Authors: Scott R. Beach (a.Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; b.Harvard Medical School, Boston, MA, USA), James Luccarelli (a.Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; b.Harvard Medical School, Boston, MA, USA), Nathan Praschan (a.Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; b.Harvard Medical School, Boston, MA, USA), Mark Fusunyan (c.Department of Psychiatry, Santa Clara Valley Medical Center, San Jose, CA, USA), Gregory L. Fricchione (a.Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; b.Harvard Medical School, Boston, MA, USA)
Categories: Article, Catatonia, inflammation, akinetic mutism, neuroleptic malignant syndrome, immunoactivation
Source: Schizophrenia research
Authors: Scott R. Beach, James Luccarelli, Nathan Praschan, Mark Fusunyan, Gregory L. Fricchione
Catatonia occurs secondary to both primary psychiatric and neuromedical etiologies. Emerging evidence suggests possible linkages between causes of catatonia and neuroinflammation. These include obvious infectious and inflammatory etiologies, common neuromedical illnesses such as delirium, and psychiatric entities such as depression and autism-spectrum disorders. Symptoms of sickness behavior, thought to be a downstream effect of the cytokine response, are common in many of these etiologies and overlap significantly with symptoms of catatonia. Furthermore, there are syndromes that overlap with catatonia that some would consider variants, including neuroleptic malignant syndrome (NMS) and akinetic mutism, which may also have neuroinflammatory underpinnings. Low serum iron, a common finding in NMS and malignant catatonia, may be caused by the acute phase response. Cellular hits involving either pathogen-associated molecular patterns (PAMP) danger signals or the damage-associated molecular patterns (DAMP) danger signals of severe psychosocial stress may set the stage for a common pathway immunoactivation state that could lower the threshold for a catatonic state in susceptible individuals. Immunoactivation leading to dysfunction in the anterior cingulate cortex (ACC) /mid-cingulate cortex (MCC)/medial prefrontal cortex (mPFC)/paralimbic cortico-striato-thalamo-cortical (CSTC) circuit, involved in motivation and movement, may be particularly important in generating the motor and behavioral symptoms of catatonia.
Catatonia is a disorder impacting motor function, behavior and affect, that has been shown to be associated with dozens of underlying conditions. In his original description of catatonia, Kahlbaum presented cases of catatonia arising in the context of both primary psychiatric illnesses, such as schizophrenia, and neuromedical conditions, now generally termed psychogenic and neuromedical catatonia, respectively.(Kahlbaum 2012) Gelenberg later examined diverse etiologies for catatonia in his 1976 review.(Gelenberg 1976)
A burgeoning literature uses certain conditions to probe the linkage between psychogenic and neuromedical brain conditions in the hope of bridging the dualism gap in our understanding of psycho-neuropathology.(Udina et al. 2012; Zhang et al. 2020; Anderson et al. 2013; Berk et al. 2013; Kayser and Dalmau 2016; Pollak et al. 2014; Herska et al. 1987; Roy and Campbell 2013) Catatonia is one such probe, in that neuroinflammatory pathophysiology may play a prominent role in the phenotypic expression of both psychogenic and neuromedical catatonias.(Rogers et al. 2019) In his systematic review of 11 studies, Oldham found that inflammatory brain disorders contribute 28.8% out of a total of 302 patients with secondary (or medical) causes of catatonia, including encephalitis (most common) and systematic lupus erythematosus (SLE).(Oldham 2018) In a study of catatonia diagnoses at discharge among general hospital patients, nearly 40% of cases of catatonia had a neuromedical primary diagnosis.(Luccarelli, Kalinich, McCoy, Fernandez-Robles, et al. 2022) In another review, NMDA-receptor encephalitis was the most frequent cause of autoimmune catatonia, occurring in 72% of the 346 cases.(Rogers et al. 2019) While primary inflammatory disease is responsible for a fair share of catatonia cases, the role of the central nervous system (CNS) immune response to a variety of stressors and insults may impact catatonia risk in other conditions, both psychogenic and neuromedical.
