SYSTEMATIC REVIEW published: 30 June 2022 doi: 10.3389/fpsyt.2022.877566 Catatonia and Cognitive Impairments: A Systematic Review Francesc Serrat 1,2* , Maria Iglesias-Gónzalez 1,2,3,4 , David Sanagustin 1,2 , Mikel Etxandi 1 , Joan de Pablo 1,2 and Jorge Cuevas-Esteban 1,2,5 1 Servei de Psiquiatria, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 2 Departament de Psiquiatria, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, 4 Institut de Recerca Germans Trias i Pujol, Badalona, Spain, 5 Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain Background: Catatonia is an underdiagnosed and undertreated neuropsychiatric syndrome characterized by catalepsy, negativism, mutism, muscular rigidity, and mannerism, often accompanied by autonomic instability and fever. Although there is growing interest in studying cognitive impairments before and after catatonia, little is known about the cognitive features of the syndrome. Edited by: Methods: This systematic review was registered at PROSPERO (CRD42022299091). Jordi Serra-Mestres, Cardinal Clinic, United Kingdom Using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Reviewed by: approach, we searched PubMed, ScienceDirect, and PsycArticles using a combination Gábor Gazdag, of the terms “Catatonia” and “Cognitive impairment” and “Executive function” and Jahn Ferenc Dél-Pesti Kórház és Rendelőintézet, Hungary “Frontal lobe” and “Parietal lobe.” Studies included original research articles enrolling Sebastian Walther, patients with catatonic syndrome according to specified criteria. Fourteen studies were University of Bern, Switzerland deemed relevant for inclusion. The abstraction form included age, assessment during *Correspondence: acute episode, associated diagnosis, assessment procedure, and cognitive domains. Francesc Serrat fserrat@ssibe.cat Outcome measures were extracted. Specialty section: Results: Executive functions and visuospatial abilities proved to be the most This article was submitted to investigated domains. A great heterogeneity has been observed in the assessment Child and Adolescent Psychiatry, tools used among the 14 evaluated studies. Findings showed that catatonic patients a section of the journal Frontiers in Psychiatry had worse performance than healthy and non-catatonic psychiatric patients in frontal Received: 16 February 2022 and parietal cortical functions. Accepted: 10 June 2022 Published: 30 June 2022 Conclusion: Because of the small number of studies in such heterogeneous areas Citation: and significant methodological limitations, the results should be regarded with caution. Serrat F, Iglesias-Gónzalez M, Future research assessing cognitive impairments on catatonic patients is needed. Sanagustin D, Etxandi M, de Pablo J and Cuevas-Esteban J (2022) Catatonia and Cognitive Impairments: Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_ A Systematic Review. record.php?RecordID=299091], identifier [CRD42022299091]. Front. Psychiatry 13:877566. doi: 10.3389/fpsyt.2022.877566 Keywords: catatonia, cognitive impairments, executive function, frontal lobe, review Frontiers in Psychiatry | www.frontiersin.org 1 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review INTRODUCTION The brain structures affected in catatonia is not fully understood; however, the majority of neuroimaging studies have Catatonia is an underdiagnosed and undertreated pointed to dysfunction in the frontal and parietal cortices (11). neuropsychiatric syndrome first described by Kahlbaum in Despite Taylor’s assertion (12), that catatonia is a frontal lobe 1874, who defined it as “a motor syndrome occurring in syndrome due to its role in attention, emotion control, and motor association with affective disorders, epilepsy, and tuberculosis” regulation, there are few detailed outcome studies of catatonia (1). It’s characterized by catalepsy, negativism, mutism, muscular in terms of cognitive impairments, and the catatonia/frontal rigidity, and mannerisms, often accompanied by autonomic lobe association remains unclear due to a lack of clarity instability and fever. Volitional disturbances led to the about the clinical epidemiology of cognitive impairment among classification of catatonia as a subtype of schizophrenia for catatonia patients. The purpose of this review is to deliver most of the 20th century. However, revisions in nosology have empirical support to the hypothesis that patients with catatonic recognized a great prevalence in mood disorders, their overlap syndrome will present specific cognitive impairments in the with delirium, and comorbidity with medical conditions (2), and form of executive dysfunction. A comprehensive synthesis of has finally been separated from schizophrenia in the Diagnostic all published literature can provide useful information in this and Statistical Manual of Mental Disorders, Fifth Edition case. The aim of this study is to deliver