Apraxia Test Research Articles

Ideomotor limb apraxia in Huntington's disease

Ideomotor limb apraxia is the disturbance of planning and of execution of motor activity,which is not caused by a dysfunction of the motor or sensory nervous system. Apraxia is a diagnostic criterion in dementialike Alzheimer's disease. However, this symptom may also occur in dementia with subcortical lesions like Huntington's disease (HD), a hereditary, devastating neurodegenerative disease leading to neurological and psychiatric dysfunction. The aim of our study is to determine the correlation between the occurrence of ideomotor limb apraxia and neuropsychological deficits in HD. To assess the correlation between apraxia and neuropsychological abilities in HD, 41 patients with HD and 33 age- and sex-matched controls were examined. The De Renzi test for apraxia and an apraxia test battery containing tests of i) imitation of meaningless gestures of hands, ii) imitation of meaningless gestures of fingers, iii) performance of meaningful gestures on demand, and iv) pantomime of tool use were used to assess apraxia. Moreover, neuropsychological function was rated by the Mini Mental State Examination (MMSE), the Rey Complex Figure Memory Test, the Trail Making Test A and B, the California Verbal Learning Test (German version), the Stroop Color and Word Test, the Controlled Oral Word Association Test, and the Mehrfachwahl- Wortschatz-Intelligenztest for measuring verbal intelligence. Motor function was assessed in all HD patients by the Unified HD Rating Scale (UHDRS), rating oculomotor and orolingual function, fine motor tasks, parkinsonism, dystonia, chorea and statics and gait. Apraxic HD patients showed worse results than non-apraxic HD patients in three items of the Rey Complex Figure Memory Test (Organisation, short-term and longterm memory), but not in other assessed neuropsychological tests. In assessment of meaningful gestures on demand 39.3% of HD patients were apraxic, in assessment of pantomime of tool use 67.9% of HD patients showed apraxia. Patients with HD showed highly significant worse results than controls in the De Renzi test, in hands' and fingers' imitation, in performance of gestures on demand, in pantomime of tool use and every neuropsychological test except for the test measuring verbal intelligence. Apraxic HD patients showed worse results than non-apraxic HD patients in the UHDRS total motor score and the score for oculomotor function. This is the largest study on apraxia in HD. Ideomotor limb apraxia is a common sign in HD patients, occurring in a high percentage. In contrast to the opinion of several authors, occurrence of apraxia in HD is independent from neuropsychological decline and the severity of most neurological symptoms.

Pantomime of Tool Use Depends on Integrity of Left Inferior Frontal Cortex

Pantomime of tool use is a frequently used test for apraxia. For basic cognitive neuroscience, pantomime of tool use is of interest because it constitutes a link between instrumental and communicative manual actions. We used lesion subtraction analysis to determine the locations specifically associated with defective pantomime of tool use in patients with left-brain damage and aphasia. Subtraction of lesions of patients with normal pantomime from those with defective pantomime yielded a maximum difference in the inferior frontal gyrus and adjacent portions of the insula and precentral gyrus. This result remained essentially the same when possible confounding influences of impaired language comprehension and of lesion size were controlled by selecting patients equated on these measures and when only patients with preserved imitation of gestures were considered. By contrast, parietal lesions did not have a specific impact on pantomime. We speculate that the vulnerability of pantomime to lesions of left inferior frontal cortex is due to the high demands on selection of a very restrained range of features out of the many features that may come to mind when imagining the actual use of the tool.

The course of apraxia and ADL functioning in left hemisphere stroke patients treated in rehabilitation centres and nursing homes

Objective: To study the course of apraxia and daily life functioning (ADL) in left hemisphere stroke patients with apraxia. Design: Prospective cohort study. Setting: Rehabilitation centres and nursing homes. Subjects: One hundred and eight left hemisphere stroke patients with apraxia, hospitalized in rehabilitation centres and nursing homes. Measures: ADL-observations, Barthel ADL Index, Apraxia Test, Motricity Index. Results: During the study period of 20 weeks, patients showed small improvements in apraxia (standardized mean differences of 0.19 and 0.33) and medium-sized improvements in ADL functioning (standardized mean differences from 0.37 to 0.61). About 88% of the patients were still apraxic at week 20. Less improvement in apraxia was observed in initially less severe apraxic patients. Less improvement in ADL functioning was found to be associated with more severe apraxia, a more independent initial ADL score, higher age, impaired motor functioning and longer time between stroke and first assessment. Conclusions: Apraxia in stroke patients is a persistent disorder, which has an adverse influence on ADL recovery.

