|Year : 2022 | Volume
| Issue : 3 | Page : 202-208
Noninvasive brain stimulation for cognitive impairment in schizophrenia: Shreds of evidence
Sujita Kumar Kar, Amit Singh
Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||02-Jun-2022|
|Date of Decision||29-Jun-2022|
|Date of Acceptance||31-Jul-2022|
|Date of Web Publication||31-Oct-2022|
Dr. Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Schizophrenia is a chronic illness that causes significant impairment in various areas of life. Patients with schizophrenia typically develop symptoms in their second to third decades of life and have a waxing-waning course. The combination of genetics and the environment is essential in developing schizophrenia. Despite proper treatment trials, many patients remain sick and dysfunctional. In patients with schizophrenia, cognitive impairment is a prevalent symptom. Patients frequently display a variety of cognitive abnormalities, including those affecting verbal fluency, executive function, working memory, attention, focus, visuospatial skills, and social cognition. Neuroplasticity is impaired in schizophrenia, and cognitive remediation procedures have improved neuroplasticity. Evidence suggests that cognitive remediation procedures can help patients with schizophrenia address their cognitive difficulties. This review attempts to evaluate the scope of various noninvasive brain stimulation to treat cognitive impairment in schizophrenia.
Keywords: Brain stimulation, cognitive deficits, neuromodulation, schizophrenia, treatment
|How to cite this article:|
Kar SK, Singh A. Noninvasive brain stimulation for cognitive impairment in schizophrenia: Shreds of evidence. Ann Indian Psychiatry 2022;6:202-8
|How to cite this URL:|
Kar SK, Singh A. Noninvasive brain stimulation for cognitive impairment in schizophrenia: Shreds of evidence. Ann Indian Psychiatry [serial online] 2022 [cited 2023 Mar 22];6:202-8. Available from: https://www.anip.co.in/text.asp?2022/6/3/202/360066
| Introduction|| |
Schizophrenia is a severe mental disorder that often results in significant impairment in multiple domains of life. Patients with schizophrenia often have the onset of illness during the second to third decade of their life and run a chronic course. Genetics and environmental complex interaction play a significant role in developing schizophrenia. The patients may display a broad range of positive, negative (deficit), affective, and cognitive symptoms. Antipsychotic medications are the mainstay treatment for patients with schizophrenia. Psychosocial treatment and neuromodulation strategies also play an essential role in managing schizophrenia. Despite adequate treatment trials, a significant proportion of patients remains symptomatic and dysfunctional. Maintaining remission is a challenging task in schizophrenia as many patients during illness become nonadherent to treatment, and psychosocial triggers may precipitate the symptoms. Medication adherence and adequate and continuous psychosocial and family interventions reduce the risk of relapse in schizophrenia. The conventional treatment strategies can manage the positive symptoms, aggression and affective symptoms in patients with schizophrenia to a greater extent. However, cognitive and negative symptoms are often difficult to be treated through conventional treatment strategies and often persist despite adopting various treatment strategies, which usually affect the real-world functioning of the individual. This article attempts to discuss the role of different noninvasive brain stimulation techniques in the management of cognitive symptoms of schizophrenia.
| Cognitive Impairment in Schizophrenia|| |
Cognitive impairment is a common manifestation in patients with schizophrenia. Patients with schizophrenia present with a spectrum of cognitive symptoms, including impairments in attention, concentration, processing speed, executive function, working memory, verbal fluency, visuospatial abilities, and social cognition., Facial emotion recognition is an essential domain of social cognition deficient in patients with schizophrenia.
Recent systematic reviews and meta-analyses have revealed that even individuals clinically at high risk for psychosis had definite cognitive deficits, even though they do not have any apparent symptoms of psychosis. The cognitive deficits often range from mild to moderate neuropsychological deficits. The evidence suggests that the cognitive deficits were more pronounced in the clinical high-risk group who later developed psychosis than the clinically high-risk group, who had not developed psychosis in due course of time. It indicates that there is probably a spectrum of cognitive deficits ranging from milder intensity to severe, and in this spectrum, at the end of milder deficit lies individuals with a clinically high risk of psychosis (but not developed overt psychotic symptoms), followed by individuals of clinically high risk of psychosis, who develop psychosis over due course of time and at the other extreme end, lies schizophrenia and related psychotic disorders with severe deficits in cognitive functions [Figure 1].