Many disorders that predispose to the development of catatonia have been associated with neuroinflammation. For example, among psychiatric illnesses, unipolar and bipolar depression are both closely linked to catatonia, and studies have suggested an inflammatory basis for depression.(Bauer and Teixeira 2019) Catatonia is also highly co-morbid with autism-spectrum disorders (ASD), which themselves may be linked to an abnormal inflammatory response.(Luccarelli, Kalinich, Fernandez-Robles, et al. 2022) Furthermore, several syndromes thought to be related to catatonia, including akinetic mutism, have evidence of inflammatory linkages as well.(Fusunyan et al. 2021)
Environmental stressors that engage amygdalar threat signaling may enhance vulnerability to catatonia via pro-inflammatory processes.(Schiller, Ben-Shaanan, and Rolls 2021) Increased and persistent exposure to stressful life situations is correlated with elevated expression of pro-inflammatory genes and reduced expression of type I interferon gene sets).(Cole 2014) In addition, chronic stress-related cytokine output is thought to dysregulate THelper -1/THelper-2 immune balance, predisposing to autoimmune disorders.(McEwen and Stellar 1993) Clear implications for neuroinflammatory, autoimmune and infectious etiologies for the catatonic syndrome emerge.
In this review, we will first introduce and outline key inflammatory principles central to our understanding of the ways in which catatonia may be driven in part by inflammatory processes. We will then explore various etiologies of catatonia in detail, with a focus on their own neuroinflammatory linkages. We will provide a brief overview of several related syndromes that may be influenced by neuroimmunologic processes. Finally, we will offer some hypotheses regarding specific immunologic factors that may lead to the development of catatonia. Specifically, we will suggest that vulnerability to both psychogenic and neuromedical catatonia may arise from activation of an immune cell threat response leading to impairments in the cortico-striato-thalamo-cortical (CSTC) loop systems that link motivation and movement.
The narrative review was conducted to address a predefined question about the relationship between inflammation and catatonia. Search strings composed of terms related to immune system activation (e.g., inflammation, infection) as well as catatonia-spectrum and conceptually or etiologically-linked disorders (e.g., severe mood disorders) were entered into PubMed from inception to August 2022. Full-text, peer-reviewed manuscripts were included for manual review and synthesis, while conference abstracts and non-English articles were excluded. Included articles were also reviewed for eligible references that were incorporated into the narrative review. Study methodologies reflecting stronger levels of evidence were prioritized for synthesis, including systematic reviews and meta-analyses, randomized-clinical trials, and cohort/longitudinal studies.
The innate immune system is an evolutionarily ancient component of host defense, present in all multicellular organisms. In contrast to the adaptive immune system, which is specific to previously-encountered pathogens, the innate immune system is genetically pre-programmed to react first to common broad classes of pathogens and potential threats.(Turvey and Broide 2010) Select innate immune cells express germline-encoded receptors termed “pattern recognition receptors” (PRRs) that recognize select molecular threat signals. These include pathogen-associated molecular patterns (PAMPs) - conserved molecular motifs expressed by some pathogens, such as bacterial lipopolysaccharides or endotoxins. Other PRRs recognize “damage-associated molecular patterns” (DAMPs)—sometimes termed alarmins or danger signals—which are released in the context of tissue damage or cell lysis. Examples include heat shock proteins (HSPs), uric acid, and S100 proteins. Once a PRR binds to its target signal, it activates the innate inflammatory response through the release of cytokines, chemokines, and interferons.(Kumar, Kawai, and Akira 2011) This promotes the migration of further immune cells to the site of damage. As the adaptive immune system co-evolved with the innate immune system in vertebrates, the two systems are intimately linked, and innate immune response therefore has significant impacts on both the initial and later stages of immune response.(Jain and Pasare 2017)
In addition to the link between innate and adaptive immune responses, we are beneficiaries of another evolutionary survival strategy—namely a social attachment bias. Threats to this mammalian strategy provoke an acute stress response that can persist if left unmodulated to become a chronic stress response, increasing the vulnerability to non-communicable diseases (NCDs) including neuropsychiatric disorders. Nucleotide-binding oligomerization domain-like receptor proteins (NLRPs), through the formation of an inflammasome, help regulate immune response to injury, toxins, or invasion by microorganisms as well as to stress. Stressful social-environmental signals of threat are “listened for” in anticipation of the risk of wound or injury related to assault. The result in threatened humans is an intertwining of the immune response and the stress response.(Raison and Miller 2013; Slavich and Cole 2013)
As a first step in exploring possible linkages between catatonia and the inflammatory system, it is informative to consider inflammatory aspects of various conditions, both neuromedical and psychiatric, that have been etiologically linked to catatonia.
