Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia

Horne, Charlotte Mary; Vanes, Lucy; Verneuil, Tess; Mouchlianitis, Elias; Szentgyorgyi, Timea; Averbeck, Bruno B.; Leech, Robert; Moran, Rosalyn J.; Shergill, Sukhwinder S.

doi:10.1016/j.nicl.2021.102631

Cited by 19 publications

(28 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, a reported significant alteration in cognitive flexibility in TRS is believed to tap into a distinct underlying neurobiological mechanism and may inform future treatment strategies (e.g. glutamatergic targets and giving clozapine earlier in resistant patients) (Horne et al, 2021). Our findings suggest that language-related tasks, and potentially verbal memory and learning tasks, have likely applications in multidisciplinary strategies to elucidating the pathophysiology of TRS and to developing predictive models and personalised medical approaches.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

et al. 2021

View full text Add to dashboard Cite

Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…This suggested that while the RPE signal generation was intact in treatment-resistant patients, the cognitive control needed to overcome the emotional bias to make optimal predictions was impaired. We were then able to use dynamic causal modelling to demonstrate that while the treatment-responsive patients had increased top-down connectivity from ACC to sensory regions (fusiform gyrus and amygdala) and reduced connectivity from all regions into the striatum during this task, the treatment-resistant group did not show any enhanced top-down connectivity from the ACC ( Horne et al, 2021 ). This supported the proposition that increased cognitive control - indexed by enhanced top-down connectivity over incoming sensory information - may provide the striatum with contextual information to appropriately integrate with incoming sensory information in treatment responsive patients.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the absence of this top-down cognitive control may contribute to persistence of psychotic symptoms in the treatment-resistant patients. Moreover, top-down connectivity from ACC to sensory regions was inversely related to positive symptoms in the treatment-responsive group further suggesting that effective cognitive control may be important in controlling positive symptoms ( Horne et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The aim of the current study was therefore to understand whether poor top-down cognitive control functioning is a neural mechanism underlying high levels of positive symptoms in a larger sample of patients with early psychosis (<5 years duration) and healthy controls. We did this by splitting patients into high symptom (HS) and low symptom (LS) groups based on the positive symptom threshold for determining treatment resistance ( Conley & Kelly, 2001 ), comparable to our previous study ( Horne et al, 2021 ). We investigated fMRI activation during the same reward learning task used in our earlier paper ( Horne et al, 2021 ) but focused on two conditions with varied levels of cognitive demand: a ‘neutral’ condition (low demand) and an ‘emotional’ condition (high demand).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of cognitive control in the positive symptoms of psychosis

Horne

Sahni

Pang

et al. 2022

NeuroImage: Clinical

Self Cite

View full text Add to dashboard Cite

“…It is important to note that our findings were observed in the real-world context of TRS that included failed antipsychotic trials and concomitant use of non-CLZ, D2 receptor-blocking antipsychotic drugs. TRS may represent a pathophysiologic subtype of schizophrenia characterized by more global disruptions in functional connectivity and a unique pattern of activation of cognitive systems (Ganella et al 2017 ; Horne et al 2021 ). Furthermore, evidence from positron emission tomography studies implicate a non-DA signature of illness, relative to responders of non-CLZ antipsychotic drugs (Demjaha et al 2012 ; Kim et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment‑resistant schizophrenia

et al. 2022

View full text Add to dashboard Cite

Rationale Though numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ’s efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ’s unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning. Objective In a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2’), which demonstrates utility as a proxy measure for elements of DA functioning. Methods Participants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2’ in relation to CLZ response (% reduction of psychotic symptoms). Results We first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network ( P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2’ across CLZ treatment. Conclusion Overall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-022-06138-0.

show abstract

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia

Cited by 19 publications

References 43 publications

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

The role of cognitive control in the positive symptoms of psychosis

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment‑resistant schizophrenia

Contact Info

Product

Resources

About