|Figure 1: Spectrum of cognitive deficits among various vulnerable groups of psychosis|
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Initial studies reported that the use of atypical antipsychotics such as olanzapine, risperidone, and aripiprazole are associated with improvement in cognitive functions such as verbal learning, visual learning, attention, vigilance, and processing speed.,, However, evidence also suggests that the medications used to treat schizophrenia affect cognitive functions. For example, the use of benzodiazepines may reduce the ability to process emotions and recognition of emotions by attenuating the activity of the amygdala. Similarly, antipsychotics were found to have a variable effect on the social cognition domain in patients with schizophrenia. In the long-term follow-up studies, it was seen that patients with long-term antipsychotic treatment and higher doses of antipsychotic medications have more cognitive decline (particularly in the domains of verbal learning and memory)., The improvements in cognition with antipsychotic treatments might be due to global improvement of the patient's mental well-being due to improvement of psychopathology; however, long-term use might result in slowing the cognitive function due to interference of the medications in the cognitive processing. A recent network meta-analysis of 54 randomized controlled trials (involving 5866 patients with psychotic disorders) revealed that various antipsychotic medications concluded that poor cognitive performance is associated with the use of antipsychotics such as haloperidol and clozapine; however, better cognitive functioning is related to the use of antipsychotics such as amisulpride, olanzapine, risperidone, lurasidone, perphenazine, ziprasidone, and sertindole.
Cognitive deficits in patients with schizophrenia give rise to significant disability in multiple domains of life, which interfere with real-world functioning.,, The degree of disability in schizophrenia directly correlates with the degree of cognitive impairment., Evidence supports that the cognitive deficits in schizophrenia result from the involvement of specific brain areas. The deficits of working memory, processing speed, prediction errors, and executive control largely depend on the concentration of gamma-amino butyric acid (GABA) and glutamate in the prefrontal cortex.
Evidence support that cognitive remediation strategies help address the cognitive deficits in patients with schizophrenia. A meta-analysis of randomized controlled trials found that cognitive remediation is more suitable for persons with schizophrenia who have more severe psychopathology at baseline, lower intelligence quotient (IQ), and lower educational levels. Schizophrenia causes impairment in neuroplasticity, and cognitive remediation strategies are known to enhance neuroplasticity.
| Treating Cognitive Deficits in Schizophrenia|| |
The strategies to improve cognition and reduce cognitive deficits include pharmacotherapy, cognitive rehabilitation therapies, and invasive and noninvasive brain stimulation. However, the evidence regarding the improvement in cognition with antipsychotic medication treatment has been mixed. A randomized, double-blind study in a cohort of 1460 patients with chronic schizophrenia enrolled in the CATIE trial was evaluated for the neurocognitive effects of antipsychotic medications, including olanzapine, risperidone, perphenazine, quetiapine fumarate, and ziprasidone. Slight yet significant improvement was noticed with most antipsychotics at 2-month, 6-month, and 18 months' follow-up assessment. However, another study on 60 patients with schizophrenia from the Northern Finland Birth Cohort 1966 found that high-dose, long-term antipsychotic treatment has a deleterious effect on cognition in people with schizophrenia.
Similarly, a recent study with a double-blind placebo-controlled, cross-over study design in 71 inpatients with schizophrenia reported no significant improvements in cognitive symptoms. In addition, results with acetylcholinesterase inhibitors, including rivastigmine, galantamine, and donepezil, were not encouraging. Similarly, the effects with various drugs targeting glutamate, GABA, serotonin, noradrenaline, dopamine, and endocannabinoid receptor system for cognition enhancement are predominantly negative.
The cognitive remediation therapies have the most evidence base among the interventions targeted toward cognitive enhancement. A meta-analysis of 26 randomized-controlled trials published between 1968 and 2006 reported a medium effect size for improvements in cognitive performance (0.41) and psychosocial functioning (0.36) with cognitive remediation in schizophrenia. Furthermore, the benefits of this evidence-based treatment are long-lasting. Moreover, both computerized and noncomputerized training methods of varying length, intensity and complexity are available. Besides, experts have also tried to identify the critical components of cognitive remediation programs for effective intervention, including the availability of a trained therapist, practicing of cognitive exercises, attention to the development of cognitive strategies, and generalizing the cognitive gains to everyday functioning. In addition, the employment of cognitive remediation strategies early in schizophrenia has been suggested to produce more significant benefits.
