Systematic Review of the Neural Effect of Electroconvulsive Therapy in Patients with Schizophrenia: Hippocampus and Insula as the Key Regions of Modulation

Article information

Psychiatry Investig. 2021;18(6):486-499
Publication date (electronic) : 2021 June 24
doi :
1Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
2Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
3Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea
4Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea
Correspondence: Minah Kim, MD, PhD Department of Neuropsychiatry, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea Tel: +82-2-2072-7211, Fax: +82-2-747-9063, E-mail:
Received 2020 December 21; Revised 2021 February 21; Accepted 2021 March 3.



Electroconvulsive therapy (ECT) has been the most potent treatment option for treatment-resistant schizophrenia (TRS). However, the underlying neural mechanisms of ECT in schizophrenia remain largely unclear. This paper examines studies that investigated structural and functional changes after ECT in patients with schizophrenia.


We carried out a systematic review with following terms: ‘ECT’, ‘schizophrenia’, and the terms of various neuroimaging modalities.


Among the 325 records available from the initial search in May 2020, 17 studies were included. Cerebral blood flow in the frontal, temporal, and striatal structures was shown to be modulated (n=3), although the results were divergent. Magnetic resonance spectroscopy (MRS) studies suggested that the ratio of N-acetyl-aspartate/creatinine was increased in the left prefrontal cortex (PFC; n=2) and left thalamus (n=1). The hippocampus and insula (n=6, respectively) were the most common regions of structural/functional modulation, which also showed symptom associations. Functional connectivity of the default mode network (DMN; n=5), PFC (n=4), and thalamostriatal system (n=2) were also commonly modulated.


Despite proven effectiveness, there has been a dearth of studies investigating the neurobiological mechanisms underlying ECT. There is preliminary evidence of structural and functional modulation of the hippocampus and insula, functional changes in the DMN, PFC, and thalamostriatal system after ECT in patients with schizophrenia. We discuss the rationale and implications of these findings and the potential mechanism of action of ECT. More studies evaluating the mechanisms of ECT are needed, which could provide a unique window into what leads to treatment response in the otherwise refractory TRS population.


Schizophrenia affects approximately 1% of global population, with more than 21 million patients worldwide [1]. Treatment- resistant schizophrenia (TRS) is defined as the absence of a response after two different antipsychotics at an adequate dosage and duration. Twenty to 50% of patients with schizophrenia are considered treatment-resistant [2-4], and, not surprisingly, treatment-resistance results in an additional socioeconomic burden that is approximately 3 to 11 times greater than the burden experienced by patients with schizophrenia who remain in remission [5]. The treatment of choice for these patients is to introduce the medication clozapine [2,4,6], but 40% to 70% of treatment-resistant patients will not respond to clozapine [7], leaving 14% to 20% of all patients with schizophrenia to be treatment refractory without better treatment options [5].

Electroconvulsive therapy (ECT) was first introduced to treat schizophrenia before antipsychotic medication was available [8]. After the late 1950s, with the advent of antipsychotic agents, the use of ECT in schizophrenia declined worldwide [9], with its primary indication being catatonia, psychotic depression, suicidality, and drug intolerability [10]. Although its main pattern of use somewhat differs among countries (according to a systematic review in 2011, in United States, Europe and Australia, 8–29% of patients receiving ECT were patients with schizophrenia, while in Asia and Africa it was 60–83%),9,11,12 ECT is currently most commonly used for patients with treatment- resistant depression [11], where its efficacy is robust and superior compared to the standard combination of antidepressants [13,14]. TRS is another clinical group in which ECT is commonly used to augment standard antipsychotic treatment [10,15]. A large volume of clinical research literature and systematic reviews along with an increasing number of treatment guidelines support the addition of ECT to antipsychotic agent regimens [15-23], including a recent review from the Cochrane systematic reviews [24]. Considering the prevalence and rather striking socioeconomic consequences of TRS, clinicians have argued that ECT should not be used as the ‘last resort’ and that it should be increasingly applied to patients with schizophrenia [9,25].

Despite this context of robust effectiveness, the underlying mechanism of action of ECT has largely remained elusive. Historically, the generalized seizure hypothesis, changes in neurotransmitters and neuroendocrine function hypothesis, and the neurotrophic hypothesis has been postulated as working models of ECT [26]. Recent studies examining depressive patients have consistently found increased bilateral hippocampal volumes by ECT [27-31], providing support for the neurotrophic hypothesis, but correlations between volumetric changes and clinical improvements were found to be repeatedly inconclusive, leaving out the main ‘key’ factor regarding the long unanswered question of ECT’s clinical effectiveness. Furthermore, the factors leading to clinical improvement after ECT in schizophrenia patients are cryptic, with only a small number of studies and divergent findings. This is indicative of a largely underrepresented current state of research for a disease with such great burden and the tantalizing problems of obstinacy. Identification and delineation of the common and disease-specific effects of ECT can serve to provide insights into the currently ‘untreatable’ TRS population, which constitutes a major problem in the modern practice of psychiatry. Thus, we aimed to systematically review the current status of research investigating the effects of ECT in schizophrenia patients using, utilizing etc. various neuroimaging modalities.


PubMed, EMBASE, and the Cochrane Reviews were searched for publications with the following keywords: ‘ECT’, ‘schizophrenia’, and the terms of various neuroimaging modalities. Studies available based on the search by May 1, 2020, were included. We intended to include articles that examined patients with schizophrenia undergoing ECT sessions and implemented at least one neuroimaging modality according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Articles published before the 1990s were excluded owing to two reasons: 1) to minimize the heterogeneity among study methods, and because 2) earlier studies tended to focus on deleterious side effects of ECT [32-34]. While ECT can bring about selective cognitive side effects such as acute delirium or impairments in autobiographic memory, it is nowadays widely agreed that ECT does not cause other severe long-lasting side effects such as brain damage or dementia [35]. Detailed descriptions of the methods are provided in the supplementary methods in the supplementary material.


Study selection and characteristics

During the initial search, 325 articles were found, and after removing 3 duplicates, 322 articles were screened. A total of 305 records that unmet the inclusion criteria were excluded after abstract screening (PRISMA flowchart, Figure 1).

Figure 1.

Flowchart of the literature review process. *Three studies studied both structural and functional MRI changes after ECT, and thus was included in both structural and functional MRI categories. ECT: electroconvulsive therapy, MRI: magnetic resonance imaging, MRS: magnetic resonance spectroscopy, PET: positron emission tomography, SPECT: single positron emission computer tomography, NIRS: near-infrared spectroscopy.

A total of 17 studies were selected and considered eligible for inclusion in the current review. Three of the studies explored the role of ECT in changes in cerebral blood flow (CBF), 3 studies used magnetic resonance spectroscopy (MRS) to measure changes in brain metabolites, and 11 studies used magnetic resonance imaging (MRI) as the study modality (6 structural and 8 functional studies, with 3 using both modalities). Detailed information about each study eligible for inclusion in the review is provided in Supplementary Results and Supplementary Table 1 in the Supplementary Materials (in the online-only Data Supplement).

Effect of ECT on cerebral blood flow

Three studies measured changes in CBF using differing study modalities, namely, of positron emission tomography (PET), single-photon emission computed tomography (SPECT), and near-infrared spectroscopy (NIRS) (Table 1).

Cerebral blood flow in patients with schizophrenia receiving electroconvulsive therapy (ECT)

A PET study reported decreased CBF in the bilateral frontal lobes, right temporal lobe, and right putamen after ECT (n=5) compared to controls (n=6) [36]. In another study, CBF in the right parietal and bilateral temporal lobes measured using SPECT was increased in patients with schizophrenia (n=5) compared with MDD patients (n=5) [37]. A NIRS study revealed an increased blood flow ratio of the left prefrontal cortex (PFC) to right PFC in patients with schizophrenia (n=11) after ECT, an asymmetry that was not observed in the MDD (n=10) group [38].

