The authors have declared that no competing interests exist.
Conceived and designed the experiments: JRB MH SV MCK JRH. Performed the experiments: JRB SV MH. Analyzed the data: JRB MH. Contributed reagents/materials/analysis tools: JRB SV MH MCK JRH. Wrote the paper: JRB SV MH MCK JRH.
Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.
Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination – Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.
In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/− 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.
Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy.
Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by a combination of cognitive deficits and multi-faceted motor system dysfunction,
Transcranial magnetic stimulation of the motor cortex has been used to explore motor system dysfunction in CBS. Previous studies have demonstrated altered resting motor threshold (RMT)
Although apraxia may be seen in other neurodegenerative diseases,
A range of pathologies may present as CBS. Initial reports emphasized an underlying tauopathy (referred to pathologically as corticobasal degeneration), with similar features to those seen in many cases of frontotemporal lobar degeneration. More recently Alzheimer's disease, TAR DNA-binding protein 43 intraneuronal inclusions, and progressive supranuclear palsy have been reported in cases of CBS.
Although the pattern of cerebral atrophy in CBS varies significantly, previous studies have consistently demonstrated atrophy of the primary motor cortex.
The present study explored several hypotheses; firstly, that limb apraxia in CBS – in part – reflects impaired visuospatial processing. Secondly, that motor system dysfunction can be demonstrated in CBS, using paired-pulse threshold tracking transcranial magnetic stimulation, and that motor system dysfunction and limb apraxia both reflect pathological involvement of cortical and subcortical motor structures. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.
Patients with a clinical diagnosis of CBS were recruited consecutively from a specialist cognitive disorders clinic. The study was approved by the South Eastern Sydney Local Health District Human Research Ethics Committee and performed after written informed consent was obtained from all participants. In accordance with PLoS One policies, the data from the present study may be made available on request. The diagnosis of CBS was established through a detailed clinical assessment and neuropsychological evaluation, and all patients met recent diagnostic criteria.
In total, 34 participants were included in the study; 17 with CBS and 17 control subjects. Of the 17 patients with CBS, 41.2% were male and the mean age at assessment was 64.4+/−6.6 years. The mean symptom duration was 54.6+/−18.0 months. A database of volunteers was used to recruit control subjects. Each individual patient was matched to a control subject of the same gender (male gender in 41.2%). Where possible CBS patients were matched to a control subject of the same age in years. In practice, control subject age was matched to within 2 years of CBS patient age in all but two cases, in which the age difference was 3 and 4 years respectively. The mean age of control subjects was 64.4+/−7.3 years and this was not significantly different from that of CBS patients (P = 1.0). Controls and CBS patients were not specifically matched for handedness. Control subjects were included if they had no history of neurological diseases such as dementia, stroke, multiple sclerosis, Parkinson's disease or other movement disorders. Controls who demonstrated cognitive impairment on neuropsychological evaluation or incidental abnormalities on MRI scanning were excluded from the study.
Apraxia was systematically assessed using a semi-structured approach. Specifically, patients were asked to imitate 4–5 meaningful (for example; the “Thumb's up” or “A-Okay” gestures) and 4–5 meaningless hand gestures, using both the right and left hands,
All patients underwent a standardized clinical assessment by a single examiner (JRB) to detect clinical evidence of motor system dysfunction such as weakness and hyperreflexia.
Since a disease specific functional rating scale has not been developed for CBS, the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R),
Cognitive screening was performed using the Addenbrooke's Cognitive Examination – Revised (ACE-R).
The paired pulse, threshold-tracking transcranial magnetic stimulation protocol was used to assess cortical function in CBS patients and control subjects.
