Understanding Schizophrenia as a Disorder of Consciousness: Biological Correlates and Translational Implications from Quantum Theory Perspectives

Ganesan Venkatasubramanian 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.1

From neurophenomenological perspectives, schizophrenia has been conceptualized as “a disorder with heterogeneous manifestations that can be integrally understood to involve fundamental perturbations in consciousness”. While these theoretical constructs based on consciousness facilitate understanding the ‘gestalt’ of schizophrenia, systematic research to unravel translational implications of these models is warranted. To address this, one needs to begin with exploration of plausible biological underpinnings of “perturbed consciousness” in schizophrenia. In this context, an attractive proposition to understand the biology of consciousness is “the orchestrated object reduction (Orch-OR) theory” which invokes quantum processes in the microtubules of neurons. The Orch-OR model is particularly important for understanding schizophrenia especially due to the shared ‘scaffold’ of microtubules. The initial sections of this review focus on the compelling evidence to support the view that “schizophrenia is a disorder of consciousness” through critical summary of the studies that have demonstrated self-abnormalities, aberrant time perception as well as dysfunctional intentional binding in this disorder. Subsequently, these findings are linked with ‘Orch-OR theory’ through the research evidence for aberrant neural oscillations as well as microtubule abnormalities observed in schizophrenia. Further sections emphasize the applicability and translational implications of Orch-OR theory in the context of schizophrenia and elucidate the relevance of quantum biology to understand the origins of this puzzling disorder as “fundamental disturbances in consciousness”.

A Longitudinal Study of Relation between Side-effects and Clinical Improvement in Schizophrenia: Is There a Neuro-metabolic Threshold for Second Generation Antipsychotics?

Ganesan Venkatasubramanian,Naren P. Rao,Rashmi Arasappa,Sunil V. Kalmady,Bangalore N. Gangadhar 대한정신약물학회 2013 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.11 No.1

Objective: Classical studies demonstrated Neuroleptic Induced Extrapyramidal Side-effects (NIES; Neuroleptic threshold) to correlate with the efficacy of first generation antipsychotics. Second generation antipsychotics (SGAs), in addition to the extrapyramidal side effects, are also associated with metabolic side effects. This prospective study on antipsychotic-naïve schizophrenia patients, for the first-time, examined concurrently the relationship between clinical improvement and these side-effects NIES and Neuroleptic Induced Metabolic Side-effects. Methods: Thirty six-antipsychotic-naïve schizophrenia (DSM-IV) patients were examined at baseline and after 5 weeks of treatment with antipsychotics. At baseline and follow-up, we recorded the body mass index (BMI) and assessed psychopathology using Scale for Assessment of Positive-symptoms (SAPS) and Scale for Assessment of Negative-symptoms (SANS), extrapyramidal symptoms using Simpson-Angus Extra Pyramidal Scale (SAEPS) and improvement using Clinical Global Impression Improvement (CGI). Results: After treatment, patients showed significant reduction in SAPS (baseline, 27.97±14.47; follow-up, 14.63±13.25; p<0.001)and SANS total scores (baseline, 63.77±28.96; follow-up, 49.30±28.77; p=0.001) and a significant increase in BMI (baseline,18.5±3.37; follow-up, 19.13±3.17; p<0.001). At follow-up CGI-Improvement score was (2.55±0.65) and SAEPS score was (0.8±1.32). CGI-Improvement score had a significant negative correlation with magnitude of increase in BMI (rs=-0.39; p=0.01)and SAEPS symptom score at follow-up (rs=-0.58; p<0.001). In addition, magnitude of increase in BMI showed positive correlation with the magnitude of reduction in SAPS total score (rs=0.33; p=0.04). Conclusion: The study findings suggest a possible relation between clinical improvement and antipsychotic-induced neuroleptic as well as metabolic side-effects in schizophrenia. Though the mechanism of this relation is yet to be elucidated, insulin signaling pathways and lipid homeostasis are potential mechanisms in addition to the established neurotransmitter hypothesis. Theoretically findings support the novel hypothetical construct of ‘Neuro-Metabolic threshold’ in the treatment of schizophrenia.

Neuroimmunological Aberrations and Cerebral Asymmetry Abnormalities in Schizophrenia: Select Perspectives on Pathogenesis

Ganesan Venkatasubramanian,Monojit Debnath 대한정신약물학회 2014 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.12 No.1

Within the wide-ranging gamut of factors that comprise gene-environment interactions postulated to underlie schizophrenia,the crosstalk between environmental factors and feto-maternal immune components has been put forth as one of the importantmechanisms that increase the risk towards schizophrenia in the offspring. Interestingly, immune factors have been shown tocritically modulate the brain development during the prenatal stages. Moreover the past many decades, influential theoreticalpropositions and evidence base (albeit not unequivocally) have compellingly linked prenatal sex hormonal status to criticallyprovoke long lasting immunological changes and subsequently affect developmental programming of cerebral asymmetry inschizophrenia. In this review, we summarize the select perspectives emphasizing the role of neuroimmunoendocrine pathwaysin anomalous cerebral asymmetry in contemporary understanding of schizophrenia pathogenesis.

