As Motor System Pathophysiology Returns to the Forefront of Psychosis Research, Clinical Implications Should Hold Center Stage

Kendler contrasted early and more modern depictions of schizophrenia and observed that while abnormal motor behaviors were prominently featured in the diagnostic conceptions in the first half of the 20th century, these signs are all but entirely neglected in more modern operationalized systems.¹ This change was likely due to the mid-century advent of antipsychotic medication when characteristic motor side effects began to mask “spontaneous” movement abnormalities and investigators and clinicians turned to extrapyramidal symptoms (EPS) and tardive dyskinesia instead. As a result, motor pathology vanished as a core feature of psychosis for more than 50 years. However, a new generation of research, focusing on biological relatives, medication-naïve patients, and prospective high-risk research designs has renewed the mechanistic focus on motor function.² Dovetailing these advancements is accumulating evidence which suggests that although some motor abnormalities may prove to be unique to psychosis, that movement phenomena can be highly relevant even if they are not specific to a particular disorder.^3–5 For example, the NIMH Research Domain Criteria (RDoC) has just now released a sixth domain devoted to motor symptoms: https://grants.nih.gov/grants/guide/notice-files/NOT-MH-18-053.html. Further, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) assigned a separate diagnostic category for catatonia and emphasized association with multiple disorders. However, while mechanistic and dimensional understanding of motor behaviors has received increased attention, a focus on relevant clinical considerations has been lacking. This is unfortunate as motor phenomena have significant intervention as well as unique clinical research implications that are not addressed in other domains of psychopathology. This list ranges widely from the direct treatment of motor symptoms such as catatonia and minimization of motor medication side effects to the broader applications of driving prediction, precision medicine and highlighting novel treatment target mechanisms as well.

One prominent application relates to staging and predicting clinical outcomes. Studies in the 1990s first highlighted that abnormal and delayed premorbid period motor development characterized infants and toddlers who later developed schizophrenia.⁶ Following this work, investigators evaluated clinical high-risk individuals and observed unusual motor activity (eg, spontaneous dyskinesias) is characteristic and further, predictive of eventual onset.⁷ Along this line, recent advances in instrumental or automated motor assessments promise to dramatically improve the precision and scope of motor abnormality assessments. One excellent example of this application is the current paper of Apthorp and colleagues (in this issue)⁸ who tested postural sway with instrumental measures in schizotypal personality disorder, schizophrenia, and controls. Abnormal sway indicating poor cerebellar function was detected in both patient groups (who performed comparably, despite the fact that schizotypal individuals are typically less impaired than individuals with schizophrenia on any number of indices), suggesting that discrete disturbances of postural control are closely linked to the constitutional vulnerability underlying psychotic disorders. This type of breakthrough, which has numerous implications for informing neurodevelopmental conceptions, also highlights the promise of instrumental measures that allow for precise quantification of abnormal movements. With respect to treatment applications, this approach is likely to inform on any number of future studies designed to employ the method for detecting psychosis-risk populations as well.

An additional application of instrumental motor measures is to inform on underlying neurocircuitry. Neuroimaging studies applied these measures to identify components of the motor circuit, which is distinct from circuits involved in other psychosis dimensions.³ For example, the SyNoPsis project focuses on 3 separate key brain circuits relevant to psychosis, ie, motor circuitry in abnormal motor behavior, associative circuit in formal thought disorder, and a limbic circuit in persecutory or grandiose delusions.⁹ Knowledge on the underlying network dysfunction will be critical in developing new treatment options including targets for non-invasive brain stimulation.

Another promising clinical application relates to harnessing assessment of motor phenomena in improving treatment and promoting individualized medicine. As indicated above, in addition to “spontaneous” movement symptoms, motor abnormalities may occur as a side effect of antipsychotic medication. Investigators have been working to employ sensitive instrumental assessments (eg, such as handwriting kinematic analysis) to carefully monitor medication side-effects in a quick, standardized, and convenient fashion.¹⁰ Further, having mobile platform for motor assessments (handwriting on a tablet computer), would allow for non-specialists to incorporate motor assessments in clinical settings. In addition, by the time we can assess behaviors with portable wearable technology, we will be able to monitor these types of side effects across all settings. Another possibility is that given that some motor signs are distinctly associated with negative symptoms or disorganization,¹¹ tracking abnormalities could indicate clinically relevant changes. In this way, motor assessments may inform the treatment strategy (eg, adapt medication, schedule appointments). Likewise, motor abnormalities may reflect who might respond to a particular treatment,¹² or indicate distinct trajectory in a high-risk context. Recently Dean and colleagues stratified a sample of clinical high-risk subjects according to their motor performance on instrumental measures identifying 3 vulnerability subtypes with distinct cognitive and clinical profiles, as well as different transition risks.¹³

Finally, a body of emerging evidence suggests that the motor behavior themselves may serve as promising clinical targets. Complex motor-related behaviors such as the perception, interpretation, and performance of gesture are impacted in psychosis, and given the critical role these nonverbal behaviors play in normative everyday communication, it is not surprising that respective deficits significantly contribute to poor functional outcome and disability in schizophrenia.¹⁴ This is particularly relevant as gesture may be responsive to remediation. For example, Schülke and Straube (in this issue)¹⁵ examined abnormalities in the semantic processing of co-verbal gestures in psychosis, and observed that reducing frontal excitability (with cathodal stimulation) normalized patient group performance on a task where participants determined if the content of a storied segment matched or did not match with the gesture displayed by the actor. This type of approach, employing stimulation and targeting motor-related abnormalities and deficits, is showing promise in treating motor-related phenomena across the psychosis spectrum (eg, motor learning with cerebellar stimulation).¹⁶ Finally, ambulatory movement itself could be a target. Feedback on ambulatory movements and instructions could be given by the same mobile devices. This field of ambulatory exercise interventions is rapidly evolving and mobile devices may be an important advantage in this process.

Psychotic disorders are characterized by numerous transdiagnostic and unique movement abnormality subtypes, including those discussed presently, as well as others (eg, grip strength, neurological soft signs, eye movements).^2,3,17 We argue these behaviors may hold significant clinical relevance. In contrast to several prominent symptoms in psychosis, abnormal motor behaviors are readily observable markers, adding rigor to traditional clinical assessment and providing a potentially valuable tool for efforts to disseminate broader assessment and monitoring while staying closely tied to underlying mechanisms. In addition, the availability of novel sensitive and mobile technologies is likely to continue to improve our ability to monitor these behaviors in-depth, and across an array of settings, with minimal cost or inconvenience. Finally, attending to motor abnormalities may inform on individual risk, course, and treatment effects in psychosis, potentially directing targeted behavioral interventions or neurostimulation. As motor dysfunction continues to benefit from increased attention in our field, clinical application should be at the forefront of these efforts.