Effect of ECT on brain metabolites

Three studies examined the changes in brain metabolites using MRS (Table 2). Two independent studies (n=34 and n= 10) revealed changes of N-acetyl-aspartate/creatinine (NAA/ Cr) ratio in the left PFC and the left thalamus [39,40]. Another study showed an increase in medial prefrontal γ-aminobutyric acid (GABA) levels (n=14) [41].

Brain metabolites measured by magnetic resonance spectroscopy in patients with schizophrenia receiving electroconvulsive therapy (ECT)

Effect of ECT on brain structures

Six studies investigated structural changes after ECT in patients with schizophrenia. Table 3 demonstrates the findings of each study according to the method of analysis [wholebrain analysis or region-of-interest (ROI) analysis]. Notably, three datasets from three different study groups were analyzed, and using different and complementary analysis methods, a total of six publications were included. This relatively small number of studies may be partially attributed to the relatively restricted use of ECT in some parts of the world [11], with varying treatment guidelines across nations, and a series of index ECT treatments require approximately one month to perform, which raises the issue of accessibility.

Regional volumes measured by structural magnetic resonance imaging in patients with schizophrenia receiving ECT

One group compared the effects of ECT on patients with schizophrenia (n=9) and MDD (n=12) [42,43]. Based on the results of the whole-brain analysis, the authors found that the gray matter volume (GMV) in the medial temporal lobe (MTL) network and the left dorsolateral prefrontal cortex (DLPFC) increased in patients with schizophrenia after ECT [42]. An additional complementary analysis of the temporal regions revealed that increases in volumes of the hippocampus and insula were shared by patients with schizophrenia and MDD, but were restricted to the right side [43]. The post hoc withingroup analyses only revealed increased GMV in the right insula in the schizophrenia group.

Another group examined the effects of ECT on patients with schizophrenia (i.e., ECT+antipsychotic medication; n=21) compared with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only (n=21) [44-46]. Whole-brain analyses showed increased GMVs in the bilateral parahippocampal gyri/hippocampi, right temporal pole/right superior temporal gyrus (STG), and right insula after ECT compared to baseline and the antipsychotics only group [44]. Additional ROI analyses of the insula and hippocampus indicated increased GMVs in the bilateral dorsal anterior insula and posterior insula [46] and bilaterally increased hippocampal volumes [45]. An analysis stratified according to response status to ECT further showed that higher baseline volumes in the left hippocampus-amygdala transition area (HATA) were observed in responders [45].

A separate study group reported that baseline GMVs in the temporal region, including the right insula, left middle temporal gyrus (MTG), and the right STG, along with the left inferior frontal gyrus (IFG), predicted ECT response [47].

While the specific findings differed among studies, reviewed results overlap in findings of increased GMVs in the hippocampus (whole-brain analysis, n=2; ROI analysis, n=2) and the right insula (whole-brain analyses, n=2; ROI analysis, n=2).

Effect of ECT on functional connectivity

Eight studies from four different groups examined restingstate functional connectivity (rsFC) after ECT. Table 4 demonstrates the findings of each study according to the method of analysis (whole-brain analysis or ROI analysis). Findings common to these studies were changes in the rsFC of the default mode network (DMN), PFC, thalamus, hippocampus, and insula.

Functional connectivity measured by functional magnetic resonance imaging in patients with schizophrenia receiving ECT

The first study group, which included schizophrenia (n=9) and MDD (n=12) patients, performed a whole-brain analysis and observed increased rsFC of the medial prefrontal cortex (mPFC) within the DMN, between the executive network and the DMN, and between the executive network and salience network, along with decreased low-frequency oscillations in the striatal networks in patients with schizophrenia after ECT [48]. ROI analyses of the amygdala to other brain regions showed decreased rsFC between the right amygdala and various regions, including the mPFC, insula, and DLPFC [43].

The second study group compared patients with schizophrenia treated with either ECT (n=21) or antipsychotics alone (n=21). Whole-brain analyses showed increased connectivity of the ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) after ECT compared with the antipsychotics only group and controls [49]. This group performed ROI analyses of the insular subfields [46], hippocampus [45], and thalamic subfields [50]. While significant changes in various regions were found, responders to ECT exhibited increased rsFC of the hippocampus to the PFC and the hippocampus to the DMN [45], and between the thalamus and regions of the temporal lobe and the cerebellum [50].

The third group simulated electrical fields of ECT stimulation to select regions with large electrical fields, and compared the changes in those regions before and after ECT (n=47) [51]. After ECT, rsFC between the right amygdala and left hippocampus was increased compared to baseline.

The fourth group observed altered rsFC within various networks, including the DMN and temporal lobe networks, in the ECT group compared with antipsychotics only group [52].

The results from the aforementioned studies suggest rsFC of the DMN and associated regions (n=5), PFC (n=4), thalamus (n=2), hippocampus (n=2) and insula (n=2) were commonly altered after ECT.

Associations with clinical improvement and ECT response status

Findings of significant associations with clinical improvement and the status of the ECT response are listed in Supplementary Tables 2 and 3 (in the online-only Data Supplement), respectively. Four studies reported associations of clinical improvement with changes in the hippocampus [44,45,51,52], two studies with changes in the insula [46,47], and one study with changes in the amygdalar region, respectively [51].


This is the first systematic review to examine neural effects of ECT in patients with schizophrenia. A standardized literature search yielded 17 studies. The majority of recent studies (n=11) used MRI as the study modality, which examined morphometric (n=6) and functional (n=8) changes before and after ECT. An additional six studies investigated the effect of ECT on CBF (n=3) and brain metabolites (n=3). Overall, the reviewed publications considerably differed in both study designs and modalities, which precluded performing a metaanalysis.

Cerebral blood flow changes after ECT

Two studies compared changes in blood flow after ECT in patients with schizophrenia and patients with MDD and observed increased blood flow in patients with schizophrenia using SPECT and NIRS, respectively [37,38]. Notably, studies of patients with MDD quite frequently report decreased blood flow in various regions following ECT sessions [53]. Two other studies compared the data obtained from patients with schizophrenia before and after ECT, and one study did not report significant alterations (SPECT) [37], while the other reported decreased blood flow after ECT (PET) [36]. Due to the small numbers and discrepancies in study modalities and findings, a solid conclusion concerning changes in blood flow after ECT is difficult to obtain.

Changes in brain metabolites after ECT

Other studies examined changes in brain metabolites using MRS; interestingly, two studies reported increased NAA/Cr ratios in the left PFC and the left thalamus. The NAA/Cr ratio is considered an indicator of neuronal integrity [54,55], which is known to decrease in conditions such as aging, brain tumors, and acute pathological processes [56], and these decreases are known to be reversible with treatment [55]. Previous meta-analyses provided consistent evidence of decreased NAA/Cr ratios in the hippocampus, thalamus, frontal and temporal lobes of patients with schizophrenia [57], which, interestingly, were increased after antipsychotic treatment [58,59]. Although these findings must be replicated in the future due to the small number of studies that utilized MRS, the increase in NAA/Cr ratios in the left PFC and the left thalamus, regions that are strongly implicated in the pathophysiological hypothesis of schizophrenia [60-63], may imply therapeutic neuronal ‘reorganization’ by ECT. These results from MRS, since they contain properproperties of both structure and function, might serve integrative functions in explaining the effects of ECT when results from MRI studies are combined along with the proposed pathophysiological models of schizophrenia. Future studies examining NAA, GABA, and glutamate or glutamine in the regions highly implicated in schizophrenia and ECT (such as the frontal and temporal lobes, the hippocampus, and thalamostriatal regions), may help to further our understanding of the mechanism of action of ECT.

