Social Cognitive Impairments as a Target of Non-Invasive Brain Stimulation for Functional Outcomes in Schizophrenia

*Yuji Yamada and Tomiki Sumiyoshi*

### **Abstract**

Patients with schizophrenia suffer from impairments of social cognition that represent mental operations underlying real-world functioning. Pharmacological approaches have been attempted to overcome social cognitive disturbances of schizophrenia, but only yielded insufficient effects. As an alternative approach, some types of neuromodulations, particularly non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been drawing attention. While previous studies have performed anodal tDCS at the frontal brain regions, we hypothesized anodal stimulation at the temporal region would improve social cognitive function on the basis of the neural circuit governing it. Thus, our data indicate multisession tDCS delivered to the left superior temporal sulcus improves social cognition in patients with schizophrenia. In the present chapter, we overview studies of tDCS on social cognition and discuss optimal brain regions to be targeted for ameliorating symptoms and cognitive disturbances of schizophrenia.

**Keywords:** neuromodulation, transcranial direct current stimulation (tDCS), schizophrenia, social cognition, social function

#### **1. Introduction**

Schizophrenia is one of the most severe psychiatric diseases that affects approximately 0.75% of the world's population [1]. It is characterized by varying degrees of positive (e.g., auditory and/or visual hallucinations, delusions, psychomotor agitation, and paranoia), negative (e.g., apathy, deficits in motivation, social withdrawal, and reward-related functions), and cognitive symptoms (e.g., neurocognition and social cognition). Typically, the onset of schizophrenia is between the end of adolescence and the beginning of early adulthood. The disease has a chronic course with a myriad of psychotic episodes that generally lead to deterioration in real-world functional outcomes [2].

Cognitive impairment is a fundamental symptom of schizophrenia, with mild deficits appearing before the onset of psychosis, followed by an acute decline around

#### **Figure 1.**

*Key domains of social cognition (adapted from Pinkham et al. [3]).*

the first episode psychosis (FEP), and maintains to the chronic stages [2]. Specifically, neurocognition, e.g., working memory, verbal/visual learning and memory, attention, speed of processing, reasoning, and problem-solving, represents cognitive domains that are impaired in most patients. Similarly, impairments of social cognition have been considered as a target for the improvement of functional outcomes [2]. Social cognition is defined as mental operations underlying social behavior and includes domains of the theory of mind (ToM), emotion processing, social perception, and attributional bias/style (see **Figure 1**) [4]. Moreover, social cognition, especially ToM, is associated with social functioning [5], similar to the case for neurocognition [6]. Therefore, these areas of cognitive function have been considered a key target for interventions to improve the functionality of people with psychotic conditions.

Several pharmacological approaches have been tried to enhance social cognition in patients with schizophrenia [7]. In particular, intranasal oxytocin [8], psychostimulants (e.g., modafinil) [2], antipsychotic drugs (e.g., risperidone, olanzapine) [9], and acetylcholinesterase inhibitors [10] have been tested as candidate compounds. Of these, intranasal oxytocin and some atypical antipsychotic drugs may improve ToM [8] and emotion processing [9], respectively, while anti-dementia drugs (e.g., donepezil, galantamine, rivastigmine, and memantine) are less effective. Therefore, further research, including new therapeutic intervention techniques, is desperately needed to overcome social cognitive dysfunction.

#### **2. Non-invasive brain stimulation for social cognitive impairments**

As alternative approaches to the alleviation of social cognitive impairments, some types of neuromodulations, particularly non-invasive brain stimulation (NIBS), e.g., transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES), have been attempted [11]. NIBS has the potential to improve functional outcomes

#### *Social Cognitive Impairments as a Target of Non-Invasive Brain Stimulation for Functional… DOI: http://dx.doi.org/10.5772/intechopen.112742*

by directly stimulating social brain areas, which is likely to facilitate or modulate neurotransmissions in the central nervous system [12, 13]. In particular, TMS has the advantage of accurately stimulating deeper cortical structures that are difficult to reach with tES. On the other hand, tES techniques are advantageous in terms of cost, portability, and safety [11]. Moreover, multi-session tES is thought to promote neuroplastic changes in cortical circuits by inducing long-term potentiation (LTP), which enhances the efficiency of information processing [12, 13]. Therefore, tES may improve functional outcomes by ameliorating social cognitive impairments in patients with schizophrenia.

