Cognitive domains affected post-COVID-19; a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. METHODS: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. RESULTS: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. CONCLUSIONS: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Catatonia: demographic, clinical and laboratory associations.

BACKGROUND: Catatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia. METHODS: Electronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case-control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality. RESULTS: We identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 µmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45-0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29-1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment. CONCLUSIONS: In the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Neuropsychiatric features of Parkinson's disease in the era prior to the use of dopaminergic therapies.

BACKGROUND: Psychosis in Parkinson's disease includes hallucinations and delusions. Other non-psychotic neuropsychiatric features include depression, anxiety and apathy. There is currently controversy over whether psychosis in Parkinson's is an intrinsic part of the disorder or the result of dopaminergic medications. This study aimed to examine a historical cohort of individuals with Parkinson's prior to the use of dopaminergic therapy to assess the prevalence of psychotic and other neuropsychiatric features. METHODS: The case notes of patients with Parkinson's disease admitted to the National Hospital for Neurology and Neurosurgery, London between 1924 and 1946 were examined. Demographic and clinical variables were extracted along with any neuropsychiatric features. Cases meeting criteria for encephalitis lethargica were excluded. RESULTS: 115 cases of individuals with Parkinson's disease were identified. 58 (41.7%) were female. Mean age was 54.0 (SD 9.6) years and mean time since Parkinson's diagnosis was 5.3 (SD 5.7) years. No individuals met criteria for encephalitis lethargica. No cases of hallucinations or delusions were reported. There was one case of an illusion in a patient who was using anticholinergic medication. Other neuropsychiatric features reported were sleep disorder (present in 10, 8.7%), depression (8, 7.0%), memory impairment (5, 4.3%), impulsivity (4, 3.5%), bradyphrenia (4, 3.5%), impaired attention (3, 2.6%), anxiety (1, 0.9%), fatigue (1, 0.9%) and apathy (1, 0.9%). CONCLUSIONS: Prior to the use of dopaminergic therapies, patients with Parkinson's disease admitted to hospital rarely, if ever, reported psychotic symptoms, although other neuropsychiatric symptoms were more prevalent. The main limitation is that a lack of systematic enquiry about psychotic symptoms may have resulted in underreporting.

Clinical Neuroimaging Findings in Catatonia: Neuroradiological Reports of MRI Scans of Psychiatric Inpatients With and Without Catatonia.

OBJECTIVE: Catatonia is a debilitating psychomotor disorder. Previous neuroimaging studies have used small samples with inconsistent results. The authors aimed to describe the structural neuroradiological abnormalities in clinical magnetic resonance imaging (MRI) brain scans of patients with catatonia, comparing them with scans of psychiatric inpatients without catatonia. They report the largest study of catatonia neuroimaging to date. METHODS: In this retrospective case-control study, neuroradiological reports of psychiatric inpatients who had undergone MRI brain scans for clinical reasons were examined. Abnormalities were classified by lateralization, localization, and pathology. The primary analysis was prediction of catatonia by presence of an abnormal MRI scan, adjusted for age, sex, Black race-ethnicity, and psychiatric diagnosis. RESULTS: Scan reports from 79 patients with catatonia and 711 other psychiatric inpatients were obtained. Mean age was 36.4 (SD=17.3) for the cases and 44.5 (SD=19.9) for the comparison group. Radiological abnormalities were reported in 27 of 79 cases (34.2%) and in 338 of 711 in the comparison group (47.5%) (odds ratio [OR]=0.57, 95% confidence interval [CI]=0.35, 0.93; adjusted OR=1.11, 95% CI=0.58, 2.14). Among the cases, most abnormal scans had bilateral abnormalities (N=23, 29.1%) and involved the forebrain (N=25, 31.6%) and atrophy (N=17, 21.5%). CONCLUSIONS: Patients with catatonia were commonly reported to have brain MRI abnormalities, which largely consisted of diffuse cerebral atrophy rather than focal lesions. No evidence was found that these abnormalities were more common than in other psychiatric inpatients undergoing neuroimaging, after adjustment for demographic variables. Study limitations included a heterogeneous control group and selection bias in requesting scans.

Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study.

OBJECTIVES: We aimed to find the association of inflammation and respiratory failure with delirium in COVID-19 patients. We compare the inflammatory and arterial blood gas markers between patients with COVID-19 delirium and delirium in other medical disorders. METHODS: This cross-sectional study used the CHART-DEL, a validated research tool, to screen patients for delirium retrospectively from clinical notes. Inflammatory markers C-reactive protein (CRP) and white cell count (WBC), and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2) were compared between patients with COVID-19 delirium and delirium in other medical disorders. RESULTS: In bivariate analysis, CRP (mg/L) was significantly higher in the COVID-19 group, (81.7 ± 80.0 vs. 58.8 ± 87.7, p = 0.04), and WBC (109/L) was significantly lower (7.44 ± 3.42 vs. 9.71 ± 5.45, p = 0.04). The geometric mean of CRP in the COVID-19 group was 140% higher in multiple linear regression (95% CI = 7-439%, p = 0.03) with age and sex as covariates. There were no significant differences in pO2 or pCO2 across groups. CONCLUSION: The association between higher CRP and COVID-19 in patients with delirium may suggest an inflammatory basis for delirium in COVID-19. Our findings may assist clinicians in establishing whether delirium is due to COVID-19, which may improve management and outcomes of infected patients.

Catatonic Episodes Related to Substance Use: A Cross-Sectional Study Using Electronic Healthcare Records.

Objective: Substance use has increasingly been linked to the onset of catatonic episodes; however, no large observational studies have examined this association. This study aimed to identify catatonic episodes temporally associated with acute intoxication, withdrawal or chronic substance use, investigate which substances were involved, and compare clinical characteristics of substance-related and non-substance-related catatonic episodes. Methods: This study retrospectively identified all catatonic episodes recorded in an electronic case register hosted at a large secondary mental health trust in London, UK. Episodes were categorized as substance-related if the clinical record reported either a positive urine drug screen, an ICD-10 diagnosis of a mental or behavioral disorder due to substance use, or documented substance use between two weeks prior to the catatonic episode and the date of the catatonic episode. Results: 108 of 2130 catatonic episodes (5.1%) were deemed substance-related. The number of contemporaneously reported substance-related episodes increased between 2007 and 2016 [r = 0.72, p = 0.02]. Episodes in the context of acute intoxication (n = 54) were most frequently related to cannabis (n = 31) or cocaine (n = 5) use, whilst those in the context of drug withdrawal (n = 8) were most commonly related to alcohol, opioids and benzodiazepines. There were 50 episodes of catatonia associated with chronic substance use without intoxication or withdrawal, of which the majority were related to cannabis use (n = 37). 21 episodes had overlapping intoxication, withdrawal and chronic use of different substances within an episode. Compared to catatonic episodes not related to substance use, episodes of substance-related catatonia occurred in individuals who were younger (mean age 31.3 years [SD 12.2] vs 35.7 years [SD 16.3], p = 0.01) and more likely to be men (74.0% vs 54.3%, p < 0.001). The clinical features of catatonia were similar between the two groups. Conclusions: A relatively small proportion of catatonic episodes were temporally associated with reported substance use within their electronic records. Substance-related catatonic episodes were mostly related to cannabis use, but other substances including cocaine, alcohol, opioids and benzodiazepines were sometimes implicated. This is likely an underestimate of substance-related catatonia use due to issues with documentation and appropriate investigation.

Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives.

There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic's early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Clozapine Response in Schizophrenia and Hematological Changes.

BACKGROUND: Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation. METHODS: Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom's largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as "much," or "very much" improved on the seven-point Clinical Global Impression-Improvement (CGI-I) subscale. RESULTS: In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response. IMPLICATIONS: Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.

Brain imaging in catatonia: systematic review and directions for future research.