The invasive brain stimulation strategies such as deep brain stimulation (DBS) and vagus nerve stimulation (VNS) may also have a potential role in cognitive enhancement in schizophrenia; however, the research evidence is mostly from preclinical or small pilot studies., DBS has improved positive symptoms in some cases with refractory schizophrenia. However, the role of DBS for improving cognition is not established. VNS is shown to have procognitive effects on Alzheimer's disease, depression, and epilepsy. However, owing to a lack of research supporting VNS's role in cognition in schizophrenia, it cannot be currently recommended as a cognitive enhancement strategy.
| Noninvasive Brain Stimulation to Treat Cognitive Impairment in Schizophrenia|| |
Role of electroconvulsive therapy
Electroconvulsive therapy (ECT) is among the oldest and most widely used neuromodulation technique. It has shown effectiveness in managing schizophrenia, including the treatment-resistant ones., It is often used as an add-on to the antipsychotic treatment to reduce the schizophrenia symptom scores. The reduction primarily occurs in positive symptoms, including catatonia. Thus, the cognitive impairment resulting from general psychopathology of schizophrenia plausibly improves with electroconvulsive treatment. However, ECT itself is associated with acute impairments in cognition. Commonly noticed are post-ECT short-term deficits in retaining newly acquired information and recalling events from the preceding weeks. The parameters associated with more deficits are conventional sine wave stimulation, bitemporal application, and higher electrical dosage. Contrarily, the cognitive impairments are low with brief and ultra-brief stimulation, bifrontal application, unilateral electrode placements, and lower electric dosage., Regarding the utility of electroconvulsive treatment in improving the cognitive symptoms of schizophrenia, the long-term research evidence is limited. A 2-year follow-up study compared two groups with nine adolescents in each group matched for age, socioeconomic status, and diagnostic and positive and negative syndrome scale total score, for the effect of ECT on various domains of cognition, including the attention, verbal learning and memory, working memory, and executive functioning. The study found significant improvements in both the groups in specific attention and executive functioning tasks. However, the inter-group difference in cognition was not significant at follow-up. Another study, in 31 participants with treatment-resistant schizophrenia, to evaluate the effects of ECT augmentation of antipsychotics on cognitive functions found no significant decline in working memory, verbal memory, visual memory, psychomotor speed, verbal fluency, and executive functioning post ECT. Instead, there was a significant improvement in short-term and long-term verbal memory and measures of executive functions. Furthermore, a trend for improvement was noticed for psychomotor speed and visual memory. The authors attributed to this the moderate number of ECT sessions. However, this research was also unable to discern whether the ECT had direct procognitive effects or the improvement in cognition was consequent to an overall improvement of symptoms. Thus, the current evidence does not endorse ECT as a neuromodulation strategy for improvement in cognition. Magnetic seizure therapy produce has been used as an alternative to ECT for convulsive treatment of schizophrenia. The results are promising and comparable to ECT for the antipsychotic efficacy. Furthermore, MST is associated with fewer cognitive impairments. However, the research is limited to drawing meaningful conclusions regarding MST as a cognitive remediation strategy in schizophrenia.
Role of transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a modality of neuromodulation that modulates the superficial cortical areas. In high frequency, rTMS produces cortical excitation, and in low frequency, it inhibits the underlying cortical region. Research evidence supports that rTMS has a beneficial therapeutic role in managing schizophrenia., In the management of schizophrenia, rTMS is commonly used for treatment-refractory auditory hallucinations, where the temporoparietal junction cortical excitability is modulated by rTMS. Several studies attempted rTMS for the treatment of negative symptoms of schizophrenia (primarily targeting the left dorsolateral prefrontal cortex). However, there is a lack of research evidence regarding the effectiveness of rTMS. Researchers used rTMS to treat cognitive deficits in persons with neurocognitive disorders. The dorsolateral prefrontal cortex, precuneus, and superior parietal lobule are commonly targeted for cognitive remediation in patients with neurocognitive disorders with variable levels of success. Hasan et al., in their randomized controlled trial, used 10 Hz frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) to treat the cognitive impairments in schizophrenia and found that there is no significant difference in the cognitive benefits between patients receiving active rTMS and sham rTMS. However, Wen et al., in a recent randomized, double-blind trial (sham-controlled), used high-frequency rTMS (10 Hz) as an add-on treatment to ongoing antipsychotic treatment in patients with schizophrenia. In this trial, both patients receiving active rTMS and sham rTMS showed improvement in their cognitive symptoms after 20 sessions of rTMS over the left dorsolateral prefrontal cortex; however, the improvement in immediate memory and delayed memory were significantly better in patients receiving active rTMS than those receiving sham rTMS. Similarly, Guan et al. found high-frequency rTMS over the left DLPFC superior to sham rTMS in causing cognitive improvement (immediate memory task) in patients with schizophrenia; however, they used 20 Hz frequency for treatment. However, contradicting findings suggesting that 20 Hz frequency rTMS is not superior to sham rTMS in managing cognitive symptoms in schizophrenia were reported in an initial study.