an extensive review of (DSM-5) (3). Although the identification of catatonia is not all studies dealing with the relationship between catatonia and difficult, since its classification has been controversial, it is often cognitive impairments. missed, leading to the false notion that the syndrome is rare. A lack of comprehension of catatonia’s phenotypes could be a major reason in underdiagnosis (4). Many classic illustrations of catatonia simply show it as a hypokinetic state (5); unfortunately, METHODS such representations may limit knowledge of catatonia’s many phenotypes. Catatonia prevalence in clinical samples was 9.0% Search Strategy in a recent review of 74 studies from all continents that collected The Preferred Reporting Items for Systematic Reviews and data from 1935 to 2017 (6). Meta-Analyses (PRISMA) guidelines was followed in conducting Although various hypotheses have been postulated, including this study. The study protocol was registered in PROSPERO neurotransmitter-related, infective, genetic, immunologic, (CRD42022299091). The search was conducted in PubMed, metabolic, and psychological aspects, the pathophysiology ScienceDirect, and PsycArticles database up to December 2021, behind catatonia remains unknown. Gamma-aminobutyric according to the PRISMA guidelines (13), using search criteria acid (GABA) and glutamate signaling have been proposed as based on cognitive domains and measures of impairments on causative variables (7). Benzodiazepine and electroconvulsive catatonic patients. The search strategy included terms related to: therapy (ECT) are the treatment of choice for catatonia. “Catatonia, Cognitive impairment, Executive Function, Frontal Still, a significant number of patients do not respond well to lobe, Parietal lobe.” The detailed electronic search strategy is benzodiazepines (8). displayed in Table 1. The reference section of the retrieved Cognitive impairments range in severity from “mild,” which articles were also examined, to identify any additional relevant may be observed by the patient or healthcare providers, studies. The identified articles were imported into Zotero 5. to “severe,” such as dementia, which interferes with daily After acquiring all records, the results were validated, and the activities or prevents a patient from functioning independently. duplicates were removed. Researchers with expertise in the topic Neuropsychological testing, which compares performance across of interest suggested relevant studies. several cognitive areas against age and sex standardized mean scores, is frequently used to identify cognitive impairment. Inclusion Criteria Cognitive syndromes, such as dementia, are diagnosed clinically We included all original work (articles, case reports, and and according to a recognized classification system. studies) that reported studies dealing with the catatonia/cognitive While the criteria for catatonia in the DSM-5 do not include impairments relation in humans with diagnosed catatonia. The cognitive impairments, the syndrome involves an underlying studies examined in this review met the five criteria listed cognitive dysfunction that can be difficult to appreciate in the below: (1) original research articles that considered cognitive presence of unusual behavior and abnormal movements (9). impairment in association with catatonia; (2) the study enrolled Nowadays, the DSM-5 criteria for diagnosis requires 3 or more of patients with catatonic syndrome; (3) the diagnosis was made 12 clinical symptoms; however, consistent reference definitions according to specified criteria; (4) were published in English; are lacking and the structure of catatonia is still unclear. and (5) were published in peer-reviewed journals. No other Catatonics, unlike Parkinson’s patients, are unaware of their restrictions (e.g., date of publication) were applied. Review movement disturbances, which are likely caused by cognitive articles were excluded. The researchers screened in duplicate the changes in attentional–motor interactions (10). Understanding articles identified in the search by first reviewing the tittle and the underlying mechanisms that cause cognitive impairment abstract of the paper and, afterward, by reading the full-text among catatonia is crucial to improve knowledge of prognosis paper. The detailed research strategy is presented in a flow chart and clinical management. Figure 1. Frontiers in Psychiatry | www.frontiersin.org 2 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review TABLE 1 | Search strategy. PubMed ScienceDirect PsycArticles (Catatonia) AND (Cognitive impairments) n = 37 (Catatonia) AND (Cognitive impairments) n = 724 (Catatonia) AND (Cognitive impairments) n = 56 (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Executive Functions) n = 3 (Executive Functions) n = 148 (Executive Functions) n = 488 (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Executive