive/frontal function. However, the relationship appears to be exclusively with alogia and not with the variables contributing to fluent disorganization.

Cortical thickness and formal thought disorder in schizophrenia: An ultra high-field network-based morphometry study

BackgroundPersistent formal thought disorder (FTD) is a core feature of schizophrenia. Recent cognitive and neuroimaging studies indicate a distinct mechanistic pathway underlying the persistent positive FTD (pFTD or disorganized thinking), though its structural determinants are still elusive. Using network-based cortical thickness estimates from ultra-high field 7-Tesla Magnetic Resonance Imaging (7T MRI), we investigated the structural correlates of pFTD. MethodsWe obtained speech samples and 7T MRI anatomical scans from medicated clinically stable patients with schizophrenia (n = 19) and healthy controls (n = 20). Network-based morphometry was used to estimate the mean cortical thickness of 17 functional networks covering the entire cortical surface from each subject. We also quantified the vertexwise variability of thickness within each network to quantify the spatial coherence of the 17 networks, estimated patients vs. controls differences, and related the thickness of the affected networks to the severity of pFTD. ResultsPatients had reduced thickness of the frontoparietal and default mode networks, and reduced spatial coherence affecting the salience and the frontoparietal control network. A higher burden of positive FTD related to reduced frontoparietal thickness and reduced spatial coherence of the salience network. The presence of positive FTD, but not its severity, related to the reduced thickness of the language network comprising of the superior temporal cortex. ConclusionsThese results suggest that cortical thickness of both cognitive control and language networks underlie the positive FTD in schizophrenia. The structural integrity of cognitive control networks is a critical determinant of the expressed severity of persistent FTD in schizophrenia.

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.

SU28. Investigating Language and Neurocognition as Mechanisms of Formal Thought Disorder in Schizophrenia

SU28. Investigating Language and Neurocognition as Mechanisms of Formal Thought Disorder in Schizophrenia

Electrophysiological examination of Formal Thought Disorder in schizophrenia

Quantitave EEG profile was recorded for 60 age and sex matched drug free/naive schizophrenia patients, divided into two groups based on the presence and absence of Formal Thought Disorder (FTD) and a group of 30 matched healthy participants. Coherence and power spectrum analysis revealed that as compared to normal controls, schizophrenia patients with FTD had decreased regional power and intra hemispheric coherence; those without FTD had increased regional power and increased intra hemispheric coherence. Inter hemispheric coherence was greater in schizophrenia patients with FTD and lesser in those without FTD, as compared to healthy participants. The data were interpreted in terms of neural dis-connection which in FTD can be attributed to the existence of both a deficit and excess of neural connections, which compensate each other.

PKNOX2 is Associated with Formal Thought Disorder in Schizophrenia: a Meta-Analysis of Two Genome-wide Association Studies

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p < 10(-4). The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10(-7)) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10(-5)) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10(-5)) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10(-5)). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia.

Two new scales of formal thought disorder in schizophrenia

Information provided by patients and respective carers may help to understand formal thought disorder (FTD) in schizophrenia. Two scales, one for patients (FTD-patient) and one for carers (FTD-carer), were constructed to assess pragmatics, cognitive, paralinguistic, and non-verbal aspects of communication. In the first scale the patients themselves assess their verbal communication; in the second scale the carer assesses the speech of the respective patient. Both scales exhibited internal reliability and evidence of good test–retest reliability. Higher total scores on both scales (FTD-patient and FTD-carer) were significantly associated with positive FTD, but not with negative FTD. Principal component analysis of the scales yielded a multidimensional structure. It is suggested that FTD in schizophrenia may be associated with a range of deficits (e.g. pragmatics, lexical activation, working memory, sustained attention). These scales, in conjunction with the clinician's assessment, can provide a more comprehensive picture of FTD in schizophrenia, revealing its dimensions and making it possible to establish associations between symptoms of FTD and neuropsychological, neurophysiologic, and neuroimaging data. In addition, they provide service users' and carers' perspectives for the assessment of communication in schizophrenia.