Structural and functional changes after ECT

Only four study groups independently examined the neural effects of ECT on patients with schizophrenia. Although fewer studies of patients with schizophrenia have been reported than studies of patients with depression, the results quite consistently indicate increases in the volumes of the hippocampus (structural, n=4) and insula (structural, n=4). Additionally, a comparison of patients with schizophrenia and MDD revealed common increases in the GMVs of the hippocampus, while the increases in right insular GMV were restricted to patients with schizophrenia [43]. FC studies presented more divergent results for different ROIs, while commonly identified alterations were located within the regions of the DMN (functional, n=5), PFC (n=4), thalamostriatal system (n=2), hippocampus (n=2), and insula (n=2). Moreover, among the features that were associated with symptom reductions were the hippocampus (n=4), insula (n=2), and amygdala (n=1).

From the integrated findings of both structural and functional measures, we infer, albeit preliminarily, that the hippocampus (total, n=6; symptom associations, n=4) and insula (total, n=6; symptom associations, n=2) are the common regions of modulation in patients with schizophrenia after ECT.


The insula is located deep within the lateral sulcus of the human brain. The upper cortices that cover the insula are called the operculum, which are composed of parts of the adjacent frontal, temporal, and parietal cortices. The insula is involved in various functions, such as interoception, multimodal sensory processing [64], self-related processes [65-68], taste [69], social emotions [70-73], homeostasis [74,75] and auditory perception [76-78]. This whole spectrum of functions can be served owing to the extensive viscerosensory inputs into the region and its anatomical position amidst three different cerebral lobes permitting dense reciprocal connections with the limbic, prefrontal, somatosensory, and temporal areas [79,80].

The results from the current systematic review revealed increased GMVs in the right insula in all of the structural MRI studies that performed whole-brain analysis. While conclusion should not be drawn solely based on this result, the underlying implication of insular involvement in patients with schizophrenia suggests that the insula has some unique characteristics worth further discussion.

First, the insula is one of the most consistent regions showing structural alterations in patients with schizophrenia. An anecdotal meta-analysis that included studies performing wholebrain analyses showed that approximately 50% and 40% of studies (which ranks as 7th and 10th, respectively among all regions of interest) reported reduced volumes of left and right insular areas, respectively [81]. Indeed, structural alterations of the insula are considered the most consistent findings in psychosis subjects [82]. In a meta-analysis performed by Crow et al. [82], the insula was the most commonly reported area showing volumetric reduction, followed by the thalamus and anterior cingulate cortex. Additionally, in terms of numbers, right insula was the most commonly reported altered area, while in terms of the size of volumetric reductions, left insular defects were more profound in patients with schizophrenia [82].

Second, recent studies have demonstrated insular involvement in auditory sensory processing. Intracranial electroencephalography recordings found auditory responses of the posterior insula resembling the response in Heschl’s gyrus [77], and a separate study implicated insular involvement in auditory deviance detection and the formation of mismatch negativity [78]. Abnormal sensory gating and altered auditory evoked potentials are one of the key pathophysiological findings explaining the phenomena of hallucinations in schizophrenia patients [83]. Since clinical observations have suggested that ECT is more effective in refractory positive symptoms than in negative domains [15], amelioration of clinical symptoms after ECT might be mediated in part by modulation of the insular cortex.

Third, although its implications in schizophrenia remain unclear, lateralized functions of the insula appear to be related to the control of the autonomic nervous system. Various studies ranging from intraoperative intracranial electrical stimulation to lesion studies have shown that the right insula is involved in the top-down control of sympathetic tone [75,84-86]. While the findings have been somewhat inconsistent, various types of autonomic dysfunction, such as alterations in heart rate variability (HRV) [87,88] and decreased vagal tone [89,90], have been reported in patients with schizophrenia. Autonomic responses and control during stressful situations constitute an important axis in the stress diathesis model of psychiatric illness [91-93], and insular modulation by ECT may exert some effects on the central control of sympathetic nervous system tone.

Finally, the self-related functions of insula share striking commonalities in terms of the main psychopathology of delusions and hallucinations in patients with schizophrenia. Among the wide range of insular dysfunctions demonstrated in patients with schizophrenia [94-100], some studies have reportreported a relationship between decreased right insular volumes and delusion severity [94] or degree of insight [97]. Delusion and hallucination are considered externalizing psychopathologies, which suggest impairment in the insular functions of interoception and self-attribution in patients with schizophrenia.


The modulation of the hippocampus and its neurotrophic functions by ECT are very strongly supported by findings from animal models of electroconvulsive seizure (ECS) and patients with MDD. The increase in the hippocampal volume observed in patients with depression after ECT are not only a robust finding but also explains many aspects of depression, including its treatment and etiology. Concerning treatment, ECT is considered the most effective treatment modality in depression, including treatment-resistant cases [13,14]. Approximately 50% to 60% of treatment-resistant depression patients will respond to ECT [13], and its efficacy is deemed to be five- to six-fold greater than antidepressant therapy. In addition, the chronic stress model of depression is closely associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis [101], as both early life and chronic stress are known to increase levels of the stress hormone cortisol and alter the functions of the HPA axis [102]. Stress and HPA axis dysfunction are known to exert deleterious effect on hippocampus, including cell loss and volume reductions [103,104].

Meanwhile, most researchers appreciate that schizophrenia is a ‘dysconnection’ syndrome among large distributed brain networks [105,106], rather than problem of a single faulty region. Notwithstanding, hippocampal hyperactivity is among the most consistent functional abnormalities observed in patients with schizophrenia [107-109]. Postmortem studies have replicated reduced hippocampal volumes [110-112], which are also consistent with the current body of neuroimaging studies in patients with schizophrenia [113-116]. In addition, while the number of neurons in the hippocampus is not significantly altered, reduction in inhibitory interneuron population of the hippocampus was demonstrated [107,108,117]. Studies measuring blood flow and metabolism also replicated abnormalities in the hippocampus, and subsequent studies have found that these metabolic shifts are associated with a greater reduction in hippocampal volume with disease progression [109]. Additionally, neuroimaging and animal studies have consistently reported reductions in the volumes of hippocampal subfields, with CA1 subfield showing the most robust changes [118,119].

The dopamine hypothesis of schizophrenia was born based on the clinical effectiveness of antipsychotic agent chlorpromazine [120-122]. The modern mainstream pathophysiological hypothesis of schizophrenia focuses on abnormality of the glutamate system and impairment in interneuron functions [123-125]. Hippocampal hyperactivity can be explained by both the dopamine and glutamate hypotheses. First, while optimal levels of dopamine can enhance memory and functions subserved by the hippocampus, higher levels of dopamine were demonstrated to exert deleterious effects [112,126,127]. Neuronal connections between the ventral hippocampus and striatum are bidirectional and capable of modulating dopamine levels in the other structure [126,128,129]. This means that the dysfunctionally increased dopamine levels in the striatum can induce high dopamine levels in hippocampal areas, and vice versa, which could lead to hippocampal hyperactivity. Second, the hippocampus is among one of the most implicated areas concerning the glutamate hypothesis, which includes NMDA receptor hypofunction and reduced inhibitory interneuron function [107]. These interneuron abnormalities result not only in hyperactivity of the hippocampus but also in dysfunctional connectivity, which includes connections to the striatum and the frontal lobes [126,129,130].