Functions) AND (Frontal lobe) n = 1 (Executive Functions) AND (Frontal lobe) n = 94 (Executive Functions) AND (Frontal lobe) n = 278 (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Catatonia) AND (Cognitive impairments) AND (Executive Functions) AND (Frontal lobe) AND (Parietal (Executive Functions) AND (Frontal lobe) AND (Parietal (Executive Functions) AND (Frontal lobe) AND lobe) n = 0 lobe) n = 56 (Parietal lobe) n = 198 FIGURE 1 | PRISMA flowchart. Data Extraction episode; and (6) results. The first author extracted data from Studies that met the inclusion criteria were summarized in the studies that were included, and an independent rater terms of: (1) participants (sample characteristics and sample assessed for accuracy (JC-E). Articles were reexamined until size); (2) associated diagnostic; (3) specific cognitive domain consensus (100% agreement) was established in cases where the assessed; (4) assessment procedure; (5) assessment during acute extracted data disagreed. Frontiers in Psychiatry | www.frontiersin.org 3 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review Risk of Bias order to understand the impact on patients outcome. There Following “the Cochrane Collaboration’s tool for assessing risk of was wide variation across all studies regarding cohort sizes bias” (14), the probability of bias was reduced in the extraction of (the sample size ranged from 1 to 172) and neuropsychological data and in ratings of study quality for this review. With this tool, and/or cognitive assessment in terms of measures or tools we addressed the six collected domains with their corresponding used (see Table 4). Four studies (28.57%) were from the specific items. The analysis of the risk of bias for each of the United States, eight (57.14%) from Europe, one (7.14%) from selected studies are summarized in Table 2. South America, and one (7.14%) from Asia. The mean age across the 14 reviewed studies was 45.5 ranging from 26.8 to 67.6 years. Only four studies (28.57%) included ages over RESULTS 60 years old. Two studies used neuroimaging (15, 16), one used a combination of neuroimaging and neuropsychological Database assessment (17), while the rest used cognitive assessment tools Our search strategy revealed 817 potentially relevant manuscripts (18–28). Only three studies conducted assessments during the in PUBMED, SCIENCEDIRECT, and PSYCARTICLES. During initial acute period and the chronic period (25, 26, 28), whereas the title and abstract screening, 747 were eliminated, leaving the rest of the studies reported conducting the assessment 70 full-text publications to be evaluated for eligibility. As a during the chronic period. There was one study that did result of this phase, the present systematic review includes not report the timing of when assessments were conducted a total of 12 studies. Subsequent searches identified two (23). Affective disorders (35.71%) and psychotic disorders supplementary studies. Figure 1 describes the evaluation of these (35.71%) were the most prevalent underlying conditions, while 817 publications. two studies did not specify the underlying disease (19, 28). In total, 14 articles directly focusing on the relationship No study present in this review has taken into account the between catatonia and cognitive impairments met the inclusion somatic comorbidity. criteria (see Table 3). The studies were ordered by date of publication and are categorized by the number of participants, Neuropsychological Studies age, assessment during acute episode, associated diagnosis, Table 4 shows the various aspects of cognition that were assessment procedure, cognitive domain, and results. The examined across the studies. General intellectual functioning, analysis of the risk of bias for each of the selected studies visual–spatial abilities and executive functions (EFs) were following “the Cochrane Collaboration’s tool for assessing risk of frequently measured across the studies. Neuropsychological test bias” (14), are summarized in Table 2. measures were frequently used to identify subjectively reported cognition. The only neuropsychological instruments conducted Study Characteristics in more than one study were the Trail Making Test (TMT) The details of the included studies are shown in Table 3. Overall, (17, 19, 20), the d2 Attention Test (17, 19), the Color-Word all studies (n = 14) included in this review aimed to identify Interference Test (17, 19), and the Five Point Test (17, 19). factors associated with cognitive impairment and catatonia in In terms of EF, 22 different measures or sub-tests were used. TABLE 2 | Risk of bias analysis. Selection bias Selection bias Performance bias Detection bias Attrition bias Reporting bias Random sequence Allocation Blinding (participants Blinding (outcome Incomplete outcome Selective reporting generation concealment and personnel) assessment) data