According to the threshold tracking protocol, the motor cortex was stimulated using magnetic pulses delivered via a 90 mm magnetic circular coil placed over the subject's scalp, and the resultant motor evoked potentials were recorded from the abductor pollicis brevis muscle in the hand at rest. Patients were repeated asked to relax the hand being tested and the protocol was recommenced if voluntary or involuntary (e.g. mild dystonia) motor activity interfered with electromyographic silence. By default, the right hand was used for transcranial magnetic stimulation studies; if a stable response could not be obtained on the right, the left hand was studied. If a stable motor response could not be obtained on either side, despite maximal stimulus intensity, the motor cortex was classified as relatively inexcitable and the protocol was ceased. In such cases, no subsequent measures of cortical excitability could be determined. The optimal coil position, defined, as the position that elicited the most stable motor response, was determined first (See
(
As the protocol proceeded, the time between conditioning and test impulses – referred to as the interstimulus interval – was varied from 1 to 20 milliseconds (ms). The motor responses were amplified and filtered (3 Hz–3 kHz) using a GRASS ICP511 AC amplifier (Grass-Telefactor, Astro-Med Inc., West Warwick, RI, USA) and sampled at 10 kHz using a 12-bit data acquisition card (National Instruments PCI-MIO-16E-4). The protocol was driven by QTRACS software (Institute of Neurology, Queen Square, London, UK).
In normal individuals, increased test impulse intensity is required to produce the target motor response following a conditioning impulse when the interstimulus interval is between 1–7 ms. This phenomenon, referred to as short interval intracortical inhibition (SICI), reflects relative cortical inhibition induced by the conditioning impulse at short interstimulus intervals. In the present study SICI was defined as the increase in test impulse intensity (i.e. test - RMT) required to achieve the target response at interstimulus intervals of 1–7 ms, represented as a percentage of RMT.
All 17 CBS patients and 17 age-matched healthy controls underwent magnetic resonance imaging (MRI) according to a standardized protocol using a 3-Tesla Phillips MRI scanner with standard quadrature head coil (8 channels). The 3D T1-weighted images were acquired with the following parameters: coronal orientation, matrix 256×256, 200 slices, 1×1 mm2 in-plane resolution, slice thickness 1 mm, TE/TR = 2.6/5.8 ms, and TFE/FFE Pulse sequence.
3D T1-weighted sequences were used to perform a VBM analysis
Statistical analysis was performed by a single author (JRB) and carried out using the Statistical Package for Social Sciences (version 19.0, SPSS Inc.; Chicago, IL, USA). The Wilcoxon signed rank test was used to compare related measures (e.g. limb-meaningful and limb-meaningless apraxia scores) in individual patients, as well as compare apraxia scores between different independent raters. Comparisons of neurophysiological data were first made between patients with CBS and control subjects. Subjects were later grouped according to their RMT; patients with an RMT <50% (RMT <50%), patients with an RMT >50% (RMT >50%), and patients with an inexcitable motor cortex (inexcitable), and the three groups were compared. Neurophysiological parameters could not be determined in patients with an inexcitable motor cortex, so these patients were excluded from several subsequent analyses. In excitable patients, an RMT of 50% was used to define the groups as this approximated the median recorded RMT for the patients in the study. Continuous variables were analyzed using analysis of variance (ANOVA) when normally distributed or the Kruskal–Wallis test when non-normally distributed. Pair-wise comparisons were performed using the student's t test when the data was normally distributed and the Mann-Whitney test when non-normally distributed. Categorical data were analyzed using the Chi-Square test. Correlations between continuous variables were performed using Spearman correlation for non-normally distributed samples, after application of the Bonferroni correction,
