In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations
Abstract Treatment-resistant schizophrenia (TRS) affects approximately one-third of individuals with schizophrenia, posing significant challenges for clinical management. Clozapine treatment is often delayed, underscoring the urgent need for an early potential signature of TRS. To date, specific alt...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Schizophrenia |
| Online Access: | https://doi.org/10.1038/s41537-025-00634-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849329521774297088 |
|---|---|
| author | Annarita Barone Gianmaria Senerchia Giuseppe De Simone Marco Manzo Mariateresa Ciccarelli Stefano Tozza Valentina Virginia Iuzzolino Myriam Spisto Raffaele Dubbioso Felice Iasevoli Rosa Iodice Andrea de Bartolomeis |
| author_facet | Annarita Barone Gianmaria Senerchia Giuseppe De Simone Marco Manzo Mariateresa Ciccarelli Stefano Tozza Valentina Virginia Iuzzolino Myriam Spisto Raffaele Dubbioso Felice Iasevoli Rosa Iodice Andrea de Bartolomeis |
| author_sort | Annarita Barone |
| collection | DOAJ |
| description | Abstract Treatment-resistant schizophrenia (TRS) affects approximately one-third of individuals with schizophrenia, posing significant challenges for clinical management. Clozapine treatment is often delayed, underscoring the urgent need for an early potential signature of TRS. To date, specific alterations in cortical excitability and plasticity underlying TRS remain unexplored. We evaluated cortical excitability and plasticity in 30 patients with schizophrenia (15 TRS, 15 non-TRS) and 21 controls using transcranial magnetic stimulation (TMS). Measures included motor thresholds and protocols probing GABAergic inhibition and glutamatergic facilitatory activity, the excitation index (EI) in the primary motor cortex (M1), and long-term potentiation (LTP)-like plasticity using intermittent theta burst stimulation (iTBS). Clinical severity and cognitive performance were evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS). TRS patients exhibited significantly higher active motor thresholds (p = 0.015) and impaired short-interval intracortical inhibition (SICI) (p = 0.001) vs healthy controls, reflecting GABAergic dysfunction. EI was elevated in TRS vs non-TRS patients (p = 0.034) and controls (p = 0.002), indicating pronounced cortical hyperexcitability. Both TRS (p = 0.008) and non-TRS patients (p = 0.033) showed reduced plasticity following iTBS compared to controls, with no TRS vs non-TRS difference. SICI deficits significantly correlated with negative (r = 0.524, p adj = 0.03) and autistic (r = 0.517, p adj = 0.03) symptom severity as assessed by the PANSS negative score and Positive and Negative Syndrome Scale Autism Severity Score (PAUSS). Our findings point to a neurophysiological continuum in schizophrenia, with TRS patients demonstrating the most pronounced cortical hyperexcitability and impaired plasticity, and non-TRS patients showing intermediate deficits. |
| format | Article |
| id | doaj-art-07ff23483c4740d7b7d3fb37d1d3030c |
| institution | Kabale University |
| issn | 2754-6993 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Schizophrenia |
| spelling | doaj-art-07ff23483c4740d7b7d3fb37d1d3030c2025-08-20T03:47:14ZengNature PortfolioSchizophrenia2754-69932025-06-0111111010.1038/s41537-025-00634-wIn vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluationsAnnarita Barone0Gianmaria Senerchia1Giuseppe De Simone2Marco Manzo3Mariateresa Ciccarelli4Stefano Tozza5Valentina Virginia Iuzzolino6Myriam Spisto7Raffaele Dubbioso8Felice Iasevoli9Rosa Iodice10Andrea de Bartolomeis11Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Neurology Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Section of Psychiatry, Laboratory of Molecular and Translational Psychiatry, Unit of Treatment-Resistant Psychiatric Disorders, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples “Federico II”Abstract Treatment-resistant schizophrenia (TRS) affects approximately one-third of individuals with schizophrenia, posing significant challenges for clinical management. Clozapine treatment is often delayed, underscoring the urgent need for an early potential signature of TRS. To date, specific alterations in cortical excitability and plasticity underlying TRS remain unexplored. We evaluated cortical excitability and plasticity in 30 patients with schizophrenia (15 TRS, 15 non-TRS) and 21 controls using transcranial magnetic stimulation (TMS). Measures included motor thresholds and protocols probing GABAergic inhibition and glutamatergic facilitatory activity, the excitation index (EI) in the primary motor cortex (M1), and long-term potentiation (LTP)-like plasticity using intermittent theta burst stimulation (iTBS). Clinical severity and cognitive performance were evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS). TRS patients exhibited significantly higher active motor thresholds (p = 0.015) and impaired short-interval intracortical inhibition (SICI) (p = 0.001) vs healthy controls, reflecting GABAergic dysfunction. EI was elevated in TRS vs non-TRS patients (p = 0.034) and controls (p = 0.002), indicating pronounced cortical hyperexcitability. Both TRS (p = 0.008) and non-TRS patients (p = 0.033) showed reduced plasticity following iTBS compared to controls, with no TRS vs non-TRS difference. SICI deficits significantly correlated with negative (r = 0.524, p adj = 0.03) and autistic (r = 0.517, p adj = 0.03) symptom severity as assessed by the PANSS negative score and Positive and Negative Syndrome Scale Autism Severity Score (PAUSS). Our findings point to a neurophysiological continuum in schizophrenia, with TRS patients demonstrating the most pronounced cortical hyperexcitability and impaired plasticity, and non-TRS patients showing intermediate deficits.https://doi.org/10.1038/s41537-025-00634-w |
| spellingShingle | Annarita Barone Gianmaria Senerchia Giuseppe De Simone Marco Manzo Mariateresa Ciccarelli Stefano Tozza Valentina Virginia Iuzzolino Myriam Spisto Raffaele Dubbioso Felice Iasevoli Rosa Iodice Andrea de Bartolomeis In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations Schizophrenia |
| title | In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations |
| title_full | In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations |
| title_fullStr | In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations |
| title_full_unstemmed | In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations |
| title_short | In vivo assessment of GABAergic inhibition and glutamate facilitation in treatment-resistant schizophrenia: a TMS study integrating clinical, cognitive, and neurophysiological evaluations |
| title_sort | in vivo assessment of gabaergic inhibition and glutamate facilitation in treatment resistant schizophrenia a tms study integrating clinical cognitive and neurophysiological evaluations |
| url | https://doi.org/10.1038/s41537-025-00634-w |
| work_keys_str_mv | AT annaritabarone invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT gianmariasenerchia invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT giuseppedesimone invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT marcomanzo invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT mariateresaciccarelli invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT stefanotozza invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT valentinavirginiaiuzzolino invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT myriamspisto invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT raffaeledubbioso invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT feliceiasevoli invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT rosaiodice invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations AT andreadebartolomeis invivoassessmentofgabaergicinhibitionandglutamatefacilitationintreatmentresistantschizophreniaatmsstudyintegratingclinicalcognitiveandneurophysiologicalevaluations |