Starkstein et al. 18 + ? + + + ? Northoff et al. 19 + + + + ? + Northoff et al. 17 + + + + + + Northoff et al. 16 + + + + + + Baker et al. 20 ? + + + + + Bark et al. 21 + + + + + + Richter et al. 15 ? + + + + + Utumi et al. 22 ? + + + ? + Kontaxaki et al. 23 + − + ? ? − Colomer et al. 24 + + + + + + Medina and Cooper 25 ? + + + ? + Graziane et al. 26 ? + + + ? + Dean et al. 27 + + + + + + Jiang et al. 28 ? + + + + + “+” low risk of bias; “−” high risk of bias; and “?” unclear risk of bias. Frontiers in Psychiatry | www.frontiersin.org 4 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review TABLE 3 | Features of the 14 studies reviewed. Study Number of Age Assessment during Associated Assessment Cognitive domains Results participants (n) acute episode diagnosis procedure Starkstein N = 120 51–64 No Depression M.M.S.E Orientation Frontal dysfunction et al. 18 79 with depression Attention induced by 41 with Parkinson’s Visual construction frontotemporal lobe atrophy may be linked to catatonia. Northoff N = 39 43.4 ± 13.1 (C) No None Standard Attention In visual–spatial et al. 19 13 catatonic 50.4 ± 15.3 (nC) Progressive Matrices Executive functions ability, working 13 controls 46.5 ± 9.2 (nCP) D2 Attention Test, Working memory memory and 13 non-catatonic Color-Word Visual–spatial abilities attentional-motor psychiatric Interference Test functions catatonic Visual Object and individuals Space Perception demonstrated Test significantly lower Observation from the performance and Wilde Test distinct correlation Trail Making Test, patterns. Five Point Test, Verbal Fluency Test, Box Piling Test Progressive arithmetics. Northoff N = 30 41.6 ± 5.3 (C) No Schizophrenia Standard Attention Only in visual–spatial et al. 17 10 catatonic 40.1 ± 6.2 (nC) Affective disorders Progressive Matrices Visual–spatial abilities abilities did catatonic 10 controls 40.8 ± 4.9 (nCP) D2 Attention Test, Executive functions patients vary from 10 non-catatonic Color-Word psychiatric and psychiatric Interference Test healthy controls, with Visual Object and considerably worse Space Perception performance and Test abnormal Trail Making Test, intercorrelations with Five Point Test. attentional measures. Northoff N = 30 41.6 ± 5.3 (C) No Akinetic catatonia None (brain imaging). Affective inhibition During emotional et al. 16 10 catatonic 40.8 ± 4.9 (nC) processing, catatonic 10 non-catatonic 25.9 ± 6.1 (nCP) symptoms may be 10 non-catatonic associated to psychiatric dysfunction in the orbitofrontal cortex and subsequent changes in the prefrontal cortical network. Baker et al. N=1 46 No Depression WAIS III Memory The findings support 20 Adult Memory and Attention existing definitions of Information Executive functions catatonia as a frontal Processing Battery condition marked by Camden Memory persistent Test impairment of CANTAB executive function, Rey Complex but there was also Figure/Taylor Figure evidence of severe Trail Making Test anterograde Semantic Fluency amnesia. Test. Bark et al. N = 53 29.81 ± 9.39 (C) No Schizophrenia The Iowa Gambling Attention According to 21 8 catatonic 36.75 ± 10.48 (CS) Task Executive functions preliminary findings, schizophrenia 38.5 ± 13.99 (PS) Wisconsin Card Working memory catatonic 19 paranoid Sorting Test schizophrenia suffers schizophrenia Object Alternation from a unique 26 control Task deficiency in Go-NoGo task neuropsychological The Standard measures related to Progressive Matrices. ventral prefrontal cortical function. Richter et al. N=6 41.6 ± 5.3 No None None (brain imaging). Affective inhibition Lorazepam 15 administration causes a modulation of the BOLD-response in the OFC during (Continued) Frontiers in Psychiatry | www.frontiersin.org 5 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review TABLE 3 | (Continued) Study Number of Age Assessment during Associated Assessment Cognitive domains Results participants (n) acute episode diagnosis procedure emotional processing. Lorazepam, in particular, was found to normalize signal reduction in catatonic patients as compared to healthy controls. Utumi et al. N=3 63–74 No Bipolar mood M.M.S.E Mental rigidity Frontal dysfunction 22 disorder Cognitive flexibility induced by frontotemporal lobe atrophy may be linked to catatonia. Kontaxaki N = 91 30.23 ± 7.71 Unknown Schizophrenia Unknown Response inhibition There was no link et al. 13 71 schizophrenia Declarative memory between 20 controls Executive functions hallucinations, highly organized delusions, persecutory delusions, agitation, catatonia, or inappropriate affect and any form of cognitive impairment. Colomer N = 21 26.78 No First-episode The MATRICS Processing speed No differences in et al. 24 psychosis Consensus Cognitive Attention cognitive antipsychotic-naive Battery Working memory performance Verbal learning between catatonic Visual learning and non-catatonic Reasoning patients, although catatonic