BACKGROUND: Catatonia is a frequent, complex and severe identifiable syndrome of motor dysregulation. However, its pathophysiology is poorly understood. METHODS: We aimed to provide a systematic review of all brain imaging studies (both structural and functional) in catatonia. RESULTS: We identified 137 case reports and 18 group studies representing 186 individual patients with catatonia. Catatonia is often associated with brain imaging abnormalities (in more than 75% of cases). The majority of the case reports show diffuse lesions of white matter, in a wide range of brain regions. Most of the case reports of functional imaging usually show frontal, temporal, or basal ganglia hypoperfusion. These abnormalities appear to be alleviated after successful treatment of clinical symptoms. Structural brain magnetic resonance imaging studies are very scarce in the catatonia literature, mostly showing diffuse cerebral atrophy. Group studies assessing functional brain imaging after catatonic episodes show that emotional dysregulation is related to the GABAergic system, with hypoactivation of orbitofrontal cortex, hyperactivation of median prefrontal cortex, and dysconnectivity between frontal and motor areas. CONCLUSION: In catatonia, brain imaging is abnormal in the majority of cases, and abnormalities more frequently diffuse than localised. Brain imaging studies published so far suffer from serious limitations and for now the different models presented in the literature do not explain most of the cases. There is an important need for further studies including a better clinical characterisation of patients with catatonia, functional imaging with concurrent catatonic symptoms and the use of novel brain imaging techniques.

Catatonia with GABAA receptor antibodies.

A 22-year-old African woman developed acute behavioural change, against a background of sickle cell disease with strokes requiring a ventriculoperitoneal shunt. She alternated between mutism with prolonged staring and posturing, and a state of agitation with elation and echolalia. Cerebrospinal fluid (CSF) protein was elevated and electroencephalogram showed mild slowing with bitemporal slow and sharp waves. We suspected catatonia secondary to possible autoimmune encephalitis but her condition persisted despite intravenous methylprednisolone. After identifying a positive serum anti-gamma-aminobutyric acid-A (GABAA) antibody, treatment with intravenous immunoglobulin, oral corticosteroids and rituximab led to gradual improvement. Patients with catatonia may show reduced GABAA receptor density and there are two other reports of catatonia with anti-GABAA antibodies. This patient's treatment response supports the antibody's causative role.

Evaluation of a Specialised Counselling Service for Perinatal Bereavement.

OBJECTIVES: We aimed to evaluate the outcomes of Petals: a charitable organisation in Cambridgeshire. Petals provides counselling for women and couples who have suffered perinatal bereavement, or trauma during pregnancy or birth. This paper attempts to evaluate the effect of counseling interventions at this difficult time. METHODS: Outcomes were recorded in 107 patients using the CORE (Clinical Outcomes in Routine Evaluation) system. CORE was developed to assess the effectiveness of psychological therapies. CORE-OM (CORE Outcome Measure) involves a questionnaire that assesses subjective well-being, symptoms/problems, function, and risk to self and others. The CORE-OM questionnaire was completed before and after the counselling sessions. RESULTS: The CORE-OM scores were summated into a global representation of severity. Severity decreased in all patients. Symptoms of psychological pathology were also decreased in all cases. CONCLUSION: Offering a free specialised counselling for parents suffering perinatal loss seems to be associated with an improvement in psychological outcomes. It is possible that it is more effective among a clinical population. However, we are uncertain of the natural history of the psychological problems this group of clients are experiencing. Having a control group would show how much of any natural improvement is due to the therapy; conversely, it is possible that without intervention these problems worsen with time, so a control group could actually amplify the effect.

Suicidality in the prospective Zurich study: prevalence, risk factors and gender.