Authors have described increasing cases of catatonia associated with autoimmune conditions, including systemic lupus erythematosus (SLE),(Bica et al. 2015; Sundaram et al. 2022; Ali, Taj, and Uz-Zehra 2014; Pai, Kramer, and Rosenstein 2020; Fam et al. 2010; Leon et al. 2014; Chaudhury et al. 2017; Jones, Gausche, and Reed 2016) pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS),(Elia et al. 2005) Sjogren’s disease,(Rosado et al. 2018) and antibody-mediated encephalitis, particularly anti-N-methyl-D-aspartate (NMDA) receptor antibody encephalitis.(Dalmau et al. 2019) The mechanisms by which autoimmune conditions affect neuronal functioning are varied. In NMDA-receptor antibody encephalitis, for example, autoantibodies produced by circulating immune cells cross the blood-brain barrier (BBB), but are not thought to cause significant cytotoxicity and neuronal death.(Dalmau et al. 2019) Contrastingly, neuropsychiatric manifestations of SLE have been associated with many auto-antibodies that may infiltrate the brain and commonly produce neuronal cell death.(Bendorius et al. 2018)
Catatonia and similar syndromes have also been associated with infectious encephalitis, including HSV, (Hassan, Thomas, and Iyer 2011; Ryali et al. 1997) HIV and John Cunningham virus via progressive multifocal leukoencephalopathy, and COVID-19, (Dawood, Dawood, and Dawood 2022; Luccarelli, Kalinich, McCoy, Fricchione, et al. 2022) as well as various bacterial infections like syphilis and Borellia.(Rogers et al. 2019) In these infections, it is generally thought that neuronal death and subsequent brain network dysfunction results from either direct injury from the pathogenic entity or via activation of the innate immune system against infected cells. Interestingly, many cases of presumed autoimmune encephalitis present in the post-infectious period, through a likely mechanism of molecular mimicry.(Dalmau et al. 2019)
Despite its historic association with schizophrenia, catatonia is more frequently seen in the setting of mood disturbances, including bipolar and unipolar depression.(Grover et al. 2015; Takacs et al. 2019; Usman et al. 2011; van den Ameele, Sabbe, and Morrens 2015; Fink, Shorter, and Taylor 2010) Indeed, many features of depressive episodes are shared with catatonia, including low motivation and anergia, psychomotor slowing, and poor oral intake. These similarities and the frequency with which catatonia occurs in mood disorder exacerbations led to the creation of the “catatonic features” specifier for mood disorders in the DSM-5,(Tandon et al. 2013).
Inflammation has been thought to play a role in the genesis of depression since the discovery of a link between early life stressors, inflammation, and subsequent depressive episodes.(Pace, Hu, and Miller 2007) Further evidence came from early observations of patients who developed recurrent or new depressive episodes at a rate of 30–70% following the initiation of interferon,(Pinto and Andrade 2016; Raison and Miller 2013) a pro-inflammatory cytokine that modulates host immune defenses. Both interferon- and illness-induced cytokine responses (in particular IL-1β and TNF-α) produce a syndrome of sickness behavior characterized by reduced reward-seeking behavior, anhedonia, lethargy, social withdrawal, anorexia, and impaired sleep - a syndrome that bears striking resemblance to depression.(Raison, Capuron, and Miller 2006; Dantzer et al. 2008)
Proinflammatory cytokines may affect neurons beyond the BBB by 1) providing signal input to afferent nerves, 2) diffusing from macrophages with toll-like receptors residing in circumventricular organs and the choroid plexus, 3) overwhelming cytokine transport mechanisms in the BBB, and 4) locally producing cytokines (e.g. prostaglandin E2) by activation of IL-1 receptors on perivascular macrophages and endothelial cells in the brain.(Dantzer et al. 2008) Cytokine activity may reduce dopamine production and activity in the reward network, which may play a key role in generating sickness behavior in the ill animal.(Treadway, Cooper, and Miller 2019) Additionally, serotonin uptake and reduced expression of serotonin receptors are associated with cytokine activity, which may be reversed with antidepressant treatment.(Catena-Dell’Osso et al. 2013) These mechanisms may be triggered by psychological stressors (both acute and chronic) modulating the activity of the hypothalamic-pituitary-adrenal (HPA) axis and may also promote further activity of the HPA axis.(Raison, Capuron, and Miller 2006; Dantzer et al. 2008) These changes are thought to affect the functioning of neuroanatomical regions implicated in the development of depressive symptoms, including the dorsolateral prefrontal cortex, the insular and temporal cortices, subcortical and limbic regions, as well as the cerebellum.(Dantzer et al. 2008)