As mentioned, 34 participants were included in the study; 17 with CBS and 17 age and gender matched controls. Of patients with CBS, 7 (41.2%) were male. The mean age at assessment was 64.4+/−6.6 years and the mean symptom duration was 54.6+/−18.0 months. All but one CBS patient was right-hand dominant. The maximally apraxic hand was the right hand in 10 CBS patients, the left hand in 4 patients, and both hands were equally affected in 3 patients. The single left-hand dominant patient had bilateral limb apraxia. The right hand was studied in 11 (84.6%) CBS patients with an excitable motor cortex, whereas the left hand was used in 2 (15.4%) other patients. Motor dysfunction in CBS patients was characterized by rigidity and bradykinesia, rather than tremor (see
Patient | Age at assessment (years) | Gender | Symptom duration (months) | ACE Total (100 points) | ACE Visuospatial (16 points) | Overall apraxia (0–15) | Clinical Presentation | MRI findings |
66 | Male | 36 | 62 | 12.0 | 11.0 | Right sided limb apraxia initially, later developed language disturbance | Generalised atrophy, with symmetrical frontal, temporal, parietal and occipital lobe involvement. | |
57 | Male | 60 | 53 | 5.0 | 7.0 | Cognitive dysfunction with executive impairment, visuospatial dysfunction and later developed marked left sided limb apraxia | Generalised atrophy with particular involvement of frontal, temporal (left > right), parietal and occipital lobes bilaterally. | |
62 | Female | 48 | 84 | 14.0 | 3.0 | Speech hesitancy and deterioration in hand writing, later developed right sided limb apraxia | Frontal, temporal (left > right) and parietal atrophy. | |
56 | Female | 70 | 25 | 2.0 | 11.5 | Cognitive dysfunction with executive impairment and visuospatial deficits initially, followed by bilateral limb apraxia and language disturbance | Frontal atrophy bilaterally, particularly involving Broca's area, and a degree of parietal atrophy. | |
68 | Female | 36 | 91 | 16.0 | 6.5 | Marked left sided limb apraxia and rigidity, with subtle language dysfunction | Frontal and parietal atrophy bilaterally. | |
68 | Female | 36 | 84 | 10.0 | 6.5 | Executive dysfunction with some disorientation and difficulty writing, followed by left sided limb apraxia | Frontal atrophy, particularly involving the medial frontal lobes. | |
59 | Female | 72 | 86 | 12.0 | 6.0 | Right sided limb apraxia, with spelling errors on hand writing, executive dysfunction, and visuospatial deficits | Inferior frontal and parietal atrophy (left >right). | |
79 | Male | 36 | 78 | 15.0 | 2.5 | Progressive language disturbance with subsequent development of right upper limb apraxia | Bilateral frontal atrophy, with particular involvement of the left peri-insular region. | |
72 | Female | 83 | 86 | 15.0 | 3.5 | Difficulty using the right leg and hand, with mild visuospatial deficits | Bilateral frontal, temporal, and parietal atrophy. | |
61 | Female | 60 | * | * | 14.0 | Executive dysfunction and deterioration in handwriting, with right sided limb apraxia | Generalised atrophy (left > right). | |
70 | Female | 48 | 30 | 4.0 | 12.5 | Progressive right sided limb apraxia, with subsequent executive, visuospatial and language disturbance | Frontal, temporal, and parietal atrophy (left > right). | |
57 | Male | 21 | 77 | 14.0 | 6.0 | Problems with calculation and hand-writing, followed by language disturbance and bilateral limb apraxia | Left parietal atrophy. | |
59 | Male | 84 | 86 | 13.0 | 3.0 | Disturbance of handwriting, followed by right sided limb apraxia and language disturbance | Left inferior frontal and peri-insular atrophy. | |
65 | Male | 60 | 38 | 6.0 | 5.0 | Progressive language disturbance and difficulty writing, followed by right sided apraxia | Frontal and parietal atrophy. | |
66 | Male | 48 | 38 | 5.0 | 11.5 | Language disturbance and difficulty with hand-writing, followed by right sided rigidity and apraxia | Bilateral frontal and parietal atrophy. | |
72 | Female | 70 | 24 | 6.0 | 11.0 | Difficulty with writing and language disturbance, followed by right sided limb apraxia | Parietal and temporal atrophy (left > right), with particular involvement of Broca's area and the left mesial temporal lobe. | |
58 | Female | 60 | 79 | 8.0 | 12.5 | Difficulty writing and right sided limb apraxia, with subsequent language impairment | Bilateral frontal and parietal atrophy (right > left). |
Patients commonly presented with a mixture of limb symptoms and cognitive dysfunction, with limb apraxia and visuospatial dysfunction featuring prominently. Other cognitive deficits included language disturbance (often with early problems in hand-writing) and executive dysfunction. * ACE-R abandoned due to severity of cognitive deficit.