Moreover, with regard to the neurotrophic hypothesis of ECT, there is considerable evidence that neurogenesis functions are altered in schizophrenia [131-133]. Animal models of psychosis have demonstrated decreased adult neurogenesis [134-136]. However, animal models of schizophrenia are mainly induced by administering substances known to induce psychotic illness [129]. While the psychotic state itself is indeed important in understanding the pathology of schizophrenia, it may not be sufficient since schizophrenia follows a more chronic and deteriorating clinical course, including negative symptoms and cognitive impairment. Tracing adult neurogenesis in vivo in patients is methodologically difficult due to technical issues, and thus surrogate markers are frequently used to measure adult neurogenesis, such as Nestin, Ki-67 and Musashi-1, which are expressed in proliferating cells [132,137-139]. Of such markers, downregulation of Ki-67 has been observed in the dentate gyrus of patients with schizophrenia compared to controls [139]. In addition, induced pluripotent stem cell studies have modeled deficient functioning of dentate gyrus granule cells in schizophrenia, marked by alterations in gene expression of adult neurogenesis and decreased functioning [140]. Additionally, numerous genes implicated in schizophrenia, such as DISC1, Neuroregulin-1, Reelin, are associated with neurogenesis [132,141]. Although the direct findings of dysfunctional adult neurogenesis in patients with schizophrenia await verification, these functions are presumed to be altered when the previous literature is considered.

Specificity of the findings and implications

While these results provide evidence of changes in the hippocampus and insula of patients with schizophrenia, several important issues must be considered. First, might these results arise from nonspecific changes induced by ECT, such as edema, inflammation, or reactive gliosis [30]? While this is a possibility that needs to be addressed more thoroughly in future studies, existing evidence from both animal and human studies suggests that the effects of ECT cannot be fully attributed to these nonspecific effects. While ECS in animal models potentiates a wide range of alterations covering various regions of the brain, the results of ECS studies demonstrate rather specific changes in the hippocampal region with marked alterations in neuroplastic functions [142]. Additionally, in human studies, neuroimaging within 15 hours after ECT did not detect marked change in fluid shifts in the hippocampal region [30,143]. Moreover, studies of patients with MDD that controlled for overall cerebral volumes to address these issues have also reported a significant increase in the volume of the hippocampus apart from such nonspecific effects [30,144-147].

Second, are these changes common both to MDD and schizophrenia, or are they disease-specific? Previous attempts to explain the mechanisms underlying ECT have largely focused on the overall ECT effect, without differentiating between the two disorders [26]. While conclusions based on the currently insufficient body of evidence may be preliminary, the hippocampus appears to be commonly modulated in both animals and human subjects (including both patients with MDD and schizophrenia), while comparisons of patients with MDD with patients with schizophrenia observed increased volumes in the right insula restricted to the schizophrenia group [43]. However, this evidence is preliminary and needs replication, and current research is even more scarce in terms of what are the requisite conditions for ECT to be effective and the relationship between hippocampal modulation and symptom improvements.

An important difference in the application of ECT between patients with MDD and schizophrenia is that ECT results in a very high proportion of responses and remission among patients with MDD [148]; however, approximately one-third of patients with schizophrenia do not adequately benefit from ECT treatment [19]. Therefore, to clearly delineate schizophrenia-specific ECT treatment effects from the common effects of electrical stimulation, classifying patients into responders and nonresponders and comparing between the two groups might prove useful in future studies.

Furthermore, as the discovery of the effect of chlorpromazine preceded the development of the dopamine hypothesis, efforts to identify the mechanism of ECT may also help to improve our understanding of treatment-resistance in patients with schizophrenia. While treatment-resistance constitutes a serious mental health problem, the neurobiological underpinnings of TRS are at best only poorly understood due to the lack of consistent findings hitherto [149-151]. Because it can now be appreciated, based on large volumes of previous animal and MDD research, that the effects of ECT are specific to some regions, establishing the neurobiological substrates of ECT and combining them with stratification based on treatment response may provide some valuable insights to understanding the neural underpinnings of TRS.


There are several limitations of this review. First and most importantly, a small number of studies with divergent modalities precluded a systematic meta-analysis. Second, individually selected ROIs among various studies also made it difficult to infer which region or networks were most consistently modulated after ECT in schizophrenia patients. Third, as discussed above, hippocampal and insular modulation might be a common end result of ECT and may not define schizophrenia-specific alterations.


This systematic review presents preliminary evidence of hippocampal and insular modulation after ECT in patients with schizophrenia. This holds true for morphometry, FC, and symptom association measures. Other potential candidates include the DMN, PFC, and thalamostriatal system, as demonstrated by MRS and fMRI studies, and the amygdala, along with the hippocampus and insula, which were associated with symptom reductions. However, due to the small number of studies, replication is indispensable to generalize and elaborate our understanding of the neurobiological underpinnings of the ECT effect in schizophrenia patients.

We believe that ECT provides a unique window to the understanding and management of treatment-resistance in patients with schizophrenia. However, the effect and mechanism of action of ECT are most likely to be complex and possibly mediated by various structural, functional, and metabolic alterations. Dysfunctional neurotrophic factors in schizophrenia could partially be remedied by ECT, but other factors, including neurotransmitter changes, synaptic remodeling, and restoration of altered FC in other largely distributed networks, may also play an important role. To disentangle the mystifying mechanisms of ECT, augmentation of functional approaches (functional MRI, MRS, electroencephalography) with morphometric results might prove useful in future study designs.

Supplementary Materials


This research was supported by the Brain Research Program and the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (Grant nos. 2017M3C7A1029610 and 2019R1C1C1002457).


The authors have no potential conflicts of interest to disclose.

Author Contributions

Conceptualization: Minah Kim, Jun Soo Kwon. Data curation: Sun-Young Moon, Minah Kim. Formal analysis: Sun-Young Moon, Minah Kim. Funding acquisition: Minah Kim, Jun Soo Kwon. Investigation: all authors. Methodology: Sun-Young Moon, Minah Kim. Project administration: Minah Kim. Resources: Minah Kim, Jun Soo Kwon. Supervision: Minah Kim. Validation: Minah Kim, Se Hyun Kim, Jun Soo Kwon. Writing—original draft: Sun-Young Moon. Writing—review & editing: Minah Kim, Se Hyun Kim, Jun Soo Kwon.


1. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789–1858.
2. Elkis H, Buckley PF. Treatment-resistant schizophrenia. Psychiatr Clin North Am 2016;39:239–265.
3. Essock SM, Hargreaves WA, Covell NH, Goethe J. Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacol Bull 1996;32:683–697.
4. Lindenmayer JP. Treatment refractory schizophrenia. Psychiatr Q 2000;71:373–384.
5. Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia. Int Clin Psychopharmacol 2014;29:63–76.
6. Nucifora FC Jr, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: clinical, biological, and therapeutic perspectives. Neurobiol Dis 2018;131:104257.
7. Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994;151:1744–1752.
8. Fink M. Convulsive therapy: a review of the first 55 years. J Affect Disord 2001;63:1–15.
9. Chanpattana W, Andrade C. ECT for treatment-resistant schizophrenia. J ECT 2006;22:4–12.
10. Rosenquist PB, Youssef NA, Surya S, McCall WV. When all else fails. Psychiatr Clin North Am 2018;41:355–371.
11. Leiknes KA, Jarosh-von Schweder L, Høie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav 2012;2:283–344.
12. Sanghani SN, Petrides G, Kellner CH. Electroconvulsive therapy (ECT) in schizophrenia. Curr Opin Psychiatry 2018;31:213–222.
13. Loo C. ECT in the 21st century: optimizing treatment. J ECT 2010;26:157.
14. Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT 2004;20:13–20.
15. Grover S, Sahoo S, Rabha A, Koirala R. ECT in schizophrenia: a review of the evidence. Acta Neuropsychiatr 2018;31:115–127.
16. Ali SA, Mathur N, Malhotra AK, Braga RJ. Electroconvulsive therapy and schizophrenia: a systematic review. Mol Neuropsychiatry 2019;5:75–83.
17. Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 2016;50:410–472.
18. Grover S, Chakrabarti S, Kulhara P, Avasthi A. Clinical practice guidelines for management of schizophrenia. Indian J Psychiatry 2017;59(Suppl 1):S19–S33.
19. Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 2016;171:215–224.
20. Miller AL, Hall CS, Buchanan RW, Buckley PF, Chiles JA, Conley RR, et al. The texas medication algorithm project antipsychotic algorithm for schizophrenia. J Clin Psychiatry 2004;65:500–508.
21. Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry 2015;172:52–58.
22. Pompili M, Lester D, Dominici G, Longo L, Marconi G, Forte A, et al. Indications for electroconvulsive treatment in schizophrenia: a systematic review. Schizophr Res 2013;146:1–9.
23. Zheng W, Cao XL, Ungvari GS, Xiang YQ, Guo T, Liu ZR, et al. Electroconvulsive therapy added to non-clozapine antipsychotic medication for treatment resistant schizophrenia: meta-analysis of randomized controlled trials. PLoS One 2016;11:e0156510.
24. Sinclair DJ, Zhao S, Qi F, Nyakyoma K, Kwong JS, Adams CE. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev 2019;3:CD011847.
25. Teodorczuk A, Emmerson B, Robinson G. Revisiting the role of electroconvulsive therapy in schizophrenia: where are we now? Australas Psychiatry 2019;27:477–479.
26. Bolwig TG. How does electroconvulsive therapy work? Theories on its mechanism. Can J Psychiatry 2011;56:13–18.
27. Gbyl K, Videbech P. Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis. Acta Psychiatr Scand 2018;138:180–195.
28. Nordanskog P, Dahlstrand U, Larsson MR, Larsson EM, Knutsson L, Johanson A. Increase in hippocampal volume after electroconvulsive therapy in patients with depression. J ECT 2010;26:62–67.
29. Takamiya A, Chung JK, Liang KC, Graff-Guerrero A, Mimura M, Kishimoto T. Effect of electroconvulsive therapy on hippocampal and amygdala volumes: systematic review and meta-analysis. Br J Psychiatry 2018;212:19–26.
30. Wilkinson ST, Sanacora G, Bloch MH. Hippocampal volume changes following electroconvulsive therapy: a systematic review and metaanalysis. Biol Psychiatry Cogn Neurosci Neuroimaging 2017;2:327–335.
31. Yrondi A, Péran P, Sauvaget A, Schmitt L, Arbus C. Structural–functional brain changes in depressed patients during and after electroconvulsive therapy. Acta Neuropsychiatr 2018;30:17–28.
32. Devanand DP, Dwork AJ, Hutchinson ER, Bolwig TG, Sackeim HA. Does ECT alter brain structure? Am J Psychiatry 1994;151:957–970.
33. Weiner RD. Does electroconvulsive therapy cause brain damage? Behav Brain Sci 2010;7:1–22.
34. Menken M, Safer J, Goldfarb C, Varga E. Multiple ECT: morphologic effects. Am J Psychiatry 1979;136:453.
35. Bouckaert F, Sienaert P, Obbels J, Dols A, Vandenbulcke M, Stek M, et al. ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity. J ECT 2014;30:143–151.
36. Uesugi H, Toyoda J, Iio M. Positron emission tomography and plasma biochemistry findings in schizophrenic patients before and after electroconvulsive therapy. Psychiatry Clin Neurosci 1995;49:131–135.
37. Escobar R, Rios A, Montoya ID, Lopera F, Ramos D, Carvajal C, et al. Clinical and cerebral blood flow changes in catatonic patients treated with ECT. J Psychosom Res 2000;49:423–429.
38. Fujita Y, Takebayashi M, Hisaoka K, Tsuchioka M, Morinobu S, Yamawaki S. Asymmetric alternation of the hemodynamic response at the prefrontal cortex in patients with schizophrenia during electroconvulsive therapy: a near-infrared spectroscopy study. Brain Res 2011;1410:132–140.
39. Gan JL, Duan HF, Cheng ZX, Yang JM, Zhu XQ, Gao CY, et al. Neuroprotective effect of modified electroconvulsive therapy for schizophrenia. J Nerv Ment Dis 2017;205:480–486.
40. Lotfi M, Jahromi MG, Firoozabadi A, Jahromi LR. Effect of adjuvant electroconvulsive therapy compared to antipsychotic medication alone on the brain metabolites of patients with chronic schizophrenia: a proton magnetic resonance spectroscopy study. Iran J Psychiatry 2018;13:215–221.
41. Xia M, Wang J, Sheng J, Tang Y, Li C, Lim K, et al. Effect of electroconvulsive therapy on medial prefrontal γ-aminobutyric acid among schizophrenia patients. J ECT 2018;34:227–232.
42. Wolf RC, Nolte HM, Hirjak D, Hofer S, Seidl U, Depping MS, et al. Structural network changes in patients with major depression and schizophrenia treated with electroconvulsive therapy. Eur Neuropsychopharmacol 2016;26:1465–1474.
43. Thomann PA, Wolf RC, Nolte HM, Hirjak D, Hofer S, Seidl U, et al. Neuromodulation in response to electroconvulsive therapy in schizophrenia and major depression. Brain Stimul 2017;10:637–644.
44. Wang J, Tang Y, Curtin A, Xia M, Tang X, Zhao Y, et al. ECT-induced brain plasticity correlates with positive symptom improvement in schizophrenia by voxel-based morphometry analysis of grey matter. Brain Stimul 2019;12:319–328.
45. Jiang Y, Xu L, Li X, Tang Y, Wang P, Li C, et al. Common increased hippocampal volume but specific changes in functional connectivity in schizophrenia patients in remission and non-remission following electroconvulsive therapy: a preliminary study. Neuroimage Clin 2019;24:102081.
46. Jiang Y, Xia M, Li X, Tang Y, Li C, Huang H, et al. Insular changes induced by electroconvulsive therapy response to symptom improvements in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2019;89:254–262.
47. Gong J, Cui LB, Xi YB, Zhao YS, Yang XJ, Xu ZL, et al. Predicting response to electroconvulsive therapy combined with antipsychotics in schizophrenia using multi-parametric magnetic resonance imaging. Schizophr Res 2020;216:262–271.
48. Sambataro F, Thomann PA, Nolte HM, Hasenkamp JH, Hirjak D, Kubera KM, et al. Transdiagnostic modulation of brain networks by electroconvulsive therapy in schizophrenia and major depression. Eur Neuropsychopharmacol 2019;29:925–935.
49. Huang H, Jiang Y, Xia M, Tang Y, Zhang T, Cui H, et al. Increased resting- state global functional connectivity density of default mode network in schizophrenia subjects treated with electroconvulsive therapy. Schizophr Res 2018;197:192–199.