EVALUATION OF IDEOMOTOR APRAXIA IN PATIENTS WITH STROKE: A STUDY OF RELIABILITY AND VALIDITY

This aim of this study was to determine the reliability and validity of an established ideomotor apraxia test when applied to a Turkish stroke patient population and to healthy controls. The study group comprised 50 patients with right hemiplegia and 36 with left hemiplegia, who had developed the condition as a result of a cerebrovascular accident, and 33 age-matched healthy subjects. The subjects were evaluated for apraxia using an established ideomotor apraxia test. The cut-off value of the test and the reliability coefficient between observers were determined. Apraxia was found in 54% patients with right hemiplegia (most being severe) and in 25% of left hemiplegic patients (most being mild). The apraxia scores for patients with right hemiplegia were found to be significantly lower than for those with left hemiplegia and for healthy subjects. There was no statistically significant difference between patients with left hemiplegia and healthy subjects. It was shown that the ideomotor apraxia test could distinguish apraxic from non-apraxic subjects. The reliability coefficient among observers in the study was high and a reliability study of the ideomotor apraxia test was therefore performed.

Limb apraxia and cognitive impairment in progressive supranuclear palsy

Limb apraxia occurs in progressive supranuclear palsy (PSP); however, its characteristics and relation to dementia are unclear. We compared 25 probable PSP patients on cognitive and ideomotor apraxia tests with 19 healthy controls. Eleven PSP patients were demented (D-PSP) and 14 not (ND-PSP). D-PSP patients did worse than controls and ND-PSP patients in all cognitive tests; and ND-PSP patients did worse than controls in all except the memory test. In the apraxia test, PSP patients committed mainly sequence errors and executed complex gestures badly. Apraxia correlated strongly with dementia. In PSP, limb apraxia seems mainly due to frontal deafferentation and lesions, but only when these are severe enough to cause dementia.

Limb apraxia in corticobasal degeneration and progressive supranuclear palsy

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) share pathologic features, and cortical and subcortical signs. Apraxia is frequently described in CBD and sometimes in PSP; however, it is difficult to distinguish ideomotor from limb-kinetic apraxia, and apraxia frequency is unclear. The authors set out to clarify the nature and frequency of apraxia in these diseases. The authors compared probable CBD and PSP patients, matched for motor disability, to healthy age-matched controls on cognitive tests and the De Renzi ideomotor apraxia test. Cognitive impairment was similar, but more CBD (70.8%) than PSP (36%) patients had apraxia. CBD patients committed more apraxic errors of awkwardness and were more compromised on simple gestures; PSP patients committed more sequence errors. While progressive supranuclear palsy (PSP) patients had ideomotor apraxia, the peculiar gesture compromise in corticobasal degeneration (CBD) suggests that limb-kinetic apraxia is dominant. In both illnesses, the movement production system of Roy and Square appears compromised: in CBD defective control of muscle activation seems likely, producing clumsy movements; in PSP, control of motor program activation appears defective, resulting in sequence errors and perseverations. The De Renzi test can reliably estimate apraxia frequency and may be used to distinguish limb-kinetic from ideomotor apraxia.

Assessment of apraxia: inter-rater reliability of a new apraxia test, association between apraxia and other cognitive deficits and prevalence of apraxia in a rehabilitation setting

To investigate the inter-rater reliability of a new apraxia test. Furthermore to examine the association of apraxia with other neuropsychological impairments and the prevalence of apraxia in a rehabilitation setting on the basis of the new test. Cross-sectional cohort study, involving 100 patients with a first stroke admitted to a rehabilitation centre in the Netherlands. General patient characteristics and stroke-related aspects. Cognitive screening involving apraxia, visuospatial scanning, abstract thinking and reasoning, memory, attention, planning and aphasia. The indices for inter-rater agreement range from excellent to poor. Significant correlations are found between apraxia and visuospatial scanning, memory, attention, planning and aphasia. The patients with apraxia perform significantly worse than the patients without apraxia on memory, the time needed to complete the tests for scanning and attention, and aphasia. The prevalence of apraxia is 25.3% in the total group, 51.3% in the left hemisphere stroke patients and 6.0% in the right hemisphere stroke patients. Patients with and without apraxia do not differ significantly concerning age, gender and type of stroke. The apraxia test has been shown to be a reliable instrument. Apraxia is often associated with aphasia, memory problems and mental slowness. This study shows that on the basis of the apraxia test, the prevalence of apraxia among patients in the rehabilitation centre is high, especially among patients with left hemisphere lesions.

