High-definition transcranial direct current stimulation for treating cognitive and negative symptoms in chronic schizophrenia – A sham-controlled proof of concept study

INTRODUCTION

Schizophrenia, a highly debilitating mental disorder, impacts approximately 1% of the population.^[1] This condition is marked by various cognitive factors that contribute to widespread cognitive impairment in individuals diagnosed with schizophrenia. These factors encompass processing speed, attention and vigilance, working memory, verbal learning and memory, visual learning, memory, reasoning and problem-solving, as well as verbal and social cognition.^[2] Cognitive impairments in Schizophrenia greatly debilitate and impair socio-occupational functioning.^[3] While resistant to conventional treatments, the negative symptoms of schizophrenia – social withdrawal, decreased affective response, reduced interest, impaired social drive, and diminished sense of purpose – are enduring and more predictive of outcomes than positive symptoms.^[4-6]

Prefrontal cortex (PFC) abnormalities are thought to affect cognitive and negative symptoms in patients with schizophrenia. Patients consistently show decreased dorsolateral PFC (DLPFC) activity during working memory tasks, where activation levels correlated to performance in many studies.^[7,8] Patients with negative symptoms of schizophrenia also show lower metabolism in the DLPFC.^[9] Therefore, it is reasonable to assume that changes in PFC activity may play a role in the cognitive and negative symptoms of schizophrenia. Hypometabolism and hypoperfusion of the PFC have been seen in neuroimaging studies in patients with negative symptoms of schizophrenia suggesting hypofrontality, which is more pronounced on the left side.^[10-12]

Neuromodulation techniques that are non-invasive, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are being tried for the treatment of various psychiatric disorders. tDCS is a novel technique in which two electrodes are used to deliver a weak electrical current to the scalp. The anode leads to neuronal depolarization, and the cathode facilitates neuronal hyper-polarization.^[13] tDCS-induced changes depend on the polarity of stimulation – anodal stimulation conventionally enhances excitability, while cathodal tDCS reduces it.^[14,15] Conventional tDCS affects cortical activity in a relatively larger area than that covered by the target electrode as found in neuroimaging studies.^[16]

As compared to other non-invasive neuromodulation techniques, tDCS is easy to use, cheap, and portable.^[17] High-definition tDCS (HD-tDCS) has the possibility for precise and focal neuromodulation with better predictability of effects and is a betterment of conventional tDCS. Instead of saline-soaked sponges, HD-tDCS uses a network of small electrodes (1 cm) arranged in a 4 * 1 ring electrode configuration, leading to focalized stimulation according to the finite element model analysis based on high-resolution magnetic resonance imaging (MRI).^[18] Conventional tDCS leads to the flow of current in wider brain areas, where the current might be spread diffusely and the greatest density of stimulation might not occur directly under the electrodes. HD-tDCS, on the other hand, allows an effective density of current mainly in the target area, leading to more focal, stronger, and longer-lasting effects than conventional tDCS.^[19,20]

A meta-analysis of 31 studies found a moderate effect on negative symptoms of schizophrenia using either tDCS or rTMS of the frontal cortex.^[21] A most recent meta-analysis done to assess the effects of tDCS on negative and cognitive symptoms in schizophrenia patients failed to show statistically significant results for cognitive symptoms; however, tDCS instead of HDt-DCS was used in the studies. Overall, the meta-analysis did not show a significant difference in improving negative symptoms between active and sham tDCS in patients with schizophrenia. However, in the analysis of studies with a greater frequency of stimulation, that is, twice daily, a significant difference was found in the effects of active stimulation as compared to sham tDCS suggesting a role for increasing the number of stimulations to improve effectiveness.^[22]

A recent study on the effectiveness of adjunctive HD-tDCS in schizophrenia patients with negative symptoms stated that the initial reduction in negative symptoms was maintained over a 6-week follow-up and suggested an increase in the number of stimulations for further studies.^[23] However, so far we could not find any published study on the use of 20 sessions of HDtDCS in the treatment of cognitive and negative symptoms of chronic schizophrenia (>2 years of continuous illness).^[24] Our study aimed to evaluate the effectiveness of HD-tDCS to left DLPFC in treating cognitive and negative symptoms in patients with chronic schizophrenia.