50. Wang J, Jiang Y, Tang Y, Xia M, Curtin A, Li J, et al. Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia. Schizophr Res 2020;218:209–218.
51. Yang X, Xu Z, Xi Y, Sun J, Liu P, Liu P, et al. Predicting responses to electroconvulsive therapy in schizophrenia patients undergoing antipsychotic treatment: baseline functional connectivity among regions with strong electric field distributions. Psychiatry Res 2020;299:111059.
52. Li P, Jing RX, Zhao RJ, Ding ZB, Shi L, Sun HQ, et al. Electroconvulsive therapy-induced brain functional connectivity predicts therapeutic efficacy in patients with schizophrenia: a multivariate pattern recognition study. NPJ Schizophr 2017;3:21.
53. Abbott CC, Gallegos P, Rediske N, Lemke NT, Quinn DK. A review of longitudinal electroconvulsive therapy: neuroimaging investigations. J Geriatr Psychiatry Neurol 2014;27:33–46.
54. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AMA. Nacetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007;81:89–131.
55. Soares DP, Law M. Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications. Clin Radiol 2009;64:12–21.
56. Hollingworth W, Medina LS, Lenkinski RE, Shibata DK, Bernal B, Zurakowski D, et al. A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors. AJNR Am J Neuroradiol 2006;27:1404–1411.
57. Steen RG, Hamer RM, Lieberman JA. Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis. Neuropsychopharmacology 2005;30:1949–1962.
58. Kubota M, Moriguchi S, Takahata K, Nakajima S, Horita N. Treatment effects on neurometabolite levels in schizophrenia: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Schizophr Res 2020;222:122–132.
59. Paslakis G, Träber F, Roberz J, Block W, Jessen F. N-acetyl-aspartate (NAA) as a correlate of pharmacological treatment in psychiatric disorders: a systematic review. Eur Neuropsychopharmacol 2014;24:1659–1675.
60. Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Ponto LLB, et al. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet 1997;349:1730–1734.
61. Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical- cerebellar circuitry? Schizophr Bull 1998;24:203–218.
62. Cho KIK, Kwak YB, Hwang WJ, Lee J, Kim M, Lee TY, et al. Microstructural changes in higher-order nuclei of the thalamus in patients with first-episode psychosis. Biol Psychiatry 2019;85:70–78.
63. Woodward ND, Karbasforoushan H, Heckers S. Thalamocortical dysconnectivity in schizophrenia. Am J Psychiatry 2012;169:1092–1099.
64. Bushara KO, Hanakawa T, Immisch I, Toma K, Kansaku K, Hallett M. Neural correlates of cross-modal binding. Nat Neurosci 2002;6:190–195.
65. Craig ADB. How do you feel—now? The anterior insula and human awareness. Nat Rev Neurosci 2009;10:59–70.
66. Farrer C, Frith CD. Experiencing oneself vs another person as being the cause of an action: the neural correlates of the experience of agency. Neuroimage 2002;15:596–603.
67. Karnath HO, Baier B, Nägele T. Awareness of the functioning of one’s own limbs mediated by the insular cortex? J Neurosci 2005;25:7134–7138.
68. Tsakiris M, Hesse MD, Boy C, Haggard P, Fink GR. Neural signatures of body ownership: a sensory network for bodily self-consciousness. Cereb Cortex 2006;17:2235–2244.
69. Pritchard TC, Macaluso DA, Eslinger PJ. Taste perception in patients with insular cortex lesions. Behav Neurosci 1999;113:663–671.
70. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16:331–348.
71. Quarto T, Blasi G, Maddalena C, Viscanti G, Lanciano T, Soleti E, et al. Association between ability emotional intelligence and left insula during social judgment of facial emotions. PLoS One 2016;11:e0148621.
72. Sanfey AG. The neural basis of economic decision-making in the ultimatum game. Science 2003;300:1755–1758.
73. Singer T. The neuronal basis and ontogeny of empathy and mind reading: review of literature and implications for future research. Neurosci Biobehav Rev 2006;30:855–863.
74. Critchley HD. Neural mechanisms of autonomic, affective, and cognitive integration. J Comp Neurol 2005;493:154–166.
75. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727–1727.
76. Afif A, Minotti L, Kahane P, Hoffmann D. Anatomofunctional organization of the insular cortex: a study using intracerebral electrical stimulation in epileptic patients. Epilepsia 2010;51:2305–2315.
77. Blenkmann AO, Collavini S, Lubell J, Llorens A, Funderud I, Ivanovic J, et al. Auditory deviance detection in the human insula: an intracranial EEG study. Cortex 2019;121:189–200.
78. Zhang Y, Zhou W, Wang S, Zhou Q, Wang H, Zhang B, et al. The roles of subdivisions of human insula in emotion perception and auditory processing. Cereb Cortex 2019;29:517–528.
79. Augustine J. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 1996;22:229–244.
80. Duerden EG, Arsalidou M, Lee M, Taylor MJ. Lateralization of affective processing in the insula. Neuroimage 2013;78:159–175.
81. Honea R, Crow TJ, Passingham D, Mackay CE. Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 2005;162:2233–2245.
82. Crow TJ, Chance SA, Priddle TH, Radua J, James AC. Laterality interacts with sex across the schizophrenia/bipolarity continuum: an interpretation of meta-analyses of structural MRI. Psychiatry Res 2013;210:1232–1244.
83. Smith DM, Grant B, Fisher DJ, Borracci G, Labelle A, Knott VJ. Auditory verbal hallucinations in schizophrenia correlate with P50 gating. Clin Neurophysiol 2013;124:1329–1335.
84. Chouchou F, Mauguière F, Vallayer O, Catenoix H, Isnard J, Montavont A, et al. How the insula speaks to the heart: cardiac responses to insular stimulation in humans. Hum Brain Mapp 2019;40:2611–2622.
85. Meyer S, Strittmatter M, Fischer C, Georg T, Schmitz B. Lateralization in autononic dysfunction in ischemic stroke involving the insular cortex. Neuroreport 2004;15:357–361.
86. Nagai M, Hoshide S, Kario K. The insular cortex and cardiovascular system: a new insight into the brain-heart axis. J Am Soc Hypertens 2010;4:174–182.
87. Castro MN, Vigo DE, Weidema H, Fahrer RD, Chu EM, de Achával D, et al. Heart rate variability response to mental arithmetic stress in patients with schizophrenia. Schizophr Res 2008;99:294–303.
88. Clamor A, Hartmann MM, Köther U, Otte C, Moritz S, Lincoln TM. Altered autonomic arousal in psychosis: an analysis of vulnerability and specificity. Schizophr Res 2014;154:73–78.
89. Chang JS, Yoo CS, Yi SH, Hong KH, Oh HS, Hwang JY, et al. Differential pattern of heart rate variability in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:991–995.
90. Clamor A, Lincoln TM, Thayer JF, Koenig J. Resting vagal activity in schizophrenia: meta-analysis of heart rate variability as a potential endophenotype. Br J Psychiatry 2016;208:9–16.
91. Berntson GG, Cacioppo JT. Heart Rate Variability: Stress and Psychiatric Conditions. In : Malik M, ed. Dynamic Electrocardiography Bath: Blackwell Futura; 2004. p. 57–64.
92. Thayer JF, Åhs F, Fredrikson M, Sollers JJ, Wager TD. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev 2012;36:747–756.
93. Vrijkotte TGM, van Doornen LJP, de Geus EJC. Effects of work stress on ambulatory blood pressure, heart rate, and heart rate variability. Hypertension 2000;35:880–886.
94. Cascella NG, Gerner GJ, Fieldstone SC, Sawa A, Schretlen DJ. The insula–claustrum region and delusions in schizophrenia. Schizophr Res 2011;133:77–81.
95. Jang DP, Kim JJ, Chung TS, An SK, Jung YC, Lee JK, et al. Shape deformation of the insula in schizophrenia. Neuroimage 2006;32:220–227.
96. Linnman C, Coombs G 3rd, Goff DC, Holt DJ. Lack of insula reactivity to aversive stimuli in schizophrenia. Schizophr Res 2013;143:150–157.