Catatonia is a common co-occurrence with delirium among hospitalized patients. Among critically ill patients, roughly one-third were found to have both catatonia and delirium, and catatonic symptoms were associated with a greatly increased likelihood of also having delirium.(Wilson et al. 2017) While the pathogenesis of delirium is complex and not yet fully elucidated, it has been proposed that some common etiologies, such as trauma, surgery, hypoxemia, and infection (including both viral and bacterial) may share similar immune mechanisms. DAMPs and PAMPs are produced in the presence of an acute medical event (e.g., a trauma or infection), which activate macrophages to trigger the secretion of pro-inflammatory cytokines that may cross the BBB and activate microglia in the brain. The presence of certain pro-inflammatory molecules such as lipopolysaccharide is also thought to contribute to disruption of the BBB and the recruitment of immune cells into brain tissue.(Cerejeira et al. 2010) Microglial activation produces nitric oxide, reactive oxygen species, and additional pro-inflammatory cytokines such as IL-1, which diffuse locally and disrupt neuronal functioning. These functions are exaggerated in older patients and those with neurodegenerative illness.(Cerejeira, Lagarto, and Mukaetova-Ladinska 2014) These same pro-inflammatory cytokines may also affect astrocyte functioning, limiting the metabolic support that astrocytes provide to neurons locally and disrupting the BBB.(Wilson et al. 2020; Obermeier, Daneman, and Ransohoff 2013)
The neurobehavioral presentations of hypoactive delirium bear striking resemblance to the sickness behavior syndrome described above, including withdrawal, apathy, somnolence, sleep-wake disturbances, and cognitive impairments. Indeed, the cascade of immune activity that occurs in the context of critical illness is thought to disrupt the functioning of the reticular activating system, the hippocampus, and cholinergic neurons in the forebrain—which may be responsible for the cognitive impairments witnessed in delirium.(Cerejeira et al. 2010) Sickness behavior syndrome may reflect an imbalance between systemic inflammation and neuropsychiatric response.(Pensato et al. 2021) In this context, an over-reactive inflammatory response in a relatively resilient brain (e.g., COVID-19-associated cytokine storm), or a fragile brain substrate dealing with a relatively minor inflammatory stress (e.g., urinary tract infection in the elderly) may be enough to precipitate a pathogenic neuroinflammatory assault, leading to encephalopathy, catatonia, or both.
Recently, neuroanatomical correlates of multiple components of sickness behavior have been elucidated.(Ilanges et al. 2022; Osterhout et al. 2022) Symptoms of sickness syndrome such as reduced food and water intake and reduced locomotor activity have been linked to a subset of neurons in the nucleus tractus solitarius (NTS)—the site of afferent dorsal vagal signals from the periphery—and in the area postrema (AP)—an area of fenestrated endothelium that is adjacent to aminergic cell bodies in the upper brainstem.(Ilanges et al. 2022) These features of decreased food and water intake and immobilization are reminiscent of similar symptoms in catatonia. In a mouse model, activation of NTS-AP with lipopolysaccharide replicates these aspects of the sickness syndrome while inhibition of this neuronal subset significantly decreased the anorexia, adipsia and locomotor cessation associated with lipopolysaccharide. Pertinent for the immune model of both catatonia and delirium neurons in other areas besides the AP, including the organum vasculosum of the lamina terminalis, the subfornical organ and the median eminence, may also react to immune response signals.(Ilanges et al. 2022)
The 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, is a genetic syndrome resulting from the deletion of a part of the 22^nd^ chromosome. Patients with 22q11.2DS frequently present with variety of neuropsychiatric manifestations including Parkinson’s disease, catatonia and a psychotic illness indistinguishable from schizophrenia.(Butcher et al. 2018) It is thought that genetic deletion of enzymes key to the production and throughput of monoaminergic neurotransmitters—including dopamine—may be at least partly involved in the development of neuropsychiatric illnesses in 22q11.2DS.(Boot et al. 2008; Evers et al. 2014) However, several markers of immune dysregulation have also been found in 22q11DS, which appear to be positively correlated with the presence of neuropsychiatric manifestations. These include elevated proinflammatory cytokines,(Mekori-Domachevsky et al. 2017) increased complement activation,(Grinde et al. 2020) elevated neutrophil to leukocyte ratio,(Mekori-Domachevsky et al. 2021) and disruptions in the BBB.(Crockett et al. 2021) The link between dysregulated immune processes and disrupted neurotransmitter synthesis and output in 22q11.2DS remains unclear—although given the similarities to the neuroimmune manifestations described above, a final common pathway to neuropsychiatric symptoms may be possible.