Xiu et al., in a double-blind controlled trial, compared 20 Hz, 10 Hz, and sham rTMS in treating the cognitive impairments in schizophrenia. The 20 Hz rTMS group significantly benefited over 32 weeks of follow-up in the domain of immediate memory. It indicates that 20 Hz is more efficacious than 10 Hz in treating the cognitive symptoms of schizophrenia. This study also found specific predictors (prolactin level at baseline, visuospatial/constructional index, and immediate memory index) for cognitive improvement in schizophrenia. In the Indian population, Chauhan et al. used intermittent theta-burst stimulation targeting the cerebellum in a randomized-controlled trial in patients with schizophrenia. This study found that there is no significant beneficial role of TMS in schizophrenia in managing the cognitive symptoms. Deep TMS has been tried in patients with schizophrenia., and results are variable (one study showed the beneficial effect of dTMS on the cognitive functioning, whereas the other found the benefit not superior to sham TMS).
A recent Cochrane database systematic review suggests that the level of evidence regarding the role of rTMS in treating the cognitive symptoms of schizophrenia is low due to the poor quality of studies.
Role of transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) is a modality of superficial cortical neuromodulation, which uses direct current as the stimulus modality. The schizophrenia treatment with electric transcranial stimulation trial, which primarily intended to measure the improvement in negative symptoms after ten sessions of tDCS over 5 days, targeting the frontotemporal region found that there is no improvement in the cognitive functions in comparison to the sham control group. Hence, the authors recommended that a different target region (other than frontotemporal, as used in the above study) may be beneficial in dealing with the cognitive impairments in schizophrenia. Similarly, Chang et al., in a randomized sham-controlled trial, attempted to target the bilateral DLPFC through anodal stimulation with an extracephalic reference in patients with schizophrenia. A total of 10 sessions were delivered over 5 days, and the patients were evaluated for change of psychopathology over 3 months. No improvement in cognitive symptoms was reported in the group receiving active tDCS than in the sham group. However, in an earlier study, Chang et al. found that frontotemporal tDCS is beneficial for improving cognitive insight and executive functions like planning ability. The effect of tDCS on social cognition was measured in recent research in patients with schizophrenia. Anodal stimulation of the DLPFC improves emotion identification significantly. However, this study was done in a small sample size (12 patients each receiving cathodal, anodal, and sham tDCS). Smith et al., in a preliminary study on the Chinese population, evaluated the cognitive benefits of tDCS in schizophrenia. It was found that there was no difference in the cognitive improvement during the therapy sessions (acute phase); however, the improvement was reported 2 weeks later in the group who received active tDCS than in the group who received sham tDCS. Improvement was noticed in processing speed and working memory. Late improvement in cognitive performance may be explained on the basis of the phenomenon of neuroplasticity. Attempts have been made to check the efficacy of a single session of tDCS in schizophrenia. It was found that though it is a safe procedure, there are no cognitive benefits (neurocognition and social cognition). Anodal tDCS over the left dorsolateral prefrontal cortex, in addition to customized psychosocial occupational therapy in patients with schizophrenia, was beneficial in improving cognitive domains such as attention, learning, and visual memory. Anodal tDCS over the left DLPFC is also found to improve verbal fluency and working memory than cathodal tDCS over the left dorsolateral prefrontal cortex. Under challenging conditions or demanding situations in patients with schizophrenia with significant cognitive deficits, anodal tDCS has been shown to improve the spatial working memory.
