A Primer on Interoception and its Importance in Psychiatry

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.

Multiple Complement Pathway-related Proteins Might Regulate Immunopathogenesis of Major Depressive Disorder

Objective@#Exacerbated inflammatory pathway has emerged as a predominant etiological construct of major depressive disorder (MDD). Innate immune molecules like complement proteins induce inflammatory responses and also regulate key neurobiological processes. However, there is a dearth of literature on the impact of critical complement proteins in MDD. Herein, plasma profiling of seven complement proteins was carried out to obtain a better insight into the role of the complement pathway in MDD. @*Methods@#Plasma levels of C1q, C3, C3b/iC3b, C4, Factor B, Factor H, and properdin were assayed in 22 patients with MDD and 27 healthy controls by multiplex suspension assay. The patients with MDD were diagnosed as per DSM IV-TR. Hamilton Depression Rating Scale (HAM-D), Montgomery Depression Rating Scale and Clinical Global Improvement were used for clinical assessments of the patients. The plasma levels of these complement proteins were also correlated with various clinical scores and phenotypes of MDD. @*Results@#The patients with MDD and healthy controls did not differ in terms of age and gender (p ＞ 0.1). The patients with MDD had a mean duration of illness of around 3 years, with average number of depressive episodes being 6 and the mean HAM-D score was 19. Of the seven complement components, the plasma levels of C1q, Factor B, and Factor H (p ≤ 0.05) were significantly elevated in MDD patients compared to healthy controls. However, the plasma levels of these complement proteins were not found to correlate with the clinical profile of MDD patients. @*Conclusion@#Both Factor B and Factor H are crucial in the induction and regulation of the alternative pathway of complement activation. The alternative pathway also plays a critical role in inflammation. These findings suggest an important role of the alternative complement pathway in immuno-inflammation in MDD.

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

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.

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

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.

A Functional Domain Based Approach in Neurocognitive Rehabilitation with Transcranial Direct Current Stimulation: A Case Report

Transcranial direct current stimulation (tDCS) is a novel brain stimulation technique which has kindled hope in alleviating motor, language as well as cognitive deficits in neuronal injury. Current case report describes application of tDCS in two phases using two different protocols in a patient with hypoxic injury. In the first phase anodal stimulation of dorsolateral prefrontal cortex improved the language fluency. Subsequently, after 6 months second phase application of anodal stimulation over posterior parietal region targeted arithmetic and working memory deficits. Individualising the treatment protocols of brain stimulation, based on the lesion and the functional deficits, for neuro-rehabilitation is emphasised.

Schizophrenia and Corollary Discharge: A Neuroscientific Overview and Translational Implications

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.

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

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.

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

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 β-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.

Neural Correlates of a Perspective-taking Task Using in a Realistic Three-dimmensional Environment Based Task: A Pilot Functional Magnetic Resonance Imaging Study

OBJECTIVE: Perspective-taking ability is an essential spatial faculty that is of much interest in both health and neuropsychiatric disorders. There is limited data on the neural correlates of perspective taking in the context of a realistic three-dimensional environment. We report the results of a pilot study exploring the same in eight healthy volunteers. METHODS: Subjects underwent two runs of an experiment in a 3 Tesla magnetic resonance imaging (MRI) involving alternate blocks of a first-person perspective based allocentric object location memory task (OLMT), a third-person perspective based egocentric visual perspective taking task (VPRT), and a table task (TT) that served as a control. Difference in blood oxygen level dependant response during task performance was analyzed using Statistical Parametric Mapping software, version 12. Activations were considered significant if they survived family-wise error correction at the cluster level using a height threshold of p<0.001, uncorrected at the voxel level. RESULTS: A significant difference in accuracy and reaction time based on task type was found. Subjects had significantly lower accuracy in VPRT compared to TT. Accuracy in the two active tasks was not significantly different. Subjects took significantly longer in the VPRT in comparison to TT. Reaction time in the two active tasks was not significantly different. Functional MRI revealed significantly higher activation in the bilateral visual cortex and left temporoparietal junction (TPJ) in VPRT compared to OLMT. CONCLUSION: The results underscore the importance of TPJ in egocentric manipulation in healthy controls in the context of reality-based spatial tasks.

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

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".

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

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

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

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 important mechanisms that increase the risk towards schizophrenia in the offspring. Interestingly, immune factors have been shown to critically modulate the brain development during the prenatal stages. Moreover the past many decades, influential theoretical propositions and evidence base (albeit not unequivocally) have compellingly linked prenatal sex hormonal status to critically provoke long lasting immunological changes and subsequently affect developmental programming of cerebral asymmetry in schizophrenia. In this review, we summarize the select perspectives emphasizing the role of neuroimmunoendocrine pathways in anomalous cerebral asymmetry in contemporary understanding of schizophrenia pathogenesis.

Transcranial Direct Current Stimulation in Schizophrenia

Transcranial direct current stimulation (tDCS) is an upcoming treatment modality for patients with schizophrenia. A series of recent observations have demonstrated improvement in clinical status of schizophrenia patients with tDCS. This review summarizes the research work that has examined the effects of tDCS in schizophrenia patients with respect to symptom amelioration, cognitive enhancement and neuroplasticity evaluation. tDCS is emerging as a safe, rapid and effective treatment for various aspects of schizophrenia symptoms ranging from auditory hallucinations-for which the effect is most marked, to negative symptoms and cognitive symptoms as well. An interesting line of investigation involves using tDCS for altering and examining neuroplasticity in patients and healthy subjects and is likely to lead to new insights into the neurological aberrations and pathophysiology of schizophrenia. The mechanistic aspects of the technique are discussed in brief. Future work should focus on establishing the clinical efficacy of this novel technique and on evaluating this modality as an adjunct to cognitive enhancement protocols. Understanding the mechanism of action of tDCS as well as the determinants and neurobiological correlates of clinical response to tDCS remains an important goal, which will help us expand the clinical applications of tDCS for the treatment of patients with schizophrenia.

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

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-naive 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-naive 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.