When brain morphology is compared between 22q11DS patients with and without ultra-high psychotic risk (UHR) or psychotic symptoms, there is a decrease in anterior cingulate cortex (ACC) volume in those with greater psychosis. Accelerated cortical thinning in the ACC and other frontal cortical areas are observed in those with UHR, (Padula et al. 2018) and these patients often exhibit features of catatonia.(Schreiner et al. 2017; Ramanathan et al. 2017; Pantelis et al. 2003; Yucel et al. 2003; Borgwardt, Radue, and Riecher-Rossler 2007) This research offers support to the hypothesis that catatonia is closely linked to psychomotor disconnection in the ACC/mid-cingulate cortex (MCC)/medical prefrontal cortex (mPFC) paralimbic CSTC circuitry designed to mediate the link of motivation to movement.(Hirjak et al. 2020; Fricchione and Beach 2019) As the ACC is closely linked to social attachment, it further suggests a role for immune activation in the setting of social threat response.
Finally, ASD commonly presents with catatonic features. Overlapping features of the two disorders are many, and include motor stereotypies, purposeless agitation, echolalia, negativism, and mutism. A recent meta-analysis found that 10% of patients with ASD also met full DSM-5 criteria for catatonia.(Vaquerizo-Serrano et al. 2022) Although the role of neuroinflammation is not clear, some have proposed that excess oxidative stress resulting from altered mitochondrial metabolism in ASD predisposes to dysregulated immune activity,(Gevezova et al. 2020) which may be further exacerbated by allostatic overload associated with neuroendocrine activation,(Theoharides, Asadi, and Patel 2013) and ultimately result in microglial and astrocyte alterations—potentially disrupting neuronal function.(Matta, Hill-Yardin, and Crack 2019; Sciara et al. 2020) Interestingly, there is also a high co-occurrence of ASD and obsessive-compulsive disorder (OCD),with the latter sharing pathophysiologic features with catatonia via disruptions in the functioning of CSTC loops. Both catatonia and OCD have been associated with the development of anti-basal ganglia antibodies.(Nicholson et al. 2007) Table 1 provides an inexhaustive list of etiologies of neuromedical and psychogenic catatonia.
Beyond the etiologies of catatonia discussed above, several syndromes that are thought to be closely related to catatonia, including neuroleptic malignant syndrome (NMS) and akinetic mutism (AM) may themselves involve inflammatory processes.
NMS is a life-threatening neuropsychiatric condition characterized by the development of stupor, muscle rigidity, fever, rhabdomyolysis, and autonomic instability in response to sudden alterations in dopaminergic tone resulting from addition of dopamine blockers or removal of pro-dopaminergic medications.(Gurrera et al. 2011) Based on overlapping motor features (i.e., immobility, mutism) and treatment modalities (i.e., benzodiazepines, electroconvulsive therapy, and amantadine) (Schonfeldt-Lecuona et al. 2020; Caroff, Jain, and Morley 2020; Beach et al. 2017; Koch et al. 2000), as well as instances of catatonia progressing to NMS after neuroleptic administration, many researchers have conceptualized NMS as form of malignant catatonia representing the severe end of the catatonia spectrum.(Fricchione 1985; Fink 1996; Northoff 2002) As such, understanding the role of inflammation in NMS may be especially helpful in providing clues regarding the development of life-threatening homeostatic derangement in other forms of MC.