Patients with CBS had moderate motor functional disability, due predominantly to limb apraxia, parkinsonism, and rigidity, rather than weakness (see
CBS | |
Number of Patients | 17 |
Male | 7 (41.2%) |
Age | 64.4+/−6.6 |
Symptom Duration (months) | 54.6+/−18.0 |
Hyperreflexia (% patients) | 12 (70.6%) |
Weakness (% patients) | 1 (6.3%) |
MRCSS Total (0–60) | 59.8+/−1.0 |
- Oro-buccal Apraxia (0–3) | 0.7+/−0.9 |
- Limb-Meaningful (0–6) | 3.6+/−1.8 |
- Limb-Meaningless (0–6) | 3.9+/−1.9 |
- Overall Apraxia Score (0–15) | 7.8+/−3.9 |
- Bulbar | 10.7+/−1.4 |
- Fine Motor | 5.7+/−3.4 |
- Gross Motor | 8.5+/−2.9 |
- Respiratory | 11.8+/−0.5 |
- Total | 36.7+/−6.2 |
- Attention (18 points) | 13.1+/−5.7 |
- Memory (26 points) | 15.5+/−8.7 |
- Fluency (14 points) | 5.4+/−4.3 |
- Language (26 points) | 17.2+/−7.7 |
- Visuospatial (16 points) | 9.2+/−5.1 |
- Total (100 points) | 60.1+/−28.7 |
19.7+/−9.3 |
CBS patients had marked functional impairment with reduced ALSFRS-R fine motor and gross motor sub-scores, despite normal limb power. CBS patients were at least moderately cognitively impaired, with deficits in multiple cognitive domains including visuospatial function. MRCSS = medical research council sum score, ALSFRS-R = amyotrophic lateral sclerosis functional rating score – revised, ACE-R = Addenbrooke's cognitive examination – Revised, MMSE = mini-mental status examination.
Patients with CBS performed poorly on the visuospatial component of the ACE-R (
Cortical function as assessed by transcranial magnetic stimulation was markedly abnormal in CBS patients with two main patterns of dysfunction. Firstly, 4 (23.5%) had a relatively inexcitable motor cortex (
Patients with CBS had evidence of cortical hyper-excitability, with reduced SICI (
CBS | Control | P value | |
RMT (mean, %) | 54.9+/−16.8 | 60.4+/−8.4 | NS |
- In-excitable | 4 (23.5%) | 1 (5.9%) | |
- <50% | 5 (29.4%) | 1 (5.9%) | <0.05* |
- >50% | 8 (47.1%) | 15 (88.2%) | |
MEP amplitude (mV) | 4.2+/−2.0 | 1.8+/−1.2 | <0.001 |
MEP amplitude (%) | 59.1+/−32.6 | 23.5+/−14.3 | <0.001 |
Average SICI (%) | 0.5+/−9.2 | 11.0+/−4.9 | <0.001 |
Peak SICI (%) | 0.8+/−12.0 | 16.6+/−8.7 | <0.001 |
CMCT (ms) | 7.1+/−0.7 | 5.8+/−1.8 | <0.05 |
Maximum CSP (ms) | 198.6+/−48.0 | 213.0+/−26.5 | NS |
Some CBS patients had a relatively inexcitable motor cortex and transcranial magnetic stimulation measures could not be determined. The remaining CBS patients had evidence of cortical excitability, characterized by reduced peak and average SICI, and increased motor evoked potential amplitude expressed as a percentage of compound motor action potential amplitude. CBS = corticobasal syndrome, RMT = resting motor threshold, SICI = short-interval intra-cortical inhibition, MEP = motor evoked potential, CSP = cortical silent period. *P-value calculated using the Chi-Square test for 2×3 table (i.e. CBD/Control v Inexcitable/<50%/>50%)
The CBS cohort was grouped according to the RMT (RMT <50%, RMT >50%, and relatively inexcitable, see
RMT <50% | RMT >50% | Inexcitable | P -Value | |
Number of patients | 5 | 8 | 4 | |
Symptom Duration (months +/− SD) | 54.8+/−13.1 | 59.3+/−22.6 | 45.0+/−11.5 | NS |
Age (years +/−SD) | 62.4+/−6.3 | 64.3+/−5.9 | 67.3+/−8.7 | NS |
MRCSS Total | 60.0+/−0.0 | 59.5+/−1.4 | 60.0+/−0.0 | NS |
Hyperreflexia (% patients) | 4 (80%) | 6 (75%) | 2 (50%) | NS |
- Orobuccal Apraxia (0–3) | 0.7+/−0.8 | 0.2+/−0.4 | 1.5+/−1.3 | NS |
- Limb-Meaningful (0–6) | 3.9+/−2.2 | 2.8+/−1.5 | 4.4+/−1.6 | NS |
- Limb-Meaningless (0–6) | 4.5+/−1.9 | 3.3+/−1.8 | 3.9+/−2.3 | NS |
- Overall Apraxia Score (0–15) | 9.1+/−4.2 | 5.9+/−2.6 | 9.4+/−4.6 | NS |