patients scored lower in all domains. Medina and N=1 40 During acute state Bipolar mood Clock Drawing Test Visual–spatial abilities Greater catatonic Cooper 25 and after lorazepam disorder Executive functions severity is associated challenge with greater cognitive dysfunction. Graziane N=1 66 During Acute state Bipolar mood Montreal Cognitive Executive and Memantine improves et al. 26 and after disorder Assessment visuospatial both catatonic administration of functioning symptoms and memantine Language co-occurring Attention cognitive impairment. Memory Orientation Dean et al. N = 172 27.4 ± 8.15 (C) No Schizophrenia Screen for Cognitive Verbal Fluency When compared to 27 43 catatonic 27.9 ± 6.63 (nC) Impairment in Processing speed patients without a 43 non-catatonic 29.9 ± (nCP) Psychiatry Memory history of catatonia, schizophrenia people with a history 86 control of catatonia exhibit more cognitive difficulties with verbal fluency and processing speed. Jiang et al. N=1 74 During acute state None Unknown Executive function After 5 months on 28 and after Cognitive control clonazepam, testing administration of revealed that the clonazepam executive dysfunction had nearly resolved, with very minor residual deficits. C, catatonic; nC, non-catatonic; nCP, non-catatonic psychiatric; CS, catatonic schizophrenia; PS, paranoid schizophrenia. Measures infrequently capture overall cognition function, while On seven studies assessments were conducted using global some test measures were used to assess as many as three cognition measures. Starkstein et al. (18) and Utumi et al. (22) cognitive domains. For example, the Wechsler Adult Intelligence studies, used the Mini-Mental State Examination (MMSE) to Scale (WAIS) digit span was used to assess attention, working evaluate the cognitive state of their subjects. Both reports revealed memory and memory. poorer performances on catatonic patients, specially regarding Frontiers in Psychiatry | www.frontiersin.org 6 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review TABLE 4 | Neuropsychological tests used across cognitive domains. Cognitive domain Measure General intellectual functioning 1. Standard Progressive Matrices (SPM) 2. Multiple Vocabulary Test-B (MWT-B) Visual–spatial abilities 1. Observation from the Wilde Test (BO-WIT) 2. Visual Object and Space Perception Test (VSOP) 3. Subtest 7 and 9 from the performance investigation systems (LPS) 4. Clock Drawing Test Executive functions (general) 1. Rey Complex Figures Test-copy trial 2. Clock Drawing Test 3. Five Point Test (5PT) Executive functions (attention) 1. D2 Attention Test 2. Color-Word Interference Test (CWI) 3. Trail Making Test A and B (TMT) 4. WAIS digit span 5. WAIS digit symbol 6. WAIS spatial span forward Executive functions (working memory) 1. The MATRICS Consensus Cognitive Battery 2. Progressive arithmetics 3. WAIS digit span 4. WAIS spatial span 5. WAIS spatial working memory task 6. Object Alternation Task (OAT) Executive functions (processing speed) 1. Trail Making Test A Executive functions (decision making) 1. The Iowa Gambling Task Executive functions (planning) 1. Box-Piling Test Executive functions (response inhibition) 1. Go-NoGo task Executive functions (cognitive flexibility) 1. Trail Making Test B 2. Wisconsin Card Sorting Test (WCST) 3. Two-group color test Memory 1. Adult Memory and Information Processing Battery 2. Rey–Osterrieth Complex Figure Test 3. WAIS digit span 4. WAIS picture naming 5. WAIS similarities 6. Camden Memory Test Overall cognitive assessment 1. M.M.S.E 2. MoCA 3. Screen for Cognitive Impairment in Psychiatry (SCIP) 4. CANTAB WAIS, Wechsler Adult Intelligence Scale; MoCA, Montreal Cognitive Assessment; CANTAB, Cambridge Neuropsychological Test Automated Battery; MMSE, Mini-Mental State Examination. attention and visual construction domains. The Starkstein state that improved after treatment administration. Using the study compared catatonic patients with mood disorders with Screen for Cognitive Impairment in Psychiatry (SCIP) test, Dean non-catatonic Parkinson’s patients, while Utumis report only et al. (27), compared schizophrenia patients with a history of assessmented on three patients without control group. Medina catatonia to schizophrenic patients without a history of catatonia et al. (25), applied the Clock Drawing Test on one catatonic and a healthy control group. While both schizophrenic groups patient, the assessment were conducted during the catatonic were shown to be impaired in all cognitive areas when compared acute state and after deliver of lorazepam, revealing severe to healthy control participants, the catatonic group performed impairments on executive planning and visuospatial construction considerably worse on verbal fluency and processing speed during the acute state. A similar study conducted by Graziane assessments. Colomer et al. (24), assessed six catatonic