MATERIAL AND METHODS

Participants

The study was conducted at the Brain Stimulation Lab, Center for Cognitive Neurosciences, Central Institute of Psychiatry, Ranchi, India. Subjects between the ages of 18 and 60 years, who met International Classification of Diseases, Tenth Edition (ICD-10) DCR criteria for schizophrenia, illness duration >2 years with continuous course, and right-handed, with a scale for assessment of negative symptoms (SANS) score of more than 20 were included in the study.^[23] The handedness preference schedule was used to assess handedness.^[25] The diagnosis of schizophrenia was established using ICD-10 after detailed clinical evaluation through clinical interviews.

The study excluded patients with substance dependence except for nicotine and caffeine, comorbid medical/ neurological disorders, and developmental delay, as well as those who were receiving depot antipsychotics to minimize confounding factors that could affect the study outcomes. Patients having metallic implants/parts and who had received electroconvulsive therapy in the past 6 months were also excluded from the study.

Before conducting the study, a thorough explanation of the research was provided to the participants, and written informed consent was taken following the approval of the protocol by the Institute’s Ethics Committee.

A total of 26 inpatients were initially assessed for eligibility. However, four patients did not cooperate in the beginning and were excluded from further participation. An additional two patients dropped out due to an increase in positive symptoms.

Ultimately, a group of 20 patients successfully completed the entire duration of the study, as illustrated in [Figure 1]. Throughout the study duration, the patients remained on stable doses of antipsychotic medication, as determined by the treating team.

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Figure 1:

CONSORT 2010 flow diagram.

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Design/intervention

This double-blind and sham-controlled study randomly allocated participants into two groups. Both evaluators and patients were unaware of the assignment of treatment to either the active or sham group. The active HD-tDCS stimulation was delivered using a wearable device called Starstim 32 from Neuroelectrics BE, Spain. The device wirelessly transmitted 32-channel data through Wi-Fi. NG Pistim electrodes that had a 1 cm radius were used in a 4 × 1 ring montage. The electrode placement on the scalp was facilitated by an electroencephalogram (EEG) cap and plastic casing for stability. The anode electrode (central electrode) was positioned at F3 (Left DLPFC) following the 10/10 montage of EEG electrode placement. Four return electrodes (FC1, F7, FC5, AF3) surrounded the central electrode, defining the modulation area [Figure 2]. Even though very low electric current can have local effects, studies have found that induced electric fields are grossly constrained to the cortical area circumscribed by the ring. [30] Throughout the sessions, side effects were monitored using a checklist specifically designed for HD-tDCS (HD-tDCS side effect checklist).^[31]

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Figure 2:

Simulated electric field maps produced over the left dorsolateral prefrontal cortex by a high-definition – transcranial direct current stimulation.

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In line with previous research, the active group received stimulation of 2 mA with two sessions per day for 10 days. The stimulation included a 3-s ramp up and ramp down.^[22,23] The full duration of each stimulation session was 20 min.^[32,33] A minimum interval of 3 h separated two consecutive sessions. For the sham stimulation, electrodes were positioned in the same locations as in the active group. However, a 1 mA direct current was delivered for 30 s with a 3-s ramp up and ramp down to give a sensation of stimulation while reducing actual stimulatory effects.^[34] Enveloped randomization was used for allocating participants to active and sham groups.

The study received ethical approval from the Institute Ethics Committee of the Central Institute of Psychiatry, Ranchi. The trial protocol was registered with the Clinical Trials Registry – India (CTRI) at http://ctri.nic.in/Clinicaltrials/login.php with the number CTRI/2021/07/034759.

RESULTS

Out of the 20 patients who completed the study, ten received active HD-tDCS stimulation, while the other ten received sham stimulation. The allocation of participants to the active and sham groups was determined using the sealed envelope method. Sociodemographic and clinical characteristics were compared between the active and sham groups, and the analysis showed no significant differences in terms of age, duration of illness, income, education, sex, religion, marital status, or choice of drug [Tables 1 and 2].

The safety and tolerability of HD-tDCS were assessed using a checklist developed by Eryilmaz et al.^[31] Among the patients receiving active stimulation, itching at the site of stimulation was complained of by four patients during seven sessions total, while a burning sensation at the stimulation site was reported by two patients, each during a single session. No other major or debilitating side effects were reported. All reported side effects were transient and did not need discontinuation of sessions.

