Association of intracortical inhibition with social cognition deficits in schizophrenia: Findings from a transcranial magnetic stimulation study
Introduction
Social cognition (SC) deficits not only contribute to functional disability in schizophrenia (Fett et al., 2011) but are also emerging as composite endophenotype markers of schizophrenia (Mehta et al., 2013). Pathophysiological mechanisms underlying these complex cognitive processes are poorly understood.
One hypothesized pathophysiological mechanism resulting in social information-processing deficits in schizophrenia is increased ratio of neocortical cellular excitation to inhibition (Yizhar et al., 2011)—increased activity in excitatory neurons or reduced activity in inhibitory neurons. Gamma aminobutyric acid (GABA) is a crucial inhibitory neurotransmitter in the brain. There is increasing evidence for abnormal GABA activity in schizophrenia as demonstrated by gene-expression (Akbarian et al., 1995), immuno-histopathological (Joshi et al., 2012), in vivo brain imaging (Rowland et al., 2013) and electrophysiological studies (Daskalakis et al., 2002). Neuropathological changes in schizophrenia have demonstrated reduced density of GABA interneurons in the superficial layers of the prefrontal cortex. This is accompanied by a significant increase in the number of these cells in the subcortical white matter (Benes, 2012). These probable migration defects may result from decreased expression of glutamic acid decarboxylase 67, a marker for the functional differentiation of GABA cells (Benes, 2011). However, the association between SC deficits and abnormal cortical-inhibition has not been explored.
GABA-mediated cortical-inhibition can be studied using short (SICI) and long interval intracortical-inhibition (LICI) transcranial magnetic stimulation (TMS) paradigms (Nakamura et al., 1997). Cortical inhibitory inter-neuronal circuits that employ GABAA receptors are thought to mediate SICI (Ziemann et al., 1996, Di Lazzaro et al., 2006). LICI is thought to represent cortical-inhibition due to GABAB receptor-mediated inhibitory postsynaptic potentials (Wasserman, 2008). In SICI, a subthreshold conditioning pulse delivered about 1–5 milliseconds prior to the suprathreshold test pulse, activates cortical GABA-ergic interneurons. This results in an attenuation of the motor evoked potential (MEP) produced by the activation of the cortical pyramidal neurons with the suprathreshold test stimulus (Kujirai et al., 1993). In contrast, in the LICI paradigm, a supra-threshold conditioning stimulus inhibits the MEP response to the test stimulus (conditioned MEP) (Valls-Sole et al., 1992). A recent meta-analysis reported that schizophrenia patients have reduced SICI compared to healthy subjects (Radhu et al., 2013). However, it should be noted that deficits in SICI are not restricted to patients with schizophrenia. They have been, in fact, demonstrated in patients with OCD and Tourette Syndrome (Bunse et al., 2014) as well.
In this paper, we report an analysis of the relationship between cortical-inhibition (SICI & LICI) and SC abilities in antipsychotic-naïve & medicated schizophrenia patients, and healthy comparison subjects.
Section snippets
Methods
Data for this analysis were obtained from 54 right-handed (Oldfield, 1971) schizophrenia patients (33 antipsychotic-naïve and 21 prescribed medications) and 45 right-handed healthy comparison subjects, recruited for a study exploring the neurobiology of SC deficits in schizophrenia (Mehta et al., in press). Patients were diagnosed independently by two qualified psychiatrists according to DSM IV criteria, and confirmed using the Mini-International Neuropsychiatric Interview (Sheehan et al., 1998
Demographic, clinical and cognitive variables
As summarized in an earlier paper (Mehta et al., in press) the three groups were matched for age, gender and education. Patients in the medicated group were on atypical antipsychotics with median duration of treatment with anti-psychotics being 60 days and mean chlorpromazine equivalents of 413.43 ± 226.95 mg/day (Woods, 2003). Patients demonstrated significant deficits across all SC domains when compared to healthy comparison subjects. Post-hoc analysis (Tukey's test) revealed better ToM and
Discussion
Antipsychotic-naïve schizophrenia patients had reduced cortical-inhibition as measured using SICI. Further, in this group, SICI had a significant inverse association with ability to process emotions from facial cues and overall social cognition ability. However, there was no association between LICI and any of the SC measures.
Our results suggest that poor cortical-inhibition, mediated by GABAA-receptor neurotransmission (SICI), is associated with SC deficits in antipsychotic-naïve
Role of funding source
The Department of Biotechnology, Government of India, had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
UMM wrote the study protocol, recruited the patients/healthy subjects, trained RB in social cognition test administration, conducted the TMS experiment and analysis, and prepared the manuscript. JT conceptualized the research question, supervised protocol/manuscript writing, conduct of the experiment and guided UMM in manuscript writing. RB performed symptom and SC assessments and assisted in participant recruitment and the TMS experiment. BNG contributed in interpreting the statistical
Conflict of Interest
All authors declare that they have no conflicts of interest.
Acknowledgments
We acknowledge grant support to Dr. Mehta from the Department of Biotechnology, Ministry of Science & Technology, Government of India, (Grant number BT/PR14311/Med/30/470/2010) for funding this study.
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2018, Psychiatry ResearchCitation Excerpt :The first subthreshold conditioning stimulus (CS) was at the intensity of 80% RMT and the intensity of the second, testing stimulus (TS) was suprathreshold (120% RMT), which have been reported for SICI and/or ICF (Garry and Thomson, 2009; Kujirai et al., 1993; Maeda et al., 2002; Orth et al., 2003). Many other studies set the intensity of TS to 1 mV (e.g., Fitzgerald et al., 2002; Mehta et al., 2014; Eichhammer et al., 2004) and our TS evoked MEP did not differ from 1 mV in both schizophrenia patients (all p > 0.05) and healthy individuals (all p > 0.05). Typically, SICI protocols include 1 and 3 ms ISIs to induce inhibition (Fisher et al., 2002; Roshan et al., 2003; Vucic et al., 2009), while ICF protocols are more variable although 9 to 15 ms ISIs can typically elicit facilitation (e.g., Saisanen et al., 2011; Wobrock et al., 2008).
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2016, CortexCitation Excerpt :Another animal study failed to find any evidence of impaired attention after reducing cortical GABA synthesis (Asinof & Paine, 2013). In humans, reduced GABAergic inhibition (measured with SICI) has also been linked to impaired working memory (Takahashi et al., 2013) and with emotional and social deficits in schizophrenia (Mehta et al., 2014). Further study of the behavioural correlates of GABA dysfunction along with the molecular and cellular mechanisms mediating SICI is warranted.
- 1
Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), BANGALORE-560029, India. Tel.: + 91 80 26995350; fax: + 91 80 26564830/26562121.
- 2
Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), BANGALORE-560029, India. Tel.: + 91 80 26995320; fax: + 91 80 26564830/26562121.
- 3
Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), BANGALORE-560029, India. Tel.: + 91 80 26995261; fax: + 91 80 26564830/26562121.