While NMS is often understood in terms of dopaminergic dysfunction, immune dysfunction has also been proposed as a contributory factor.(Anglin, Rosebush, and Mazurek 2010) In particular, NMS patients are known to exhibit a range of laboratory abnormalities consistent with the acute phase response (APR), an innate immune mechanism triggered by pro-inflammatory cytokine release in response to infection, tissue injury, or other major systemic perturbations, (Gabay and Kushner 1999) resulting in downstream homeostatic changes in protein levels and other laboratory markers known as “acute phase reactants.” Clinical and laboratory abnormalities in NMS consistent with APR physiology include neutrophil-predominant leukocytosis, (Perry and Wilborn 2012; Kalelioglu et al. 2021) hyperthermia, (Gurrera et al. 2011) and elevations in acute phase reactants such as c-reactive protein (CRP), erythrocyte sedimentation rate, D-dimer, fibrinogen, and alpha-1 chymotrypsin. (Rosebush et al. 2008; Perry and Wilborn 2012; Tse et al. 2015) Also elevated is interleukin-6, a key inflammatory cytokine in the APR cascade which trended closely with severity of autonomic instability, rhabdomyolysis, and mutism in one case report.(Rosebush et al. 2008) Moreover, multiple case studies of NMS have reported elevated levels of procalcitonin,(Cabot et al. 2009) an acute phase protein that is used clinically in sepsis as a marker of potential bacterial infection consistent with activation of pathogen-response mechanisms within the innate immune system.
In addition to “positive” acute phase reactants that increase during APR, certain “negative” laboratory markers typically decrease, including serum iron and albumin. Interestingly, low serum iron is a common laboratory abnormality in NMS and has been posited as a risk factor for the progression of catatonia to NMS upon exposure to antipsychotics.(Lee 1998; Rosebush and Mazurek 2010) Serum iron levels may also be dynamic in NMS, decreasing during the early course of illness and normalizing with recovery, offering further support for the APR hypothesis.(Rosebush and Mazurek 1991; Anglin, Rosebush, and Mazurek 2010)
While converging lines of evidence suggest activation of the APR in NMS, the nature of the interrelationship is complex. The initiation of the APR may impact central dopaminergic transmission and confer neuroleptic sensitivity via multiple mechanisms, including decreased iron availability for dopamine synthesis and maintenance of D2 receptor availability, (Kim and Wessling-Resnick 2014) as well as impaired striatal dopamine function as a result of a pro-inflammatory cytokine milieu, (Treadway, Cooper, and Miller 2019) previously discussed with regards to “sickness behavior” in depression. (Burfeind, Michaelis, and Marks 2016) The consequent hypodopaminergic state may then impair homeostatic mechanisms in multiple neural systems, contributing to temperature dysregulation, autonomic instability, and neuromuscular hyperactivity.(Anglin, Rosebush, and Mazurek 2010; Horseman and Gregerson 2014) Without removal of the inciting dopamine blockade, downstream consequences of homeostatic derangement may intensify innate immune activation in a positive feedback loop, including massive tissue injury (i.e., rhabdomyolysis), sympathetic overdrive, as well as direct and indirect effects of hyperthermia (i.e., translocation of immunogenic endotoxins from the gastrointestinal tract). (Guinart et al. 2021; Epstein and Yanovich 2019) Rapid escalation of inflammatory cytokine release may also disrupt specialized regions of the BB and abutting deep midline brain structures, further exacerbating “sickness behavior” leading to extreme behavioral manifestations such as mutism, withdrawal, and stupor, conferring additional risk for life-threatening complications of immobility.