[Table 3] shows changes in psychopathology as seen by improvements in symptoms measured by changes in MoCA, SANS, and CGI-S scores over time. There was a significant improvement in cognitive symptoms as assessed using MoCA (F = 22.63; P < 0.001) with a good effect size (Partial eta squared = 0.72). A significant improvement was also noticed in the negative symptoms measured by SANS score (F = 15.39; P < 0.001) over time at 2 weeks in both active and sham groups, which was maintained even after 4 weeks of completion of HD-tDCS with a large effect size (Partial Eta squared = 0.64) and global severity as assessed using CGI-S (F = 49.50; P < 0.001) over time at 2 weeks in both active and sham groups with good effect sizes (Partial Eta Squared = 0.85) and the improvement was maintained at 4 weeks post HD-tDCS.

We failed to find any improvement in cognitive symptoms between active and sham HD-tDCS groups as seen on MoCA (F = 0.025; P = 0.905) [Figure 3a]. However, Group*Outcome Interaction as mentioned in [Table 4] revealed that active HD-tDCS was better at reducing negative symptoms as assessed by SANS (F = 1.73; P = 0.02) with a large effect size (Partial Eta Squared = 0.19) [Figure 3b] and clinical global improvement as assessed by CGI-S (F = 0.27; P = 0.05) with a large effect size (Partial Eta Squared = 0.20) [Figure 3c]. This implies that 20 sessions of HD-tDCS led to significant improvement in negative symptoms and global change in severity, although we failed to establish that active HD-tDCS was better than sham HD-tDCS for cognitive symptoms of schizophrenia.

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Figure 3:

(a) Estimated marginal means of Montreal cognitive assessment scale, (b) estimated marginal means of scale for assessment of negative symptoms, and (c) estimated marginal means of clinical global impression severity.

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DISCUSSION

Significant advancements have been made in the treatment of schizophrenia in recent years. However, addressing negative symptoms and cognitive deficits remains a significant challenge in patient care. The treatment of cognitive symptoms has received limited attention, highlighting the need for effective interventions.^[35] Existing therapies for negative symptoms in schizophrenia lack robust efficacy. Conversely, research on improving cognitive symptoms is limited, primarily relying on anecdotal evidence. This highlights the importance of further investigation and the development of effective treatments in this area.

Non-invasive brain stimulation techniques like tDCS offer promise as alternative treatments for medication-resistant symptoms in schizophrenia, particularly negative and cognitive symptoms. However, the optimal implementation of these treatments is still being explored. The previous studies utilizing conventional tDCS have demonstrated notable positive effects, although there have also been instances of negative outcomes with similar or slightly varied approaches.

We aimed to investigate the potential of HD-tDCS as a novel method for enhancing cognitive and negative symptoms in schizophrenia. Our study is the first to utilize more than ten sessions with a ring electrode arrangement to target symptom improvement in this population. The previous studies have primarily used conventional tDCS or HD-tDCS with limited session duration.^[36,37] In contrast, we assessed the effects of 20 sessions of HD-tDCS specifically targeting the left DLPFC in chronic schizophrenia.

One advantage of our study was the inclusion of a sham control group, reducing unsystematic factors that could influence treatment outcomes. While previous studies have explored the utility of HD-tDCS for managing negative symptoms, none have utilized 20 sessions of HD-tDCS. Results from previous studies have been inconsistent, with some demonstrating significant improvement in negative symptoms while others failed to replicate these findings.^[38-40]

Our study found significant improvements in cognitive, negative, and overall symptom severity over time in both the active and sham groups. These effects could be attributed to medication, the HD-tDCS intervention, or even a placebo response in both groups. General linear model-repeated measures ANOVA revealed significant differences in the changes in SANS and CGI-S scores over time between the active and sham groups. These findings are consistent with another study conducted by Dharani and colleagues, which also showed significant reductions in SANS and PANSS scores between the active and sham HD-tDCS groups, persisting at the 6-week follow-up.^[23]

CONCLUSION

Our study adds to the evidence of the effectiveness of adjuvant HD-tDCS in reducing negative symptoms of schizophrenia; however, we failed to find a reduction of cognitive symptoms in patients using a novel protocol implying the use of HDtDCS which appeared to be safe. Given the inconsistent findings in the existing literature, further exploration is necessary to determine the ideal combination of HD-tDCS parameters for effectively treating cognitive symptoms in schizophrenia. This exploration should involve larger sample sizes and utilize objective markers, such as task-based functional MRI and similar techniques, to measure improvements in a more objective and reliable manner.