patients et al. (26), using the Montreal Cognitive Assessment tool using the MATRICS Consensus Cognitive Battery (MCCB) and (MoCA) on a single patient during the catatonic acute state and confronted them with fifteen non-catatonic patients (both groups after delivering of memantine, showed similar results; cognitive suffered first-episode non-affective psychosis), their results did dysfunction improving after treatment. Another similar study, not find differences in cognitive performance between catatonic assessing cognition during the acute state and after 5 months on and non-catatonic patients, although catatonic patients scored clonazepam on a single patient, was conducted by Jiang et al. (28). lower in all domains. The assessment tool was undisclosed, but the results were similar The other five studies included in this review used tailored to the ones discussed; executive dysfunctions during the acute neuropsychological assessment tests, being the visuospatial Frontiers in Psychiatry | www.frontiersin.org 7 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review abilities and the EF the main cognitive domains assessed. and controls in the study were required to complete an emotional Northoff et al. (19) presented a study, where catatonic patients regulation test. Changes in orbitofrontal cortex (OFC) activation were compared to psychiatric non-catatonic patients (matched were linked to abnormal functional connectivity between the with regard to underlying psychiatric diagnosis; schizophrenic OFC and the medial prefrontal cortex (mPCF), as well as between or affective psychosis) and healthy controls. The researchers prefrontal and motor areas, according to the findings. The employed a battery to evaluate a variety of neuropsychological findings of Ritcher et al. (15) study, demonstrated that lorazepam abilities that are presumed to depend on frontal (EFs, attention, might be used to treat abnormal activation of the OFC during working memory) and parietal (visuospatial abilities) cortical an emotional task. function. Their findings demonstrated that catatonic patients varied solely in visuospatial ability from psychiatric and healthy controls, with considerably worse performance and DISCUSSION intercorrelations with attentional measures. Baker et al. (20), reported a detailed neuropsychological evaluation in a single In this review, we aimed to identify studies that investigate the case of catatonia almost 3 years after recovery from the acute relationship between catatonia and cognitive impairments by episode. A battery of tests, assessing general intellectual abilities, analyzing the evidence from 14 studies meeting a criteria defined memory, EF, and visuospatial abilities, was performed 2 weeks in the methods section. EF, attention and visuospatial abilities are after patients last ECT and repeated 2 years and 8 months later. among the most assessed cognitive domains, and the results lend Selective deficits in EF and anterograde amnesia were evident evidence to support the frontal lobe syndrome theory proposed on the first evaluation and continued to be present at follow-up by Taylor (12), but it is worth mentioning that the studies revealed after almost 3 years, and cannot be explained convincingly by some limitations. First, we only found one study with a large the administration of ECT due to the relatively small number sample size of n = 172 participants (27). All other studies reviewed of sessions received. Patients with catatonic schizophrenia used smaller samples ranged from n = 120 to n = 1. As a result, were compared to patients with paranoid schizophrenia and limited sample sizes may result in false negatives and/or restrict healthy volunteers by Bark et al. (21). Their team performed a the capacity to identify cognitive deficits in some of the assessed neuropsychological assessment that focused on EF presumed to domains. Moreover, it is not clear that some of the subjects in be related to the function of the ventral prefrontal cortex. General the Northoff et al. (17, 19) studies, were distinct in each study, intellectual functioning, visuospatial abilities, and attention were resulting in the impression of overly robust results. also assessed. Their results revealed specific deficits in decision Furthermore, the majority of the studies included in making and set-shifting in catatonic patients in contrast to this systematic review were conducted in Western countries, healthy and paranoid schizophrenic subjects. Finally, a study according to the findings. There were too few studies from non- conducted by Kontaxaki et al. (23), run and undisclosed battery Western countries (22), to make any meaningful comparisons. of neuropsychological tests in patients of the schizophrenic In order to tackle this geographical distribution bias, further spectrum. Their results indicate that hallucinations, highly cross-cultural