Previous studies with TMS or tES, with the dorsolateral prefrontal cortex (DLPFC), as the stimulation site, have shown limited effects on social cognition, especially ToM [11]. For example, a single-session continuous theta burst stimulation, a type of TMS, over the right inferior parietal lobe (IPL) enhanced social perception [14], while multi-session high-frequency repetitive TMS over the left DLPFC improved emotional recognition (**Table 1**) [15]. On the other hand, single-session transcranial direct current stimulation (tDCS) delivered to the left frontal pole improved emotion recognition [16], whereas stimulation of the left DLPFC did not show such effects (**Table 2**) [17]. Overall, stimulations of frontal brain regions are advantageous to improve emotion recognition and social perception, but not ToM. To enhance the latter domain of social cognition, other stimulation sites need to be investigated.

The neural substrates governing social cognition include the superior temporal sulcus (STS), amygdala, medial prefrontal cortex, and orbitofrontal cortex. Specifically, functional connectivity among these brain regions is weakened in patients with schizophrenia [18–20]. Among them, the amygdala is involved in emotion recognition, while the prefrontal cortex is responsible for generating ToM. On the other hand, the STS is considered to play a role in both domains of social cognition (**Table 3**) [18, 19]. Therefore, we hypothesized that anodal stimulation over the left STS would be advantageous for treating social cognition disturbances [18, 19].


*Theta Burst Stimulation, cTBS: continuous Theta Burst Stimulation, TULIA: Test of Upper Limb Apraxia. In both studies [14, 15], sham stimulation was performed with a sham coil system without a magnetic field.*

#### **Table 1.**

*Characteristics of TMS studies (adapted from Yamada et al. [11]).*


*Montage is described by the International 10–20 electroencephalography system. TASIT: The Awareness of Social Inference Test, PONS: Profile of Nonverbal Sensitivity, EAT: Empathic Accuracy Task, EIT: Emotion Identification Test, FEIT: Facial Emotion Identification Test, MSCEIT: Mayer-Salovey-Caruso Emotional Intelligence Test.*

#### **Table 2.**

*Characteristics of tES studies (adapted from Yamada et al. [11]).*


#### **Table 3.**

*Neural basis of social cognition (adapted from Yamada et al. [18]).*

### **3. tDCS over the left temporal brain region improves social cognition**

We conducted an open-label, single-arm trial designed to evaluate the effects and safety of multi-session tDCS on the left STS [18, 21]. The intervention was performed by a 1 × 1 transcranial direct current low-intensity stimulator (Model 1300 A; Soterix Medical Inc., New York, NY, USA). For the tDCS montage, the anode electrode was placed for the left STS and the cathode for the contralateral supraorbital region, which corresponded to the T3 and FP2 regions (**Figure 2**) in the International 10–20 electroencephalography system. We applied 10 sessions of direct current of 2 mA for 20 min on 5 consecutive days (twice per day, with an interval of 30 min). Clinical data were collected at baseline and 1 month after the final stimulus (**Table 4**). As a result, significant improvements were found on the tests of ToM, i.e., Social Cognition Screening Questionnaire (SCSQ ) (*d = 0.53*) and Hinting Task scores (*d = 0.49*) (**Figure 3**) [21]. Moreover, serious adverse events were absent. To our knowledge, this study is the first to suggest the ability of multi-session tDCS delivered to the left STS to improve social cognition, especially ToM, in patients with schizophrenia.