Abnormal Object Recall and Anterior Cingulate Overactivation Correlate with Formal Thought Disorder in Schizophrenia

The neural basis of formal thought disorder (FTD) is unknown. An influential theory is that FTD results from impaired semantic memory processing. We explored the neural correlates of semantic memory retrieval in schizophrenia using an imaging task assessing semantic object recall. Sixteen healthy control subjects and sixteen schizophrenia patients whose FTD symptoms were measured with the Thought Disorder Index completed a verbal object-recall task during functional magnetic resonance imaging. Participants viewed two words describing object features that either evoked (object recall) or did not evoke a semantic concept. Schizophrenia patients tended to overrecall objects for feature pairs that did not describe the same object. Functionally, rostral anterior cingulate cortex (ACC) activation in patients positively correlated with FTD severity during both correct recalled and overrecalled trials. Compared with control subjects, during object recalling, patients overactivated bilateral ACC, temporooccipital junctions, temporal poles and parahippocampi, right inferior frontal gyrus, and dorsolateral prefrontal cortex, but underactivated inferior parietal lobules. Our results support impaired semantic memory retrieval as underlying FTD pathophysiology. Schizophrenia patients showed abnormal activations of brain areas involved in semantic memory, verbal working memory, and initiation and suppression of conflicting responses, which were associated with semantic overrecall and FTD.

What happens to semantic memory when formal thought disorder remits? Revisiting a case study

Introduction. Laws, Kondel, and McKenna (1999) previously reported a case study analysis of a schizophrenic patient (TC) with severe formal thought disorder (FTD). Examining consistency across item and modality of input, Laws et al. documented an impairment of access to semantic knowledge in TC. Method. Following substantial improvement in his FTD, we readministered the same extensive battery of neuropsychological tests tapping semantic memory functioning.Results. Whilst TC's naming remained relatively good, it also became more consistent across both time and modality. Tasks tapping language comprehension and understanding of semantic association revealed some significant improvements. Nevertheless, TC showed a residual propensity to verify false information.Conclusion. Improvement in FTD in schizophrenia was accompanied by a better and more stable semantic memory performance in TC. The findings are consistent with, and expand upon the original suggestion that thought disorder reflects disorganised access to semantic memory.

Neural correlates of formal thought disorder in schizophrenia: preliminary findings from a functional magnetic resonance imaging study.

Formal thought disorder (FTD) is a core symptom of schizophrenia, but its pathophysiology is little understood. We examined the neural correlates of FTD using functional magnetic resonance imaging. Blood oxygenation level-dependent contrast was measured using functional magnetic resonance imaging while 6 patients with schizophrenia and 6 control subjects spoke about 7 Rorschach inkblots for 3 minutes each. In patients, varying degrees of thought-disordered speech were elicited during each "run." In a within-subject design, the severity of positive FTD was correlated with the level of blood oxygenation level-dependent contrast in the 2 runs that showed the highest variance of FTD in each patient. The severity of positive FTD in patients was negatively correlated (P<.001) with signal changes in the left superior and middle temporal gyri. Positive correlations were evident in the cerebellar vermis, the right caudate body, and the precentral gyrus. The severity of positive FTD was inversely correlated with the level of activity in the Wernicke area, a region implicated in the production of coherent speech. Reduced activity in this area might contribute to the articulation of incoherent speech. Because of the small sample size, these findings should be considered preliminary.

Associating Semantic Space Abnormalities With Formal Thought Disorder in Schizophrenia: Use of Triadic Comparisons

Recent studies of schizophrenia have suggested that thought disorder results from abnormalities in semantic processing. In the following pilot study, the cognitive system used for organizing and associating concepts was examined using a triadic comparison task. The semantic maps of schizophrenia patients with high thought disorder (N5) were compared to that of schizophrenia patients with low levels of thought disorder (N5) and normal controls (N10) with multidimensional scaling analysis. At initial testing and at retest, patients with high levels of thought disorder exhibited consistently lower semantic goodness of fit scores and failed to map results of triadic comparisons along well-defined dimensions. Results suggest that thought disorder in schizophrenia is related to a disturbance in the organization of semantic networks.