research is needed to understand the EF deficits on organized delusions, persecutory delusions, agitation, catatonia, catatonia within different cultural and geographical settings. and inappropriate affect did not associate with any subtype of As age is an important factor for cognitive impairment, cognitive deficit. cognitive changes should be reviewed separately in young or adult. Surprisingly, we only found two studies with participants Mixed Studies older than 65 (22, 26). There have been a few reports on Only one study investigated catatonia and cognitive impairments the association between frontotemporal dementia (FTD) and using a combination of neuroimaging and neuropsychological catatonia (29, 30), since the diagnostic criteria for catatonia and assessment. Northoff et al. (17), conducted a combined FTD partly overlap (31). Catatonic symptoms are not unusual in investigation, using a single photon emission computerized FTD, according to Northoff et al., because catatonia is associated tomography (SPECT) and cognitive measures (d2 Attention Test, to frontal dysfunction (16), but this relationship is still not clear Visual Object and Space Perception Test, TMT, and Standard due to lack of studies. Progressive Matrices), on 10 catatonic patients, 10 psychiatric This research reveals that a wide range of measures have controls (with similar underlying psychiatric conditions but been used to assess cognitive impairments in relation to different without catatonia), and 10 controls. This study revealed a domains, particularly on EF, and the constructs studied are significantly lower regional cerebral perfusion (r-CBF) in right heterogeneous. It should be highlighted, however, that the lower prefrontal and parietal cortex in catatonia than in current study does not examine whether those measures are psychiatric and healthy controls, as well as poorer performance valid or reliable in detecting cognitive deficits. For example, in visuospatial abilities associated with right parietal function. the study conducted by Northoff et al. (19), revealed no significant differences on EF impairments between catatonics Neuroimaging Studies and psychiatric controls while the results of Bark et al. (21), The two neuroimaging studies of this review, were conducted suggest a specific deficit in EF measures associated with decision using functional brain magnetic resonance imaging (fMRI) making in catatonic schizophrenic patients when confronted technique. On the study conducted by Northoff et al. (16), after with paranoid schizophrenia. A possible explanation for the successfully treating a catatonic episode with lorazepam, patients controversial results is that open-ended tasks compared to more Frontiers in Psychiatry | www.frontiersin.org 8 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review structured task may be more sensitive to reveal group differences fulfills the concept of endophenotype, and this could be a crucial in some cognitive domains like EF. Another relevant aspect, that piece in determining whether executive dysfunctions are a cause can explain these results, is that while decision making may be or a consequence of catatonia. We propose that a model of EF related to dysfunction in the ventral prefrontal cortex, other EF in catatonia that bridges the pathway from genetics to neural domains, like attention, are more related with the dorsolateral circuitry and to be observed EF phenotype may better capture the prefrontal region (32). heterogeneity of EF in catatonia. The precise brain mechanisms that could be the source of the Conclusion is that the relationship between catatonia and symptoms are very poorly known. Ritcher et al. (15) and Northoff cognitive impairments is still not fully clarified, and more et al. (16), used brain imaging to demonstrate that emotional advanced research may help develop better understanding of regulation, functional connectivity, and the GABAergic system frontal lobe syndrome. To detect subtle subclinical deficits in play a significant role in catatonic patients, but the exact the target population, future studies should utilize a more neurophysiological and neuropsychological mechanisms of comprehensive and quantitative framework with more robust catatonia remain unclear, since there is a lack of combined measures. Moreover, to gain an overview of all cognitive studies of neuropsychology and neuroimage. We only found impairments related to catatonia, future studies should included one study combining these factors (17), and while the results samples across the whole age, and need to be sufficiently large pointed the role of the right parietal cortex in catatonia, showing a to have enough power to detect group differences. This wide significant decrease of r-CBF, and are at the same time supported range of cognitive alterations found, as well as many others to by results from