Systematic review and meta-analysis were attempted to evaluate the possible role of tDCS in the management of cognitive symptoms of schizophrenia.,,, The existing evidence suggests a possible role of tDCS in improving cognitive symptoms in schizophrenia, particularly the working memory; however, the studies had significant limitations of small sample size, short follow-up period, and tDCS being used as an add-on treatment.
Role of other brain stimulation techniques
Transcranial alternating current stimulation (tACS) is a novel neuromodulation strategy with some initial promising results in enhancing cognitive performance in patients with schizophrenia. It attempts to modulate the intrinsic oscillatory activity of specific brain areas by passing alternating current through the scalp via electrodes placed over defined regions of interest. In schizophrenia, aberrant synchronization of beta- and gamma-band activity, deemed to be resulting from an imbalance between excitation and inhibition, is reported. It implies that defective oscillations may play a key role in developing cognitive impairments. Thus, tACS has been used in attempts to normalize pathological brain oscillations.
A male patient with paranoid schizophrenia administered online theta tACS (6 Hz frequency) over left DLPFC (F3) and the left posterior parietal region (P3) for 20 min on 5 consecutive days had improved performance in working memory, attention, and processing speed task. The improvement persisted at 50 days' follow-up. A single-blinded, randomized, repeated-measures study attempted to target frontal gamma oscillations in patients with schizophrenia. Ten patients were administered 20-min sessions of 40 Hz tACS over the left DLPFC area. Other stimulation protocols comprised tDCS and sham stimulation. The study had no significant impacts of tACS on working memory task parameters. However, the lack of findings was attributed to a small sample size and methodological limitations, including the absence of pre-and post-electroencephalogram recordings and utilization of field modeling tools. Overall, the research suggests tACS as a safe and potential tool for cognitive remediation.
Transcranial random noise stimulation (tRNS) has been used in the treatment of schizophrenia. tRNS uses alternating current oscillations in random frequencies for neuromodulation. A study that compared the cognitive benefits of active tDCS, sham tDCS, and tRNS revealed that tRNS to be not significantly superior to sham tDCS in producing benefits in cognition, though the study had a small sample size and several methodological limitations. Murphy et al. had tried tRNS with a direct current offset (tRNS + DC) and compared it with anodal tDCS and sham tDCS. Among the three groups, individuals receiving tRNS with DC offset had shown the best cognitive performance, improving working memory accuracy. This study was conducted on healthy individuals. If patients with schizophrenia were treated with this protocol and parameters, it may produce benefits in cognition; however, it needs to be evaluated in future research.
Noninvasive transcutaneous VNS (tVNS) was used in 20 patients with schizophrenia in a randomized, sham-controlled, double-blind trial to evaluate its feasibility, safety, and efficacy. Daily active stimulation of the left auricle was applied for 26 weeks in the active tVNS group. The sham tVNS group received sham stimulation for 12 weeks before receiving active stimulation for 14 weeks. Although the intervention was well tolerated, no significant differences were observed between the study groups on the psychopathological and neurocognitive measures. However, tVNS merits more investigation before being refuted as a treatment option.
[Table 1] summarizes the domains of cognition improved and the level of evidence about various neuromodulation techniques used in schizophrenia.
|Table 1: Neuromodulation technique in the management of cognitive symptoms of schizophrenia|
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| Conclusion and Future Directions|| |
Cognitive deficits are one of the core symptoms of schizophrenia that are relatively refractory to treatment. Existing evidence suggests that improvement in core psychotic psychopathology helps in some improvement of cognitive abilities; however, the cognitive deficits mostly persist, causing significant psychosocial impairment. Various noninvasive neuromodulation techniques were found to be well tolerated and effective in producing cognitive improvements in patients with schizophrenia. However, there are contradicting findings, too, and the majority of research is limited by a small sample size. Similarly, evidence is scarce regarding the long-term efficacy of noninvasive neuromodulation techniques in managing cognitive deficits in patients with schizophrenia. Future research may attempt to overcome the shortcomings of the current studies through better research design, longer follow-up assessment, and recruiting more patients by involving multiple centers.
- Conceptualization, literature search, manuscript writing, manuscript editing: 1st Author
- Literature search, manuscript writing, manuscript editing: 2nd Author.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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