The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: The Boston Circulatory Arrest Trial

Objectives Despite the technical advantages of total circulatory arrest for vital organ support during infant heart surgery, many centers have moved away from its use because of the demonstrated effects of circulatory arrest of long duration on neurodevelopmental outcomes. Our goal was to determine the functional form of the association between duration of circulatory arrest and risk of neurodevelopmental dysfunction. Methods From 1988 to 1992, in a single-center trial, infants with d-transposition of the great arteries underwent the arterial switch operation after random assignment to circulatory arrest or low-flow bypass. The alpha-stat method was used, and hematocrit on bypass was maintained at 20%. Developmental, neurologic, and speech outcomes were assessed at 8 years of age in 155 of 160 eligible children (97%). Outcomes selected for analysis were Full-Scale, Verbal, and Performance IQ, Reading and Mathematics Composite, time to complete the Grooved Pegboard (dominant hand), and the Mayo Test for Apraxia. Results Nonparametric regression and piecewise linear models indicated that neurodevelopmental outcomes were generally not adversely affected unless the duration of circulatory arrest exceeded a threshold of 41 minutes (95% 1-sided lower confidence limit of 32 minutes). Conclusions We found that the effect of duration of total circulatory arrest on later neurodevelopmental outcomes is nonlinear, with little influence at shorter durations and with steadily worsening outcomes after longer durations of circulatory arrest. Because the effects of duration of circulatory arrest may vary according to diagnosis, age at surgery, and other bypass and perioperative variables, this study cannot ascertain a universally “safe” duration of total circulatory arrest.

Limb apraxia, pantomine, and lexical gesture in aphasic speakers: Preliminary findings

Background: Speech-language pathologists considering the use of gesture as a therapeutic modality for clients with aphasia must first evaluate the integrity of their cleints' gesture systems. Questions arise with respect to which behaviours to assess and how to assess the chosen behaviours. There has been a long-held belief that tests of limb apraxia and pantomime provide valid information about candidacy for gesture-based interventions, yet the theoretical and empirical basis of this assumption is limited. Further, the relationship between conversational gesture skill and limb apraxia in co-occurring aphasia has been largely unexplored. It is possible that a client's gesture performance in natural conversation provides more valid information about gesture treatment candidacy than do tests of limb apraxia. Aims: This study aimed to investigate the relationship between the presence of limb apraxia and conversational gesture use in speakers with nonfluent aphasia. Following the assumption that limb praxis and conversational gesture reflect differing underlying processing, it was hypothesised that speakers with aphasia and limb apraxia would produce the full range of conversational gesture types in a conversational context. Further, it was hypothesised that speakers with demonstrated pantomime deficits on formal tests of pantomime would produce pantomimes naturally in conversation. Thus, a dissociation would be demonstrated between the processing responsible for gesture production as measured in limb apraxia tests and that subserving the production of conversational gesture. Methods & Procedure: Seven participants with nonfluent aphasia and ideomotor and conceptual limb apraxia conversed in a semi-structured conversation with the researcher. All arm and hand gestures produced by the participants were counted and rated according to guidelines provided by Hermann, Reichle, and Lucius-Hoene (1988), and the time they spent in either gesture or spoken expression was compared. Correlations were calculated between limb apraxia scores and proportions of meaning-laden gestures used in conversation. Outcomes & Results: All seven participants produced a wide range of gesture types. Participants with limited verbal output produced large amounts of meaning-laden gesture. Importantly, even participants with severe limb apraxia produced high proportions of meaning-laden gestures (codes and pantomimes) in the natural setting. There were no significant relationships found between scores on limb apraxia tests and natural gesture use. Conclusions: Patients with nonfluent aphasia and limb apraxia may still use meaningful conversational gesture in naturalistic settings. Tests of limb apraxia may be poor predictors of use of lexical gesture. Thus, clinicians are advised to sample lexical gesture use in spontaneous interactions.