- Bulbar | 11.4+/−0.9 | 10.4+/−1.6 | 10.3+/−1.3 | NS |
- Fine Motor | 5.2+/−3.3 | 6.6+/−3.0 | 4.5+/−4.7 | NS |
- Gross Motor | 8.4+/−2.9 | 8.9+/−2.6 | 7.8+/−4.2 | NS |
- Respiratory | 12.0+/−0.0 | 11.6+/−0.7 | 12.0+/−0.0 | NS |
- Total | 37.0+/−5.7 | 37.5+/−5.7 | 34.5+/−9.0 | NS |
- Attention | 8.8+/−6.4 | 15.0+/−4.7 | 14.5+/−5.1 | 0.09a |
- Memory | 7.8+/−7.9 | 18.9+/−7.6 | 18.3+/−6.8 | 0.06a,b |
- Fluency | 5.8+/−5.2 | 6.4+/−3.5 | 3.3+/−5.3 | NS |
- Language | 13.0+/−9.4 | 19.3+/−7.9 | 18.3+/−3.0 | NS |
- Visuospatial | 4.2+/−3.8 | 12.0+/−3.9 | 10.0+/−4.4 | <0.05a,b |
- Total | 38.4+/−31.7 | 71.5+/−25.6 | 64.3+/−19.2 | NS |
Although there were no differences in patient age, symptom duration, limb weakness, or limb functional capacity, patients with a an RMT <50% were significantly more impaired on the visuospatial subtask of the ACE-R, with a trend for impaired performance on the attention and memory ACE-R sub-tasks. CBS = corticobasal syndrome, RMT = resting motor threshold, MRCSS = medical research council sum score, ALSFRS-R = amyotrophic lateral sclerosis functional rating score – revised, ACE-R = Addenbrooke's cognitive examination – Revised, MMSE = mini-mental status examination. Note: P-Values quoted in the right hand column refer to inter-group comparisons. Post-hoc pairwise comparisons are indicated by: aRMT <50% versus RMT <50%, P<0.05; bRMT <50% versus Inexcitable, P = 0.063.
Although there was no significant inter-group difference, the CBS sub-group with reduced RMT had a markedly reduced ACE-R total, suggesting severe cognitive impairment. Intergroup comparisons revealed a significant (P<0.05) difference in the visuospatial sub-score, with post-hoc pairwise comparisons confirming a significant reduction in the RMT <50% group compared to the RMT >50% group (P<0.05), and a trend for reduced visuospatial sub-score compared to the relatively inexcitable group (P = 0.06). There were also trends for an intergroup difference in performance on the memory and attention ACE-R subscores, and post-hoc analyses revealed that the RMT <50% group had significantly lower memory and attention sub-scores (P<0.05) compared to the RMT >50% group.
To further clarify the basis of cortical dysfunction, VBM analyses were performed using transcranial magnetic stimulation excitability measures (RMT, SICI) and the overall apraxia score. Since RMT and SICI could not be measured in patients with a relatively inexcitable motor cortex, these cases were excluded from VBM analyses using SICI and RMT as covariates. Importantly, visual inspection of MRI scans did not reveal differences in the degree or pattern of atrophy in cortical and subcortical motor structures between patients with a relatively inexcitable motor cortex, and those in whom SICI and RMT could be measured. All CBS patients were included in the overall apraxia score VBM analysis. As demonstrated in
(A) Reduced RMT correlated with atrophy of the primary motor cortex (red circles), thalamus (blue circle) and the anterior temporal lobe (magenta circle). (B) Reduced SICI correlated with atrophy of the primary motor cortex (red circle), thalamus (blue circles), medial frontal cortex (yellow circles) and precuneus (green circles). Clusters are overlaid on the Montreal Neurological Institute standard brain (t>2.41). Colored voxels show regions that were significant in the analyses for P<0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Circled areas indicate: red = primary motor cortex; blue = thalamus; magenta = anterior temporal lobe; yellow = medial frontal cortex; green = precuneus.