Our prospective Zurich study (1978-2008) found that suicidal ideation had occurred in 40.5% and suicide attempts in 6.6% of the population by age 50. Important gender differences were found in both suicidality and its risk factors. Suicide attempts were earlier and more frequent among women than among men: 70 versus 44% reported their first suicide attempt before 20. For women, the relative risk of suicide attempts was 1.6, but the relative risk of suicidal ideation was about equal (1.1 for women). The main risk factors for suicidal ideation in women were low social support (OR 4.0) and frequent punishment in childhood (OR 3.7), and in men, a depressive (OR 6.5) and an anxious personality (OR 4.6). The main risk factors for suicide attempts in women were a broken home (OR 10.2) and sexual abuse/violence (OR 7.9) in childhood; in men, no multivariate analyses of suicide attempt were conducted because of insufficient statistical power.

Associations with quality of life and the effect of psychopathology in a community study.

PURPOSE: Quality of life (QoL) is considerably impaired in mental illness and especially in depression. In this study, we aimed to determine the demographic, personality-related and psychopathological associations with QoL. In addition, we studied how the associations with QoL differ depending on the burden of psychopathology. METHODS: We used a longitudinal observational cohort study, enriched for high levels of psychopathology, to examine data for QoL when the subjects were 34-35. We conducted a hierarchical linear regression analysis to determine how sex, personality, sociodemographics, somatic symptoms and psychopathology affect QoL. RESULTS: Once all the variables were included in the model, total psychopathology is strongly negatively associated with QoL, while mastery and income were shown to have positive associations with QoL. Sex, personality and somatic symptoms had no significant associations with QoL once the other variables had been introduced into the regression. Due to the outstanding association with psychopathology, we tested whether the relationship had any interaction with the other predictors, but none reached statistical significance. CONCLUSIONS: The most important association with QoL is psychopathology, regardless of sex, personality, coping resources, sociodemographics or the extent somatic symptoms. The relationship holds across the other variables included and the results are, thus, widely applicable.

Petals: An Assessment of the Outcomes of a Service for Bereavement during Childbirth.

OBJECTIVES: We aimed to evaluate the outcomes of Petals: a charitable organisation in Cambridgeshire. Petals provides counselling for women and couples who have suffered perinatal bereavement, or trauma during pregnancy or birth. This paper attempts to evaluate the effect of counseling interventions at this difficult time. METHODS: Outcomes were recorded in 42 patients using the CORE (Clinical Outcomes in Routine Evaluation) system. CORE was developed to assess the effectiveness of psychological therapies. CORE-OM (CORE Outcome Measure) involves a questionnaire that assesses subjective well-being, symptoms / problems, function, and risk to self and others. The CORE-OM questionnaire was completed before and after the counselling sessions. RESULTS: The CORE-OM scores were summated into a global representation of severity. Severity decreased in all patients. Symptoms of psychological pathology were also decreased in all cases. CONCLUSION: A review of the available literature indicates that little is known about the efficacy of therapy for perinatal bereavement and trauma. These original data suggest convincing efficacy and benefits, but the numbers involved are small.Further trials with greater sample sizes are required.

Catatonia in the peripartum: A cohort study using electronic health records.

BACKGROUND: Due to limited existing literature available on the presentation and treatment of catatonia in the peripartum, this retrospective descriptive cohort study aimed to examine demographic data, catatonic features, diagnoses pre- and post-catatonic episodes, treatment and the presence of obstetric complications. METHODS: Individuals with catatonia were identified in a previous study using anonymised electronic healthcare records from a large mental health trust in South-East London. The presence of features from the Bush-Francis Catatonia Screening Instrument was coded by the investigators and longitudinal data were extracted from structured fields and free text. RESULTS: 21 individuals were identified from the larger cohort, each of whom experienced one episode of catatonia in the postpartum period, and all had had an inpatient psychiatric admission. 13 patients (62 %) presented after their first pregnancy and 12 (57 %) experienced obstetric complications. 11 (53 %) attempted breastfeeding and 10 (48 %) received a diagnosis of a depressive disorder following the episode of catatonia. The majority presented with immobility or stupor, mutism, staring and withdrawal. All were treated with antipsychotics and 19 (90 %) received benzodiazepines. CONCLUSIONS: This study suggests that signs and symptoms of catatonia during the peripartum are similar to other catatonic presentations. However, the postpartum may be a period of high risk for catatonia and obstetric factors, such as birth complications, may be relevant.