The Brave New World of the Cyber Speech and Hearing Clinic

The Brave New World of the Cyber Speech and Hearing Clinic

"Motor" Impairment in Asperger Syndrome: Evidence for a Deficit in Proprioception

Motor impairment has frequently been described in Asperger syndrome (AS), a pervasive developmental disorder included in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Previous research focusing on this motor dysfunction has yielded inconsistent results, and the "clumsiness" observed clinically remains poorly defined. To clarify further the issue of motor impairment, we compared a group of 10 children and young adults who met DSM-IV criteria for AS with a control group with no neurological impairment. Subjects were matched on age, sex, socioeconomic status, and Verbal IQ. A broad battery of motoric tests was administered. Subjects with AS were found to perform more poorly than controls on tests of apraxia, one-leg balance with eyes closed, tandem gait, and repetitive finger-thumb apposition. No significant differences were found on tests of finger tapping, grooved pegboard, trail making, or visual-motor integration. The pattern of impairments suggests that a proprioceptive deficit may underlie the incoordination observed in AS and that these individuals may be overreliant on visual input to maintain balance and position in space.

Measuring disabilities in stroke patients with apraxia: A validation study of an observational method

The objective of the present study was to determine the clinical and construct validity of the assessment of disabilities in stroke patients with apraxia. Disabilities were assessed by means of observation of activities of daily living (ADL), such as washing the face and upper body and putting on a blouse or shirt. The study was carried out at occupational therapy departments in general hospitals, rehabilitation centres, and nursing homes. Patients diagnosed to have had a stroke in the left hemisphere and to have apraxia participated in the study (n = 45, 21 males, 24 females age 39–91). Guidelines were offered for the ADL observations and the assessment of disabilities in these activities. Clinical validity was investigated by comparing the scores of the patients with those of a group of stroke patients without apraxia (n = 36, 14 males, 22 females age 35–88). Construct validity was examined by investigating relationships between several measures of interest: an apraxia test, a motor functioning test, a set of ADL observations, and the Barthel index as a general measure of disability. Comparison of the results of the patients with apraxia with the control group of stroke patients without apraxia showed that the clinical validity of the ADL observations is good: On the basis of the ADL observations, differences between patients with apraxia and patients without apraxia are measured. Correlation analyses of the group of patients with apraxia showed that the ADL observations were highly associated with apraxia, but only to a lesser degree with motor impairments; while motor impairments correlated strongly with the Barthel index (a general measure of physical disability), but only marginally with ADL observations. A LISREL analysis supported these findings. The results indicate that ADL observations have clinical validity and that the construct validity of the observational method is good. ADL observations appear to measure disability ties caused by apraxia in stroke patients.

The rehabilitation of limb apraxia: A study in left-brain–damaged patients

Smania N, Girardi F, Domenicali C, Lora E, Aglioti S. The rehabilitation of limb apraxia: a study in left-brain–damaged patients. Arch Phys Med Rehabil 2000;81:379-88. Objective: To assess the effectiveness of a rehabilitative training program for patients with limb apraxia. Design: Randomized, controlled trial. Setting: Neurologic rehabilitation unit of a university hospital. Patients: Thirteen patients with acquired brain injury and limb apraxia (lasting more than 2 months) as a result of lesions involving the left cerebral hemisphere. Patients were assigned to a study group or to a control group following a randomization scheme. The study group underwent an experimental training for limb apraxia. The control group received conventional treatment for aphasia. Intervention: A behavioral training program consisting of gesture-production exercises. The rehabilitative program was made up of 3 sections dedicated to the treatment of gestures with or without symbolic value and related or nonrelated to the use of objects. Thirty-five experimental sessions, each lasting 50 minutes, were given. Main Outcome Measures: Neuropsychologic tests for assessment of aphasia, verbal comprehension, “general intelligence,” oral apraxia, constructional apraxia, and 3 tests concerning limb praxic function (ideational apraxia, ideomotor apraxia, gesture recognition). Scores related to each test were used to measure the outcome. Video recordings of ideational and ideomotor apraxia tests allowed us to register type and number of praxic errors. All outcome measures, except the aphasia test, were recorded before and after the experimental (or control) treatment time interval. Results: The patients in the study group achieved a significant improvement of performance in both ideational (p =.039) and ideomotor (p =.043) apraxia tests. They also showed a significant reduction of errors in ideational (p =.001) and ideomotor (p <.001) apraxia tests. A trend toward improvement was found in the gesture comprehension test (p =.058), while other outcome measures did not show any significant amelioration. Control patients did not show any significant change in performance. Conclusions: The results show the possible effectiveness of a specific training program for the treatment of limb apraxia. © 2000 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Limb-kinetic Apraxia: A Neuropsychological Description