neuropsychological measures, the study suffers be assessed, may underly multiple pathobiological mechanisms from methodological limitations, and more combined studies are that should be taken care in future studies. Another important needed to clarify this relationship. factor would be the need to control the somatic comorbidity While most of the studies focused their attention on working and the importance of differentiating between acute, post- memory, other forms and processes of memory where only acute and chronic period. Functional neuroimaging studies can considered in studies using global cognition measures. Only support neuropsychological information during acute periods one study conducted by Baker et al. (20), performed a detailed due to the difficulty of obtaining information from patients longitudinal neuropsychological assessment. As commented when acute catatonia is present, specially in severe hypokinetic before, the results pointed to a permanent cognitive impairment or hyperkinetic states. Regarding the control of the effects of of the patient, focally affecting memory and EF. Rather than benzodiazepines on neuropsychological examinations, it should a pure amnesic state, focal frontal lesions tend to result in a be taken into account for future studies, what medication failure to use memory methods to improve coding and recall each subject was taking before and during hospital admission. (33), but due to the small size of the study (n = 1), this It will also be interesting to monitor which medication is assumption of memory impairments on catatonic patients due administered at the time of catatonia assessment and during to EF dysfunction should be treated as a working hypothesis cognitive examination. Studies on cognitive impairments on awaiting further empirical support. catatonia will continue to provide important insights by bringing To the best of our knowledge there are no studies dealing researchers closer to the genetic etiology and neurobiological with the relation between somatic disorders and catatonia. Since pathways underlying catatonia. catatonia can have a somatic etiology, it would be important to control for somatic comorbidity. None of the reviewed studies have taken into account the role of somatic factors in the etiology of catatonia and the cognitive implications that this may entail. DATA AVAILABILITY STATEMENT Leaving aside these discrepancies, the most promising The datasets presented in this study can be found in online cognitive domains impairments related to catatonia to explain repositories. The names of the repository/repositories Taylor’s frontal lobe syndrome theory were EF, attention and and accession number(s) can be found in the visuospatial abilities. Because of the small number of studies article/supplementary material. in such heterogeneously broad domains and methodological limitations, findings should be interpreted with caution. However, all those results linking EF with catatonia support its potential as an endophenotype. AUTHOR CONTRIBUTIONS Executive function has measurable behavioral effects (34), and is linked to genetic (35), and neurobiological mechanisms FS developed the study concept, selected the manuscript, and (36). Neuropsychological measures of EF have been associated reviewed the clinical data under the supervision of JC-E and to activation of brain areas such as the frontoparietal (35) MI-G. All authors reviewed and approved the final manuscript. and frontal cortical areas (37), according to functional imaging studies. The neural substrates of GABA and glutamate present a neural link for the EF (common factor), which has a genetic ACKNOWLEDGMENTS basis but may be assessed using cognitive tasks (38). In addition, genetic factors account for about half of the variation in EF We would like to thank JP and the Germans Trias I Pujol performance (39). In summary, research on EF reveals that it Research Institute for their support. Frontiers in Psychiatry | www.frontiersin.org 9 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review REFERENCES 22. Utumi Y, Iseki E, Arai H. 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Deficit in decision making in Publisher’s Note: All claims expressed in this article are solely those of the authors catatonic schizophrenia: an exploratory study. Psychiatry Res. (2005) 134:131– and do not necessarily represent those of their affiliated organizations, or those of 41. doi: 10.1016/j.psychres.2004.04.013 the publisher, the editors and the reviewers. Any product that may be evaluated in Frontiers in Psychiatry | www.frontiersin.org 10 June 2022 | Volume 13 | Article 877566 Serrat et al. Catatonia and Cognitive Impairments: A Systematic Review this article, or claim that may be made by its manufacturer, is not guaranteed or the Creative Commons Attribution License (CC BY). 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