Contrary to the results of our observations, previous studies report the absence of sufficient improvement of social cognitive functioning, including ToM, during or immediately after one or two sessions of tDCS in patients with schizophrenia (**Table 2**). By contrast, the effects in our study became evident 1 month after the last tDCS. The specific effects of multi-session tDCS that are associated with the

*Social Cognitive Impairments as a Target of Non-Invasive Brain Stimulation for Functional… DOI: http://dx.doi.org/10.5772/intechopen.112742*

#### **Figure 2.**

*Experimental setup for tDCS on the left DLPFC or STS (Yamada et al. [19]). tDCS: transcranial direct current stimulation, DLPFC: Dorsolateral Prefrontal Cortex, STS: Superior Temporal Sulcus. An administrator controls the stimulator (a). Anodal (b) and cathodal (c) electrodes of 35-cm2 in size are placed on F3/T3 and the right supraorbital region, respectively. A head strap (d) is used as needed to increase reproducibility.*


*tDCS: transcranial direct current stimulation, SCSQ: Social Cognition Screening Questionnaire, FEST: Facial Emotion Selection Test. The timepoint of follow-up evaluation was allowed to be up to 7 days off.*

#### **Table 4.**

*Study schedule (adapted from Yamada et al. [18]).*

prolonged (i.e., 1-month) change of social cognition may be mediated through several mechanisms, including the LTP, a continuous enhancement of signal transduction between neurons, and related neural events [12, 13]. As social cognition is considered to be linked to functional outcomes [5], multi-session, rather than single-session tDCS may provide benefits for functional recovery in patients with schizophrenia.

The current results, with tDCS as an interventional tool, may facilitate an understanding of the neural basis for social cognitive dysfunction. The neural circuity

#### **Figure 3.**

*Outcome measures at baseline and follow-up (1 month after the tDCS). tDCS: transcranial direct current stimulation, SCSQ: Social Cognition Screening Questionnaire, FEST: Facial Emotion Selection Test.*

governing social cognition consists of the orbitofrontal cortex, medial prefrontal cortex, superior temporal sulcus/gyrus, and amygdala, in which the amygdala is considered as a hub [18–20]. Specifically, the amygdala interconnects with both temporal lobes, e.g., STS, and frontal lobes, e.g., orbitofrontal and medial prefrontal cortex (**Figure 4**) [20]. Also, the amygdala receives various sensory stimuli, and

**Figure 4.** *Neural bases associated with social cognitive functions.*

*Social Cognitive Impairments as a Target of Non-Invasive Brain Stimulation for Functional… DOI: http://dx.doi.org/10.5772/intechopen.112742*

projects them to a wide range of cortical areas, most notably the STS and orbitofrontal cortex [20]. In patients with schizophrenia, functional connectivity among these brain regions is weakened [18–20]. Thus, pro-cognitive effects of tDCS may be associated with modification of functional connectivity, possibly through modulation of neurotransmissions [12, 13].

A strength of tDCS is its simplicity, which allows implementation in clinical settings without requiring expensive equipment, e.g., magnetic resonance imaging (MRI) machines. Such feasibility of tDCS is advantageous in, e.g., being built-in the telemedicine system.

#### **4. Limitations**

First, the small sample size of the present study may raise caution in assuming that the results can be generalized to the population. Second, as the study design is not randomized or blinded, the possibility of a placebo effect may not be completely ruled out. Third, although tDCS allows the selection of stimulation sites according to the targeted symptoms, it is difficult to fully ascertain if the electrical stimulation effectively modulates the targeted functional connectivity.

#### **5. Conclusions**

tDCS delivered to the left STS may produce benefits for some domains of social cognition, especially ToM, in patients with schizophrenia. Further investigations are warranted to determine if the type of functional outcome (e.g., daily-living activities, social function) would depend on the region of the brain stimulated by tDCS. These efforts may provide an effective therapeutic strategy to facilitate personal recovery for these patients.

#### **Acknowledgements**

We would like to thank Dr. Zui Narita and Mr. Kazuki Sueyoshi at the National Center of Neurology and Psychiatry for their valuable help.

#### **Funding**

The studies discussed in this chapter were partly supported by the Japan Society for the Promotion of Science KAKENHI Grant No.20 K16635 to YY, as well as JSPS KAKENHI Grant No. 20H03610, the Japan Health Research Promotion Bureau Grants (2020-B-08, 2021-B-01), Intramural Research Grant (2-3, 3-1) for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry to TS.

#### **Conflict of interest**

The authors declare no conflict of interest.