Exploring seasonality in catatonia diagnosis: Evidence from a large-scale population study.

Catatonia is a severe psychomotor syndrome mainly associated with psychiatric disorders, such as mood disorders and schizophrenia. Seasonal patterns have been described for these psychiatric disorders, and a previous study conducted in South London showed for the first time a seasonal pattern in the onset of catatonia. In this study, we aim to extend those findings to a larger national sample of patients admitted to French metropolitan hospitals, between 2015 and 2022, and to perform subgroup analyses by the main associated psychiatric disorder. A total of 6225 patients diagnosed with catatonia were included. A seasonal pattern for catatonia diagnosis was described, using cosinor models. Two peaks of diagnoses for catatonic cases were described in March and around September-October. Depending on the associated psychiatric disorder, the seasonality of catatonia diagnosis differed. In patients suffering with mood disorders, peaks of catatonia diagnosis were found in March and July. For patients suffering with schizophrenia, no seasonal pattern was found.

Seasonality of presentation and birth in catatonia.

BACKGROUND: Catatonia is a neuropsychiatric syndrome associated with both psychiatric disorders and medical conditions. Understanding of the pathophysiology of catatonia remains limited, and the role of the environment is unclear. Although seasonal variations have been shown for many of the disorders underlying catatonia, the seasonality of this syndrome has not yet been adequately explored. METHODS: Clinical records were screened to identify a cohort of patients suffering from catatonia and a control group of psychiatric inpatients, from 2007 to 2016 in South London. In a cohort study, the seasonality of presentation was explored fitting regression models with harmonic terms, while the effect of season of birth on subsequent development of catatonia was analyzed using regression models for count data. In a case-control study, the association between month of birth and catatonia was studied fitting logistic regression models. RESULTS: In total, 955 patients suffering from catatonia and 23,409 controls were included. The number of catatonic episodes increased during winter, with a peak in February. Similarly, an increasing number of cases was observed during summer, with a second peak in August. However, no evidence for an association between month of birth and catatonia was found. CONCLUSIONS: The presentation of catatonia showed seasonal variation in accordance with patterns described for many of the disorders underlying catatonia, such as mood disorders and infections. We found no evidence for an association between season of birth and risk of developing catatonia. This may imply that recent triggers may underpin catatonia, rather than distal events.

From one to many: Hypertonia in schizophrenia spectrum psychosis an integrative review and adversarial collaboration report.

Different types of resistance to passive movement, i.e. hypertonia, were described in schizophrenia spectrum disorders (SSD) long before the introduction of antipsychotics. While these have been rediscovered in antipsychotic-naïve patients and their non-affected relatives, the existence of intrinsic hypertonia vs drug-induced parkinsonism (DIP) in treated SSD remains controversial. This integrative review seeks to develop a commonly accepted framework to specify the putative clinical phenomena, highlight conflicting issues and discuss ways to challenge each hypothesis and model through adversarial collaboration. The authors agreed on a common framework inspired from systems neuroscience. Specification of DIP, locomotor paratonia (LMP) and psychomotor paratonia (PMP) identified points of disagreement. Some viewed parkinsonian rigidity to be sufficient for diagnosing DIP, while others viewed DIP as a syndrome that should include bradykinesia. Sensitivity of DIP to anticholinergic drugs and the nature of LPM and PMP were the most debated issues. It was agreed that treated SSD should be investigated first. Clinical features of the phenomena at issue could be confirmed by torque, EMG and joint angle measures that could help in challenging the selectivity of DIP to anticholinergics. LMP was modeled as the release of the reticular formation from the control of the supplementary motor area (SMA), which could be challenged by the tonic vibration reflex or acoustic startle. PMP was modeled as the release of primary motor cortex from the control of the SMA and may be informed by subclinical echopraxia. If these challenges are not met, this would put new constraints on the models and have clinical and therapeutic implications.