97. Palaniyappan L, Mallikarjun P, Joseph V, Liddle PF. Appreciating symptoms and deficits in schizophrenia: right posterior insula and poor insight. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:523–527.
98. Palaniyappan L, Simmonite M, White TP, Liddle EB, Liddle PF. Neural primacy of the salience processing system in schizophrenia. Neuron 2013;79:814–828.
99. White TP, Joseph V, Francis ST, Liddle PF. Aberrant salience network (bilateral insula and anterior cingulate cortex) connectivity during information processing in schizophrenia. Schizophr Res 2010;123:105–115.
100. Wylie KP, Tregellas JR. The role of the insula in schizophrenia. Schizophr Res 2010;123:93–104.
101. Gotlib IH, Joormann J, Minor KL, Hallmayer J. HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry 2008;63:847–851.
102. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 2008;33:693–710.
103. Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord 2002;4:117–128.
104. Lucassen P, Heine V, Muller M, van der Beek E, Wiegant V, Ron De Kloet E, et al. Stress, depression and hippocampal apoptosis. CNS Neurol Disord Drug Targets 2006;5:531–546.
105. Friston K, Brown HR, Siemerkus J, Stephan KE. The dysconnection hypothesis (2016). Schizophr Res 2016;176:83–94.
106. Friston KJ, Frith CD. Schizophrenia: a disconnection syndrome. Clin Neurosci 1995;3:89–97.
107. Benes FM. Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry 1999;46:589–599.
108. Benes F, Berretta S. GABAergic interneurons implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;25:1–27.
109. Heckers S, Konradi C. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res 2015;167:4–11.
110. Bogerts B, Falkai P, Haupts M, Greve B, Ernst S, Tapernon-Franz U, et al. Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Schizophr Res 1990;3:295–301.
111. Dwork AJ. Postmortem studies of the hippocampal formation in schizophrenia. Schizophr Bull 1997;23:385–402.
112. Heckers S, Heinsen H, Heinsen YC, Beckmann H. Limbic structures and lateral ventricle in schizophrenia. A quantitative postmortem study. Arch Gen Psychiatry 1990;47:1016–1022.
113. van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry 2016;21:547–553.
114. Okada N, Fukunaga M, Yamashita F, Koshiyama D, Yamamori H, Ohi K, et al. Abnormal asymmetries in subcortical brain volume in schizophrenia. Mol Psychiatry 2016;21:1460–1466.
115. Koshiyama D, Fukunaga M, Okada N, Yamashita F, Yamamori H, Yasuda Y, et al. Subcortical association with memory performance in schizophrenia: a structural magnetic resonance imaging study. Transl Psychiatry 2018;8:20.
116. Koshiyama D, Fukunaga M, Okada N, Yamashita F, Yamamori H, Yasuda Y, et al. Role of subcortical structures on cognitive and social function in schizophrenia. Sci Rep 2018;8:1183.
117. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 1998;44:88–97.
118. Adriano F, Caltagirone C, Spalletta G. Hippocampal volume reduction in first-episode and chronic schizophrenia. Neuroscientist 2012;18:180–200.
119. Lieberman JA, Girgis RR, Brucato G, Moore H, Provenzano F, Kegeles L, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry 2018;23:1764–1772.
120. Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988;1:179–186.
121. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull 2009;35:549–562.
122. Meltzer HY, Stahl SM. The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 1976;2:19–76.
123. Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci 2015;1338:38–57.
124. Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 2012;37:4–15.
125. Tamminga CA. Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 1998;12:21–36.
126. Grace AA. Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology 2012;62:1342–1348.
127. Lodge DJ, Grace AA. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol Sci 2011;32:507–513.
128. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001;21:4915–4922.
129. Grace AA. Ventral hippocampus, interneurons, and schizophrenia. Curr Dir Psychol Sci 2010;19:232–237.
130. Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci 2007;27:11424–11430.
131. Reif A, Schmitt A, Fritzen S, Lesch KP. Neurogenesis and schizophrenia: dividing neurons in a divided mind? Eur Arch Psychiatry Clin Neurosci 2007;257:290–299.
132. Toro C, Deakin J. Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophr Res 2007;90:1–14.
133. Weissleder C, North HF, Shannon Weickert C. Important unanswered questions about adult neurogenesis in schizophrenia. Curr Opin Psychiatry 2019;32:170–178.
134. Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, et al. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 2007;130:1146–1158.
135. Ouchi Y, Banno Y, Shimizu Y, Ando S, Hasegawa H, Adachi K, et al. Reduced adult hippocampal neurogenesis and working memory deficits in the Dgcr8-deficient mouse model of 22q11.2 deletion-associated schizophrenia can be rescued by IGF2. J Neurosci 2013;33:9408–9419.
136. Wolf SA, Melnik A, Kempermann G. Physical exercise increases adult neurogenesis and telomerase activity, and improves behavioral deficits in a mouse model of schizophrenia. Brain Behav Immun 2011;25:971–980.
137. Blümcke I, Schewe JC, Normann S, Brüstle O, Schramm J, Elger CE, et al. Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 2001;11:311–321.
138. Crespel A, Rigau V, Coubes P, Rousset MC, de Bock F, Okano H, et al. Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiol Dis 2005;19:436–450.
139. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006;11:514–522.
140. Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Rep 2014;2:295–310.
141. Bobilev AM, Perez JM, Tamminga CA. Molecular alterations in the medial temporal lobe in schizophrenia. Schizophr Res 2020;217:71–85.
142. Altar CA, Laeng P, Jurata LW, Brockman JA, Lemire A, Bullard J, et al. Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways. J Neurosci 2004;24:2667–2677.
143. Szabo K, Hirsch JG, Krause M, Ende G, Henn FA, Sartorius A, et al. Diffusion weighted MRI in the early phase after electroconvulsive therapy. Neurol Res 2007;29:256–259.
144. Abbott CC, Jones T, Lemke NT, Gallegos P, McClintock SM, Mayer AR, et al. Hippocampal structural and functional changes associated with electroconvulsive therapy response. Transl Psychiatry 2014;4:e483.
145. Joshi SH, Espinoza RT, Pirnia T, Shi J, Wang Y, Ayers B, et al. Structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy in major depression. Biol Psychiatry 2016;79:282–292.
146. Ota M, Noda T, Sato N, Okazaki M, Ishikawa M, Hattori K, et al. Effect of electroconvulsive therapy on gray matter volume in major depressive disorder. J Affect Disord 2015;186:186–191.
147. Tendolkar I, van Beek M, van Oostrom I, Mulder M, Janzing J, Voshaar RO, et al. Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study. Psychiatry Res 2013;214:197–203.
148. Greenberg RM, Kellner CH. Electroconvulsive therapy: a selected review. Am J Geriatr Psychiatry 2005;13:268–281.
149. Gillespie AL, Samanaite R, Mill J, Egerton A, MacCabe JH. Is treatment- resistant schizophrenia categorically distinct from treatmentresponsive schizophrenia? A systematic review. BMC Psychiatry 2017;17:12.
150. Mouchlianitis E, McCutcheon R, Howes OD. Brain-imaging studies of treatment-resistant schizophrenia: a systematic review. Lancet Psychiatry 2016;3:451–463.
151. Nakajima S, Takeuchi H, Plitman E, Fervaha G, Gerretsen P, Caravaggio F, et al. Neuroimaging findings in treatment-resistant schizophrenia: a systematic review: Lack of neuroimaging correlates of treatmentresistant schizophrenia. Schizophr Res 2015;164:164–175.