Another clinical entity that may offer insight on the relationship between catatonia and inflammation is akinetic mutism (AM), a neurological syndrome where patients are awake with intact sensorimotor capacity and yet unresponsive to environmental stimulation.(Giacino 1997) Given the extreme degree of diminished reactivity, AM lies at the far end of the continuum of motivation disorders, beyond apathy and abulia,(Arnts et al. 2020), while intersecting in some ways with disorders of consciousness like the minimally conscious state.(Giacino et al. 2002) AM shares with catatonia a peculiar absence of spontaneous voluntary motor behavior, captured in the criteria of mutism, stupor, and withdrawal. Indeed, C. Miller Fisher conceptualized AM as a form of “pure motor catatonia,” without the concomitant affective state of fear or autonomic dysregulation that typifies many catatonic presentations.(Fisher 1989) AM has been associated with a range of neurological events, typically focal lesions involving the anteromedial frontal lobes or centromedian mesodiencephalic regions.(Arnts et al. 2020; Fisher 1983) Interestingly, however, there have been cases of AM associated with infectious encephalitis, as well as COVID-19 infection, typically in the absence of clear signs of direct CNS involvement, suggesting the possibility of an inflammatory mechanism at play.(Fusunyan et al. 2021; Pilotto et al. 2020; Gaughan et al. 2021)
While less is known about potential immune modulating effects of certain treatment modalities for catatonia, a few findings are intriguing in terms of linkages to inflammation. Benzodiazepines, primarily lorazepam and diazepam, are considered the first-line treatment for catatonia, often resulting in dramatic improvement in minutes to hours. Benzodiazepines primarily act on GABA-A receptors, and evidence suggests that activation of GABA-A receptors on lymphocytes reduces the release of inflammatory cytokines.(Prud’homme, Glinka, and Wang 2015; Rogers et al. 2019) Notably, diazepam and lorazepam, but not other benzodiazepines, bind to translocator protein, which is also associated with the inflammatory response.(Fernandez Hurst et al. 2017; Ramirez, Niraula, and Sheridan 2016) Lorazepam also blocks stress-induced accumulations of macrophages in the CNS.(Ramirez, Niraula, and Sheridan 2016) The other mainstay of treatment for catatonia is electroconvulsive therapy (ECT). While the mechanism by which ECT improves catatonia remains unclear, animal studies suggest that a single session of ECT increases release of some inflammatory cytokines, including interleukin-6, while multiple sessions lead to a decrease in interleukin-6 in patients who improve with treatment.(Rojas et al. 2022; Rush et al. 2016; Jarventausta et al. 2017; Rogers et al. 2019) In animal models, ECT leads to decreased proinflammatory properties in macrophages, and is thought to modulate the innate immune system.(Rojas et al. 2022; Roman, Nawrat, and Nalepa 2008; Roman and Nalepa 2005) Finally, minocycline has been used to treat catatonia in a handful of case reports. While the presumed mechanism of action involves NMDA-antagonism, the antibiotic medication clearly has anti-inflammatory properties as well.(Miyaoka et al. 2007; Ahuja and Carroll 2007)
In this section, we propose a series of interrelationships by which allostatic loading by chronic stress is mediated on the cellular and molecular level through persistent activation of the innate immune system, leading to oxidative stress and downstream degradative effects that impact synaptic and neural network function. The consequent alteration of excitatory/inhibitory imbalance in paralimbic and motor CSTC loops may then predispose to the psychomotor disorder we know as catatonia (see Figure 1).
Threat stress can be conceptualized as normal, tolerable, or toxic (McEwen, Nasca, and Gray 2016), depending on whether neurally-mediated allostatic mechanisms can adjust to maintain adequate energy regulation and physiologic stability in the face of challenges. (McEwen 1998) Threat stress may derive from a variety of causes, including neuromedical illnesses and psychosocial contributors such as severe mental illness. In mammals, a particular stress pathway mediated by the amygdala may register separation from social objects, given their vital importance to survival for some organisms. The predominant emotion of fear in catatonia (Fink and Shorter 2017) as well as the manifestation of ambitendency may reflect the bind of an organism faced with risks of social contact (i.e., predation) but also the necessity of attachment as a mammalian survival strategy.
When stress is acute, organisms deploy a varied repertoire of behavioral responses facilitated by innate immune activation, where circulating cytokines communicate conditions of threat at specialized interfaces like the circumventricular organs and vasal paraganglia. (Cunningham and Maclullich 2013; Ilanges et al. 2022; Osterhout et al. 2022; Xanthos and Sandkuhler 2014) “Sickness behavior” represents one behavioral response model, characterized by apathy, motor retardation, loss of interest and appetite, and occasionally fever, reflecting an energy-saving strategy that bears resemblance to aspects of catatonic stupor, as well as depression and hypoactive delirium. (Cunningham and Maclullich 2013) Alternatively, another defensive option would be coordinated lateral hypothalamic activation of the fight-flight response leading to energy-intensive sympathetic overdrive and behavioral excitation. The contrasting behavioral responses to threat may provide models for the primitive catatonic defenses of stupor and excitement, which may be elaborated to an extreme degree in at-risk individuals, who may be predisposed to dysregulated threat response due to downstream consequences of chronic toxic stress.