Abstract We present data from a follow-up study of two patients affected by a degenerative disorder of the central nervous system (cortico-basal degeneration). At the onset, they both complained of clumsiness in performing fine finger movements, which disturbed daily activities. In one patient, the right hand was affected, while in the other patient the left hand was involved. In both cases, we found apractic deficit which was consistent across all gesturing tasks and generalized to proximal movement and to the other side during follow-up. Preserved knowledge of tool function and use, and unimpaired gesture recognition, were found even in the later stages of the disease. These findings fulfilled Liepmann's criteria for the diagnosis of limb-kinetic apraxia. Qualitative analysis of performance on the apraxia tests showed a considerable distal/proximal dichotomy, i.e. greater difficulties in performing fine finger movements than arm trajectories. Furthermore, the two patients had greater difficulty in carry...

A Diagnostic Test for Apraxia in Stroke Patients: Internal Consistency and Diagnostic Value

The internal consistency and the diagnostic value of a test for apraxia in patients having had a stroke are presented. Results indicate that the items of the test form a strong and consistent scale: Cronbach's alpha as well as the results of a Mokken scale analysis present good reliability and good scalability. The diagnostic value of the test was determined by comparison of test results in three groups of patients: 44 stroke patients with apraxia (patients), 35 stroke patients without apraxia (patient controls), and 50 healthy nursing home residents with no history of stroke (normal controls). The diagnostic value is expressed by means of the sensitivity and specificity and the predictive value of the test. In addition, Receiver Operator Characteristics (ROC) curves are presented. The sensitivity and specificity of the apraxia test appear to be good: all values are higher than 80%. The test also has high predictive value. The ROC curves illustrate that the test is sufficiently discriminative to allow a differentiation between persons with apraxia and persons without apraxia.

A four year prospective study of age-related cognitive change in adults with Down's syndrome.

While neuropathological studies indicate a high risk for Alzheimer's disease in adults with Down's syndrome, neuropsychological studies suggest a lower prevalence of dementia. In this study, cognitive deterioration in adults with Down's syndrome was examined prospectively over 4 years to establish rates and profiles of cognitive deterioration. Fifty-seven people with Down's syndrome aged 30 years or older were assessed using a battery of neuropsychological tests on five occasions across 50 months. Assessments of domains of cognitive function known to change with the onset of Alzheimer related dementia were employed. These included tests of learning, memory, orientation, agnosia, apraxia and aphasia. The individual growth trajectory methodology was used to analyse change over time. Severe cognitive deterioration, such as acquired, apraxia and agnosia, was evident in 28.3% of those aged over 30 and a higher prevalence of these impairments was associated with older age. The rate of cognitive deterioration also increased with age and degree of pre-existing cognitive impairment. Additionally, deterioration in memory, learning and orientation preceded the acquisition of aphasia, agnosia and apraxia. The prevalence of cognitive impairments consistent with the presence of Alzheimer's disease is lower than that suggested by neuropathological studies. The pattern of the acquisition of cognitive impairments in adults with Down's syndrome is similar to that seen in individuals with Alzheimer's disease who do not have Down's syndrome.

Ideomotor apraxia test: a new test of imitation of gestures for elderly people.