A Primer on Interoception and its Importance in Psychiatry

Swarna Buddha Nayok(Swarna Buddha Nayok ),Vanteemar S. Sreeraj(Vanteemar S. Sreeraj ),Venkataram Shivakumar(Venkataram Shivakumar ),Ganesan Venkatasubramanian(Ganesan Venkatasubramanian ) 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.2

Interoception is the perception of signals from inside the body. It plays a significant role in the nervous, cardiovascular, respiratory, gastrointestinal, genitourinary, and endocrine systems. It is also closely related to the autonomic nervous system and inflammatory pathways and plays a significant role in our optimal functioning. Recently, interoception has gained more attention in neuropsychiatric research. Anatomical and physiological aspects of interoception like relevant brain areas, the role of the vagus nerve, and the autonomic nervous system are gradually being understood. Different facets of interoception like interoceptive attention, detection, magnitude, discrimination, accuracy, awareness, and appraisal have been proposed and their assessments and importance are being evaluated. Further, interoception is often dysregulated or abnormal in psychiatric disorders. It has been implicated in the psychopathology, etiopathogenesis, clinical features and treatment of mood, anxiety, psychotic, personality and addiction-related disorders. This narrative review attempts to provide a nuanced understanding of the pathway(s), components, functions, assessments, and problems of interoception and will help us to detect its disturbances and evaluate its impact on psychiatric disorders, leading to a better perspective and management. This will also advance interoception-related research.

Needs of Siblings of Persons with Psychosis: A Systematic Descriptive Review

Anekal C. Amaresha,Ganesan Venkatasubramanian,D. Muralidhar 대한정신약물학회 2014 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.12 No.2

Research on caregivers of psychosis has predominantly focused on parents and spouses. Issues related to siblings of personswith psychosis (SOPP) are yet to be evaluated comprehensively. Like parents and spouses, SOPP also share the caregiverburden and have their own issues and needs. This systematic descriptive review aims to identify the types of needs of SOPPin the published literature and gives implications for further practice and research. The primary data search was carried outwith predefined protocol in PubMed database and an additional hand search was done in EBSCOhost, ProQuest, Scopus, andPsychINFO. All the searches yielded a total of 862 titles. After screening for necessary inclusion criteria, seven studies wereincluded in the final review. The results are discussed under six major themes that emerged from this review. Six out of sevenstudies highlighted the need for information on siblings’ illness and participation in caregiver support group. Other importantneeds were illness management or rehabilitation needs; help in managing their own psychosocial issues; treatment related informationalneeds; and inclusion in treatment process. The socio-demographic details of these studies showed that majorityof the participants were female siblings of Caucasian or white British ethnicity and from developed countries. SOPP predominantlyhave specific needs such as informational and support group needs, which are different in the priority of other primary caregiverneeds. Paucity of literature from developing countries and the limitations of the existing studies warrant further systematicresearch.

Schizophrenia and Corollary Discharge: A Neuroscientific Overview and Translational Implications

Rujuta Parlikar,Anushree Bose,Ganesan Venkatasubramanian 대한정신약물학회 2019 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.17 No.2

Corollary discharge mechanism refers to the suppression of sensory consequences of self-generated actions; a process that serves to distinguish between self and non-self based on discrimination of origination of action. It explains, say for example, why we cannot tickle ourselves. This review discusses how corollary discharge model is an essential neural integration mechanism central to the motor functioning of animal kingdom. In this article, research conducted in the field of corollary discharge has been reviewed to understand the neuroanatomical and neurophysiological basis of corollary discharge and gain insight into the biochemical basis of its dysfunction. This review article also explores the role of corollary discharge and its dysfunction in the presentation of symptoms of schizophrenia, discussing the findings from corollary discharge studies on schizophrenia population. Lastly, the link between schizophrenia psychopathology and corollary discharge dysfunction has been highlighted, and an attempt has been made to establish a case for correction of corollary discharge deficit in schizophrenia through neuromodulation.

In Silico Model-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

Rimjhim Agrawal,Sunil Vasu Kalmady,Ganesan Venkatasubramanian 대한정신약물학회 2017 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.15 No.2

Objective: Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Methods: Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and -catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Results: Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. Conclusion: The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.