The degree of apraxia (as reflected in an increased apraxia score) correlated with atrophy of the medial frontal cortex (red circles) and the precuneus/posterior cingulate (blue circles). Clusters are overlaid on the Montreal Neurological Institute standard brain (t>2.41). Colored voxels show regions that were significant in the analyses for P<0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Circled areas indicate: red = medial frontal cortex; blue = precuneus/posterior cingulate.
The present study has demonstrated significant cortical dysfunction in a cohort of CBS patients. VBM established a correlation between measures of cortical dysfunction and atrophy of the primary motor cortex, as well as subcortical motor structures. A relationship between the distinctive features of CBS, namely limb apraxia and visuospatial dysfunction, was demonstrated and limb apraxia was linked to motor system dysfunction, as measured by transcranial magnetic stimulation. Altogether, the findings from the present study reinforce the role of frontal lobe (i.e. primary motor cortex) dysfunction in the development of the characteristic features of CBS.
Cortical dysfunction was indicated in the present series by a high proportion of CBS patients exhibiting an RMT <50%, reduced SICI, and an increased motor evoked potential amplitude. Although reduced SICI has been suggested in CBS previously
The mechanisms underlying cortical dysfunction in CBS remain to be fully elucidated. RMT reflects the excitability of cortical motor neurons,
Why some patients with CBS have a relatively inexcitable motor cortex while others have evidence of reduced RMT and SICI is not clear, but may relate to different underlying pathologies. Given that there were no differences between patients when grouped by RMT in symptom duration, the degree or pattern of cortical atrophy, motor weakness or functional impairment, advanced disease stage alone is unlikely to explain the finding of a relatively inexcitable motor cortex in CBS. Moreover, the relatively inexcitable group was not the most cognitively impaired. In contrast, the RMT <50% group demonstrated the greatest cognitive impairment, with poorer performance on visuospatial, attention, memory, and overall ACE-R scores. Poor performance on the attention and memory ACE-R subtasks in CBS has been linked to underlying Alzheimer's disease
Apraxia assessment tools, for example the De Renzi ideomotor apraxia test,
Several sub-types of apraxia have been described in CBS, including oro-buccal, limb-kinetic, ideomotor (i.e. temporal or spatial errors in goal-directed movements),
In the present study the degree of apraxia, reflecting impaired imitation, was strongly correlated with performance on visuospatial tasks, regardless of whether the task required manipulation of a pencil or simply the interpretation of visual information. Similarly, a correlation between impaired imitation of hand movements and visuospatial dysfunction has been suggested in Parkinson's disease.
The effect of asymmetric pathological involvement on apraxia and visuospatial dysfunction in CBS is also unknown. In the context of stroke, limb apraxia is much more likely after a left-sided than a right-sided stroke.
A clear consensus on the neuroanatomical basis of apraxia in CBS has not yet emerged, perhaps reflective of the complex neural networks involved in gesture production and tool usage. Through lesional studies, several cerebral structures have been implicated in the genesis of apraxia, including the left parietal lobe,
In summary, cortical dysfunction in CBS is associated with pathological involvement of the primary motor cortex and the basal ganglia. Motor dysfunction, as assessed by transcranial magnetic stimulation techniques, was associated with the degree of apraxia. In addition, limb apraxia was correlated with atrophy of the precuneus and the pre-motor cortex. Comparisons of cortical excitability across different pathologies in CBS are required to determine whether transcranial magnetic stimulation may be useful in predicting pathology in life. Nonetheless, by combining functional neurophysiological and neuropsychological methods, as well as VBM, the present study provides further insight into the pathogenesis of core clinical features of CBS.
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