Neuromodulatory effects of adjunctive High-definition Transcranial Direct Current Stimulation (HD-tDCS) on auditory verbal hallucinations in Schizophrenia patients: A sham controlled Diffusion Tensor Imaging study

Schizophrenia is a common and chronic neuropsychiatric disorder. It is characterised by abnormalities in one or more of the following five domains: delusions, hallucinations, disorganised thinking, grossly disorganised or abnormal motor behaviour and negative symptoms. Auditory verbal hallucinations (AVH) are core symptoms of schizophrenia. Studies have suggested that dysfunctioning and abnormality in the white matter connectivity in different parts of the cortex, may be part of the pathophysiology of auditory verbal hallucinations in schizophrenia[Kim.J.J.et al, 2007][ James, A. et al 2007][ Narr, K. L. et al2009].

Auditory Verbal Hallucinations can be defined as perceptions of speech in the absence of external stimuli, frequently associated with significant functional disability. The neurobiological bases of AVH are complex and remain unclear. Nevertheless, Recent advances in neuroimaging contributed to probable neural correlates of AVH. It has been hypothesized that alterations in connectivity between frontal and parieto-temporal speech-related areas might contribute to the pathogenesis of auditory hallucinations[Hubl, D et al,2004]. These networks are assumed to become dysfunctional during the generation and monitoring of inner speech. Magnetic resonance diffusion tensor imaging is a relatively new in vivo method to investigate the directionality of cortical white matter tracts.

A recent coordinate-based meta-analysis of functional imaging studies reported that during the occurrence of AVH, patients with schizophrenia exhibited significant over-activation in several brain areas including left temporo-parietal areas (middle and superior temporal gyri and Wernicke’s area), left inferior frontal areas (Broca’s area, frontal operculum, anterior insula, precentral gyrus), as well as in their right homologues[Hoffman, R. et al 2012]. These findings suggest aberrant activations within speech perception and production brain areas during the occurrence of AVH.

DTI is a non-invasive Magnetic Resonance Imaging technique, imposing additional magnetic field gradients, that provides information about the molecular diffusion of water within the tissue and thus allows us to characterize intrinsic features of tissue microstructure and microdynamics[Basser, P. J. et al 1995]. Fractional anisotropy (FA) has been the most widely used index in DTI to evaluate the integrity of fiber tracts in the White Matter [Pierpaoli, C. et al 1998][ Chabriat, H. et al 2001]. Fractional anisotropy roughly represents the degree to which diffusion is directionally hindered (anisotropic). It is high in areas of high structural coherence, such as white matter (WM), lower in gray matter (GM), and close to zero in cerebrospinal fluid (CSF), where diffusion is expected to be equal in all directions (isotropic). A reduction in White Matter FA is therefore usually interpreted as reflecting a reduction in WM integrity.

DTI increasingly provides evidence for abnormal anatomical connectivity in schizophrenia. Schizophrenic patients showed FA reductions indicating WM integrity disturbance in the prefrontal regions, external capsule, pyramidal tract, occipitofrontal fasciculus, superior and inferior longitudinal fasciculi, and corpus callosum. The arcuate fasciculus was the only tract which showed increased FA values in patients[Brunelin, J. et al 2016]. Increased FA values in this region correlated with increased severity of auditory hallucinations. A recent meta-analysis confirmed disruptions of white matter integrity in the left AF bundle of schizophrenia patients with AVHs[Jardri, R. at al 2014].

High-Definition transcranial Direct Current Stimulation (HD-tDCS) is a non-invasive brain stimulation technique for targeting cortical and deep brain structures with weak DC currents. In this technique specific brain regions are targeted using arrays of electrodes on the scalp. In contrast to conventional tDCS, which uses large sponge electrodes, HD-tDCS uses “High-Definition†small gel based electrodes. Through these electrodes current of 1 to 2mA is applied into the brain for several minutes resulting in a polarity-dependent modulation of brain activity[Fregni, F. et al 2013].

Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. A recent study conducted at NIMHANS, Bangalore suggest that High Definition transcranial Direct Current Stimulation  over the left TEMPORO PARIETAL JUNCTION can alleviate  AVH in patients with schizophrenia[Venkatasubramanian, G. et al 2018]. However, brain correlates of the AVH reduction by HD-tDCS are unclear.

 Need for Study

Auditory Verbal Hallucinations are a frequent symptom of schizophrenia which occurs in about 60–80% of patients (Andreasen and Flaum, 1991). The content of these hallucinations is mostly negative, often conveying anger (McCarthy-Jones et al., 2014), or terms of abuse (Nayani and David, 1996) and increasing the risk for suicidal behavior (Harkavy-Friedman et al., 2003). Alternative treatment options, other than pharmacotherapy, are scarce for these patients, and often focus on coping with the hallucinations and accepting their presence instead of reducing them (Bentall et al., 1994). Due to the distressing impact AVH have on the patients’ quality of life, their ability to concentrate and their social and professional functioning, finding an effective and adjunctive treatment option to reduce AH would be of great value.

Transcranial Direct Current Stimulation has advantage over other techniques of non-invasive brain stimulation such as cost effectiveness, small size of the apparatus, allowing portability, possibility of modulating neuronal activity. Promising results have been obtained in the study of effect of tDCS on AVH in schizophrenia. (Mondino Marine et al, 2015). To the best of our knowledge, there hasbeen no study till date assessing the cortical neuromodulatory effect of HDtDCS in Auditory Verbal Hallucinations of schizophrenia asmeasured by changes in measurement of Fractional Anisotropy in the  arcuate fasciculus  in DTI Brain. Such study will also help us in finding out the neurobiological basis of mechanism of action of HDtDCS in reducing AVH in Schizophrenia.

 Aim Of the Study

To see the neuromodulatory effect of adjunctive HD-tDCS on White Matter Connectivity in Schizophrenia Patients with Auditory Verbal Hallucinations by Diffusion Tensor Imaging.