Transcranial Alternating Current Stimulation (tACS) and Its Role in Schizophrenia: A Scoping Review

Harsh Pathak,Vanteemar S Sreeraj,Ganesan Venkatasubramanian 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.4

Transcranial alternating current stimulation (tACS) may modulate neuronal oscillations by applying sinusoidal alternating current, thereby alleviating associated symptoms in schizophrenia. Considering its possible utility in schizophrenia, we reviewed the literature for tACS protocols administered in schizophrenia and their findings. A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline in databases and clinical trial registers. The search resulted in 59 publications. After excluding review articles unrelated to tACS, trials without published results or not involving patients with schizophrenia, 14 studies were included. Among the included studies/case reports only 5 were randomized controlled therapeutic trials. The studies investigated the utility of tACS for clinical and neurobiological outcomes. All studies reported good tolerability with only transient mild side effects. It was administered mostly during the working memory task (such as computerized n-back task, dual back task, and computerized digit symbol substitution task) for schizophrenia patients with cognitive deficits and during resting state while targeting positive symptoms. A possible reduction in hallucinations and delusions using alpha tACS, and improvement in negative and cognitive deficits with theta and gamma tACS were reported. Nevertheless, one of the randomized controlled trials targeting hallucinations was negative and rigorous large-sample studies are lacking for other domains. The current evidence for tACS in schizophrenia is preliminary though promising. In future, more sham controlled randomized trials assessing the effect of tACS on various domains are needed to substantiate these early findings.

Pars Triangularis Volume Asymmetry and Schneiderian First Rank Symptoms in Antipsychotic-naïve Schizophrenia

Venkataram Shivakumar,Vanteemar Sathyanarayana Sreeraj,Sunil Vasu Kalmady,Bangalore Nanjundaiah Gangadhar,Ganesan Venkatasubramanian 대한정신약물학회 2021 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.19 No.3

Objective: Schizophrenia is a disorder of language and self, with first-rank symptoms (FRS) as one of the predominant features in a subset of patients. Abnormal language lateralization is hypothesized to underlie the neurobiology of FRS in schizophrenia. The role of Broca’s area with its right-hemispheric counterpart, consisting of pars triangularis (PTr) and pars opercularis (POp) of the inferior frontal gyrus in FRS is undetermined. We compared the volumes and asymmetries of PTr & POp in anti-psychotic-naive schizophrenia patients with FRS (FRS[+]) with those without FRS (FRS[−]) and healthy-controls (HC) using three dimensional, interactive, semi-automated volumetric morphometry. Methods: Antipsychotic naïve FRS(+) (n = 27), FRS(−) (n = 24) and HC (n = 51) were carefully assessed with structured and semi-structured clinical tools. T1-weighted images were acquired in a 3T scanner. Volumes of regions of interest were measured independently for both sides using slicer-3D software, and asymmetry indices were calculated. Results: FRS(+) but not FRS(−) had a significant volume deficit in right PTr after controlling for the potential confounding effects of age, sex, and intracranial volume (p = 0.029). There was a significant leftward asymmetry of PTr in patients with FRS (i.e., leftward asymmetry in patients) (p = 0.026). No significant volume/asymmetry abnormalities were observed in POp. Conclusion: Study findings suggest reduced right PTr volume with leftward asymmetry to be associated with FRS in schizophrenia. This is consistent with the loss of Yakovlevian torque in schizophrenia. Role of PTr in the neurobiology of schizophrenia as a disorder of self, speech, and social cognition needs further systematic evaluation in future research.

Brain Functional Magnetic Resonance Imaging Cue-reactivity Can Predict Baclofen Response in Alcohol Use Disorders

Bharath Holla,Sheshachala Karthik,Jitendriya Biswal,Biju Viswanath,Deepak Jayarajan,Rose Dawn Bharath,Ganesan Venkatasubramanian,Vivek Benegal 대한정신약물학회 2018 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.16 No.3

Objective: Baclofen is a promising treatment for alcohol use disorders (AUD), although its clinical response in humans is mixed. The present study aimed at investigating the impact of baclofen treatment on cue-induced brain activation pattern and its relationship with relapse outcomes. Methods: Twenty-three inpatients with AUD underwent a functional magnetic resonance imaging cue-reactivity task before beginning medication with baclofen and 2 weeks later. Twelve additional inpatients with AUD, who did not receive any anticraving medications, formed the control group. All subjects were prospectively followed up for 90 days post-discharge or until lapse to first alcohol use. Results: Whole-brain linear mixed effects analysis revealed a significant group-by-time interaction with greater activation of the bilateral dorsolateral pre-frontal cortex and right anterior cingulate cortex (ACC) following baclofen treatment in comparison with the control group. Further, cox regression analysis revealed that increased activation of ACC and deactivation of insular cortex (IC) was associated with longer time to first alcohol use only in the baclofen treatment group but not in the control group. Conclusion: This study provides preliminary evidence for the neural predictors of baclofen treatment response in AUD. Baclofen treatment in AUD was associated with changes in cue-reactivity at critical brain regions within the incentive- salience network. Importantly, baclofen treatment-related specific activation of regions involved in cognitive control (ACC) and deactivation of regions involved in reward anticipation (IC) prolonged the time to first alcohol drink