Whether neuromedical or psychosocial in nature, chronic toxic stress can overwhelm allostatic mechanisms contributing to allostatic load. Margolis proposed the immunoactivation hypothesis, suggesting that cumulative allostatic load may perpetuate downstream molecular and cellular changes (Margolis 2015), including long-term oxidative stress, mitochondrial dysfunction, disruption in glucose and lipid metabolism, and disrupted hormonal regulation, (Margolis 2015; Picard and Sandi 2021) that increase vulnerability to stress-related NCDs. Cellular hits involving either PAMP infectious or autoimmune damage signals (as might occur in limbic encephalitis, a neuromedical cause of catatonia) or the DAMP danger signals of severe psychosocial stress (as would be seen in severe mental illness, or psychogenic catatonia) can both set the stage for a common pathway immunoactivation state that could lower the threshold for a catatonic state in susceptible individuals. The cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which interacts with PAMPS and DAMPS, is a key mechanism in initiating the release of interferons and other immune mediators which may themselves contribute to “sickness behavior.” (Paul, Snyder, and Bohr 2021; Picard and Sandi 2021; Barrett et al. 2021).
If excessively engaged in the central nervous system (especially by microglia) (Paul, Snyder, and Bohr 2021; Picard and Sandi 2021; Barrett et al. 2021), inflammatory immune pathways like cGAS-STING may have deleterious effects on structure and function at the neuronal and synaptic level, including suppression of synaptic transmission, long-term potentiation, and sources of adaptive plasticity including hippocampal neurogenesis. (Paul, Snyder, and Bohr 2021; Xanthos and Sandkuhler 2014) Though initially reversible, chronic stress may lead to persistent deficits in dendritic remodeling and neurogenesis, impacting structural resilience to insult and increased likelihood of excitotoxic events. (McEwen, Nasca, and Gray 2016) Interestingly, animal models of catatonia have included genetic manipulation of enzymatic pathways involved in myelin synthesis, which were reversible by microglial suppression. (Janova et al. 2018; Lappe-Siefke et al. 2003) Humans homozygotes for specific single nucleotide polymorphisms in the same genetic pathways have been associated with severe catatonic presentations as well as increased frontotemporal white matter hyperdensities (Hagemeyer et al. 2012), suggesting a role for microglial activation and myelin degeneration in increasing vulnerability to catatonia.
While catatonia is a heterogenous condition with multiple etiologies and pathophysiologies, the innate neuroinflammatory cascade and consequent degradation of neuronal, synaptic, and white matter integrity may represent a final common pathway leading to excitatory-inhibitory imbalance in key neural networks involved in catatonia. For example, psychomotor features may result from dysfunction in the ACC/MCC/mPFC/CSTC circuit, which is essential for mediating motivation-to-movement pathways in collaboration with supplementary motor area (SMA)/Motor CSTC circuit. (Fricchione and Beach 2019; Hirjak et al. 2020) Meanwhile, abnormalities in emotion regulation and goal-directed behavior may result from disruption of the ACC/MCC transmodal zone, which is implicated in major psychiatric illnesses and especially prone to cytokine-mediated inflammation due to its proximity to the circumventricular blood-brain interface. (Ansell et al. 2012) Accordingly, microglial activation in the ACC may disturb synaptic functioning and contribute to the severity of disease states such as major depressive episodes, which can predispose to catatonia and feature prominent mood, psychomotor, and motivational deficits. (Setiawan et al. 2015; Hong 2013; Albrecht et al. 2019; Holmes et al. 2018) In this way, neuromedical insults, especially when compounded by second-hit of psychosocial stress, may initiate cellular and molecular immune processes that lead to alterations in neuronal structure and function resulting in the catatonia phenotype. (Anglin, Rosebush, and Mazurek 2010)
In light of the above, psychogenic catatonia risk may be perceived as a toxic stress-induced allostatic overload state leading to the microglial/macrophage activation and the incitement of mitochondrial distress associated with excessive DAMP-induced neuroinflammation and selective neuronal vulnerability. We speculate that the final common pathway nature of the catatonia, emerging as a result of psychogenic or neuromedical catatonias, has its origin in an evolutionarily preserved immune cell threat response system—the cGAS-STING pathway—which may respond with neurogenic neuroinflammation to both PAMPS and DAMPS. In vulnerable subjects, psychogenic stressors and/or neuromedical insults can lead to this final common pathway with the psychomotor cortico-striato-thalamo-cortical ramifications we recognize as catatonia. Future studies using Single Cell RNA Sequencing of macrophages and 18 kDa translocator protein (TSPO) positron emission tomography of microglial cells may be helpful in evaluating this hypothesis.