Article information Continued

Figure 1.

Flowchart of the literature review process. *Three studies studied both structural and functional MRI changes after ECT, and thus was included in both structural and functional MRI categories. ECT: electroconvulsive therapy, MRI: magnetic resonance imaging, MRS: magnetic resonance spectroscopy, PET: positron emission tomography, SPECT: single positron emission computer tomography, NIRS: near-infrared spectroscopy.

Table 1.

Cerebral blood flow in patients with schizophrenia receiving electroconvulsive therapy (ECT)

Baseline After ECT
Comparisons with MDD patients No difference (SPECT) [37] ↑ Rt. parietal and lt. and rt. temporal CBF (SPECT) [37]
↑ Lt. to rt. PFC ratio (NIRS) [38]
Comparisons with controls ↑ Both temporal lobes and lt. cerebellum (PET) [36]
Within-group comparisons (baseline vs. after ECT) in schizophrenia patients with ECT No difference (SPECT) [37]
↓ Lt. and rt. frontal, rt. temporal, and rt. putamen CBF (PET) [36]

MDD: major depressive disorder, lt: left, rt: right, CBF: cerebral blood flow, SPECT: single positron emission computer tomography, PFC: pefrontal cortex, NIRS: near-infrared spectroscopy, PET: positron emission tomography

Table 2.

Brain metabolites measured by magnetic resonance spectroscopy in patients with schizophrenia receiving electroconvulsive therapy (ECT)

Baseline After ECT
Comparisons with controls ↓ NAA/Cr ratios in the lt. PFC and lt. thalamus [39]
↓ Medial frontal GABA [41]
Comparisons with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only ↑ NAA/Cr ratios in the lt. PFC and lt. thalamus [39]
↑ NAA/Cr ratio in the lt. PFC [39]
↓ Cho/Cr ratios in the lt. PFC and lt. thalamus [40]
↑ Medial prefrontal GABA [41]

NAA/Cr: N-acetyl-aspartate/creatinine, lt: left, GABA: gamma-aminobutyrate, PFC: prefrontal cortex, Cho/Cr: choline/creatinine

Table 3.

Regional volumes measured by structural magnetic resonance imaging in patients with schizophrenia receiving ECT

Baseline After ECT
Whole brain analysis
Comparisons with controls ↓ GMV of rt. ACC [44] ↓ GMV of rt. ACC [44]
↑ GMV of precueus, ↓ GMV of bilateral thalamus, medial temporal lobe, left DLPFC/ACC, bilateral cerebellum [42]
Comparisons with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only ↓ Bilateral parahippocampal gyrus/hippocampi [44] ↑ GMV of bilat. parahippocampal gyrus/hippocampus, rt. temporal pole/STG, rt. insula [44]
↑ Temporal pole/STG, rt. insula [44]
Within group comparisons (baseline vs. after ECT) in schizophrenia patients with ECT ↑ GMV of medial temporal lobe & left DLPFC [42]
↑ GMV of bilat. parahippocampal gyrus/hippocampi, rt. temporal pole/STG, rt. Insula [44]
GMV features at baseline in the lt. IFG, rt. insula, lt. MTG, rt. STG as predictive features for response to ECT [47]
Region of interest analysis
Comparisons with controls (-) ↑ GMV of rt. insula [43]
↑ GMV of rt. amygdala/hippocampus (MDD) [43]
Comparisons with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only No significicant difference of bilat. hippocampal volume [45] ↑ GMV of bilateral dorsal anterior insula and posterior insula [46]
↑ Bilat. hippocampus volume (after controlling for overall intrancranial volume) [45]
Within group comparisons (baseline vs. after ECT) in schizophrenia patients with ECT ↑ GMV of rt. amygdala, rt. hippocampus, rt. insula (in both schizophrenia and MDD) [43]
↑ GMV of rt. insula [43]
↑ GMV of bilateral posterior insula [46]
↑ Lt. HATA volumes in responders at baseline compared with nonresponders (response defined by 50% or more decrease in PANSS score) [45]

GMV: gray matter volume, rt.: right, ACC: anterior cingulate cortex, ECT: electroconvulsive therapy, DLPFC: dorsolateral prefrontal cortex, bilat.: bilateral, STG: superior temporal gyrus, lt.: left, IFG: inferior frontal gyrus, MTG: middle temporal gyrus, MDD: major depressive disorder, HATA: hippocampus amygdala transitiona area, PANSS: positive and negative symptom scale

Table 4.

Functional connectivity measured by functional magnetic resonance imaging in patients with schizophrenia receiving ECT

Baseline After ECT
Whole brain analysis
Comparisons with controls No significant difference in rsFC [49] No significant difference in rsFC [49]
Comparisons with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only (-) ↑ gFCD in vmPFC in the ECT group [49]
Within group comparisons (baseline vs. after ECT) in schizophrenia patients with ECT ↑ rsFC in the PCC, left STG, right angular gyrus, right MTG [52]
↓ rsFC in the right ACC, left MTG, right cuneus [52]
↑ gFCD in dmPFC, vmPFC, lt. precuneus [49]
↑ rsFC of 1) mPFC within the DMN, 2) executive network and DMN, 3) executive network and salience network [48]
↓ low frequency oscillations in the striatal network [48]
↓ rsFC between rt. amygdala and lt. hippocampus [51]
Region of interest analysis
Comparisons with controls (-) ↑ rsFC between rt. amygdala & hypothalamus [43]
Comparisons with schizophrenia patients who did not receive ECT and underwent antipsychotic treatment only No significant difference in ROIs [46] ↓ rsFC between lt. post. insula and lt. MOG [46]
No significant difference in ROIs [50] ↓ rsFC between rt. post. insula and lt. OFC [46]
↑ rsFC in bilat. STG and bilat. caudal hippocampi [45] ↑ rsFC between rt. thalamus to rt. putamen [50]
Within group comparisons (baseline vs. after ECT) in schizophrenia patients with ECT ↓ rsFC between rt. amygdala and the rt. TPJ, mPFC, bilat. post. insula, rt. DLPFC [43]
↑ rsFC between rt. amygdala & hypothalamus [43]
↓ rsFC between lt. post. insula and lt. MOG [46]
↓ rsFC between rt. post. insula and lt. OFC [46]
↑ rsFC of thalamus to sensory cortex [50]
↑ rsFC between 1) hippocampus and PFC, 2) hippocampus and DMN in responders after ECT [45]
↓ rsFC between hippocampus and primary sensory network in nonresponders after ECT [45]
↑ rsFC between 1) PPtha.R and rt. inf. temporal cortex, 2) PPtha.R and rt. cerebellum in responders after ECT [50]
↓ rsFC between 1) PPtha.R and rt. inf. temporal cortex, 2) PPtha.R and rt. cerebellum, 3) PPtha.R and rt. precuneus, 4) PPtha.R and lt. cerebellum in nonresponders after ECT [50]

ECT: electroconvulsive therapy, rsFC: resting-state functional connectivity, gFCD: global functional connectivity density, vmPFC: ventromedial prefrontal cortex, PCC: posterior cingulate gyrus, STG: superior temporal gyrus, MTG: middle temporal gyrus, ACC: anterior cingulate gyrus, dmPFC: dorsomedial prefrontal cortex, mPFC: medial prefrontal cortex, DMN: default mode network, lt.: left, rt.: right, ROI: region of interest, bilat.: bilateral, MOG: middle occipital gyrus, OFC: orbitofrontal cortex, TPJ: temporoparietal junection, post.: posterior, DLPFC: dorsolateral prefrontal cortex, PFC: prefrontal cortex, PPtha.R: right posterior parietal thalamus, inf.: inferior