Reducing inhibition: A promising new strategy for the treatment of schizophrenia

Page, Carey P.; Coutellier, Laurence

doi:10.1016/j.ebiom.2018.07.043

Cited by 10 publications

(5 citation statements)

References 9 publications

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“…Locomotor hyperactivity in rodents model positive symptoms. Notwithstanding aiming to treat psychosis, this compound corroborates the potential benefits of allosteric modulators binding to GABA-A receptors [376,377]. Other selective compounds did not prove to be successful due to side effects [368].…”

Section: Gabaergic Systemmentioning

confidence: 53%

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

Bittner¹,

Barnes-Scheufler²,

Hettwer³

et al. 2021

Preprint

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Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

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Section: Gabaergic Systemmentioning

confidence: 53%

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

Bittner¹,

Barnes-Scheufler²,

Hettwer³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Specifically, reduced inhibition of excitatory pyramidal cells can cause widespread disturbances in the E/I balance (Gonzalez-Burgos, Cho, & Lewis, 2015). The bottom-up attentional bias toward salient distractors observed in our paradigm is indicative of reduced inhibition in schizophrenia, implicating GABA-A receptors as potential targets for future pro-cognitive pharmacological interventions (Page & Coutellier, 2018).…”

Section: Discussionmentioning

confidence: 68%

External cues improve visual working memory encoding in the presence of salient distractors in schizophrenia

Barnes-Scheufler,

Rösler,

Schaum

et al. 2024

Psychol. Med.

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Background People with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top–down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ encode more information in the presence of salient distractors. Methods We employed a visuospatial change-detection task using four Gabor patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two Gabor patches flickered which were designated either as targets or distractors and either a predictive or a non-predictive cue was displayed to manipulate top–down attention, resulting in four conditions. Results We observed significant effects of group, salience and cue as well as significant interactions of salience by cue, group by salience and group by cue. Across all conditions, PSZ stored significantly less information in VWM than HCS. PSZ stored significantly less non-flickering than flickering information with a non-predictive cue. However, PSZ stored significantly more flickering and non-flickering information with a predictive cue. Conclusions Our findings indicate that control of attentional selection is impaired in schizophrenia. We demonstrate that additional top–down information significantly improves performance in PSZ. The observed deficit in attentional control suggests a disturbance of GABAergic inhibition in early visual areas. Moreover, our findings are indicative of a mechanism for enhancing attentional control in PSZ, which could be utilized by pro-cognitive interventions. Thus, the current paradigm is suitable to reveal both preserved and compromised cognitive component processes in schizophrenia.

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“…FGF21 has been found to regulate sweet and alcohol preference correlated with reductions in dopamine concentrations in the nucleus accumbens, which coordinates reward behavior [87]. Interestingly, excitation/inhibition (E/I) balance is disrupted in schizophrenia [84], also based on a 'phase zero' brain organoid study [88], which can affect the neurodevelopment of the prefrontal cortex [89] (and cerebellum [84]), leading to propensity for substance abuse [90] in adolescence. In the cerebellum, the only output from the cerebellar cortex is represented by the inhibitory GA-BAergic Purkinje cells [91], while CB1 receptors are mainly expressed in the presynaptic terminals of granule cell molecular layer interneurons and climbing fibers that synapse onto Purkinje cells.…”

Section: Hypothesis 2: Cannabis Use-related Dysrhythmia In the Cerebe...mentioning

confidence: 99%

Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop—Hypothesis and Theory in Cannabis Use Disorder

et al. 2022

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Background: Maladaptive neuroplasticity-related learned response in substance use disorder (SUD) can be ameliorated using noninvasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on a competing neurobehavioral decision systems model. The next objective was to develop the theory by conducting a computational simulation of NIBS of the cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD)-related dysfunctional “cue-reactivity”—a construct closely related to “craving”—that is a core symptom. Our third objective was to test the feasibility of a neuroimaging-guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) metrics of sensorimotor gating. Therefore, we conducted a computational simulation of NIBS, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) of the cerebellar cortex and deep cerebellar nuclei (DCN) of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging-guided NIBS approach for the cerebellar lobule (VII) and prefrontal cortex based on a healthy human study. Results: Simulation of cerebellar tDCS induced gamma oscillations in the cerebral cortex, while transcranial temporal interference stimulation induced a gamma-to-beta frequency shift. A preliminary healthy human study (N = 10) found that 2 mA cerebellar tDCS evoked similar oxyhemoglobin (HbO) response in the range of 5 × 10−6 M across the cerebellum and PFC brain regions (α = 0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO-driven phase–amplitude-coupled (PAC; 4 Hz, ±2 mA (max)) cerebellar tACS evoked HbO levels in the range of 10−7 M that were statistically different (α = 0.01) across these brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC and closed-loop fNIRS-driven ctACS at 4 Hz, which may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging for closed-loop NIBS during operant conditioning.

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Reducing inhibition: A promising new strategy for the treatment of schizophrenia

Cited by 10 publications

References 9 publications

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

External cues improve visual working memory encoding in the presence of salient distractors in schizophrenia

Portable Neuroimaging-Guided Noninvasive Brain Stimulation of the Cortico-Cerebello-Thalamo-Cortical Loop—Hypothesis and Theory in Cannabis Use Disorder

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