Ideomotor apraxia is one of the earliest disturbances in Alzheimer's disease (AD); no test of this disturbance has yet been validated for elderly people. We propose a test of meaningless gesture imitation and its relevance in elderly people is studied. The Ideomotor Apraxia Test (IAT) consists of showing 10 gestures. Each item is graded from 0 to 3. IAT was carried out on 55 patients with AD (mean age: 86.8 +/- 6.8 (71-100); mean MMS score: 14.6 +/- 6.3) and 26 elderly patients without cognitive impairment (mean age: 84.1 +/- 7.5 (70-100); mean MMS score: 27.5 +/- 1.9). The inter-rater reliability, a threshold, the apparent sensitivity and specificity and the relationship between the MMS score and the ideomotor apraxia score were determined. The mean apraxia score was 14.9 +/- 7.3 in the AD group and 28 +/- 1.6 in the normal group (P < 0.0001). Inter-rater agreement is excellent (P = 0.995). The threshold is 27. The apparent sensitivity and specificity are very good (95% and 88%, respectively). The correlation between the MMS score and ideomotor apraxia score is excellent (r = 0.83 (95% CI; 0.72-0.91). Age and educational level do not influence ideomotor apraxia score. IAT is the first test that evaluates meaningless gesture imitating capacity in an elderly population. It is an easy and quick-to-perform test, useful routinely for diagnosis of AD. It could contribute to the early diagnosis of AD and is correlated with the severity of cognitive impairment. Copyright 1998 Lippincott Williams & Wilkins

Outcome of strategy training in stroke patients with apraxia: a phase II study

Evaluation of a therapy programme for stroke patients with apraxia. The programme is based on teaching patients strategies to compensate for the presence of apraxia. This programme was designed for assessment and treatment by occupational therapists. The outcome was studied in a pre-post test design. Measurements were conducted at baseline and 12 weeks later. Thirty-three stroke patients with apraxia were treated at occupational therapy departments n general hospitals, rehabilitation centres and nursing homes. The following measurements were conducted: an apraxia test, a motor functioning test, observation of activities of daily living (ADL), Barthel Index, and an ADL questionnaire for the therapist and the patient. The patients showed large improvements in ADL functioning on all measures and small improvements on the apraxia test and the motor functioning test. The effect sizes for the disabilities, ranging from 0.92 to 1.06, were large compared to the effect sizes for apraxia (0.34) and motor functioning (0.19). The significant effect of treatment is also seen when individual improvement and subjective improvement are considered. Measured with the Barthel Index for instance, 71% of the patients improved. These results suggest that the programme seems to be successful in teaching patients compensatory strategies that enable them to function more independently, despite the lasting presence of apraxia.

Outcome of strategy training in stroke patients with apraxia: a phase II study

Objective: Evaluation of a therapy programme for stroke patients with apraxia. The programme is based on teaching patients strategies to compensate for the presence of apraxia. This programme was designed for assessment and treatment by occupational therapists. Design: The outcome was studied in a pre–post test design. Measurements were conducted at baseline and 12 weeks later. Subjects: Thirty-three stroke patients with apraxia were treated at occupational therapy departments in general hospitals, rehabilitation centres and nursing homes. Main outcome measures: The following measurements were conducted: an apraxia test, a motor functioning test, observation of activities of daily living (ADL), Barthel Index, and an ADL questionnaire for the therapist and the patient. Results: The patients showed large improvements in ADL functioning on all measures and small improvements on the apraxia test and the motor functioning test. The effect sizes for the disabilities, ranging from 0.92 to 1.06, were large compared to the effect sizes for apraxia (0.34) and motor functioning (0.19). The significant effect of treatment is also seen when individual improvement and subjective improvement are considered. Measured with the Barthel Index for instance, 71% of the patients improved. Conclusions: These results suggest that the programme seems to be successful in teaching patients compensatory strategies that enable them to function more independently, despite the lasting presence of apraxia.

Testing for apraxia in neurological patients: a descriptive study in two diverse cultures.

We constructed a detailed apraxia testing battery consisting of 55 items arranged in seven subparts and applied it to a convenience series of patients with a variety of neurological diseases and asymptomatic control subjects. A total of 173 subjects were evaluated in two culturally diverse settings: Rochester, MN, USA and in Istanbul, Turkey. There was little difference between performance scores in the two sites. The test could be completed within a reasonable time (5-10 min) in cases and in controls in both sites. Patients with Parkinson's disease performed just as well as controls but patients with Alzheimer's disease or other neurodegenerative disorders did less well than control subjects. Copyright Rapid Science Ltd