Association of Circumscribed Subcortical Gray and White Matter Lesions With Apraxic Deficits in Patients With Left Hemisphere Stroke.

BACKGROUND AND OBJECTIVES: Apraxia is commonly attributed to left hemisphere (LH) lesions of the cortical fronto-temporo-parietal praxis networks or white matter lesions causing disconnections between cortical nodes. By contrast, the contribution of lesions to the subcortical gray matter, that is, basal ganglia or thalamus, to apraxic deficits remains controversial. Here, we investigate whether damage to these subcortical gray matter structures (i.e., caudate nucleus, putamen, globus pallidus, and thalamus) or the adjacent white matter tracts was associated with apraxic deficits. METHODS: We identified patients with distinct subcortical lesions with and without apraxia from a large retrospective sample of subacute LH ischemic stroke patients (n = 194). To test which subcortical structures (caudate nucleus, putamen, globus pallidus, thalamus, and adjacent white matter tracts), when lesioned, contributed to apraxic deficits, we statistically compared the proportion of lesioned voxels within subcortical gray and white matter structures between the apraxic and nonapraxic patients. RESULTS: Of the 194 stroke patients screened, 39 (median age = 65 years, range 30-82 years; median time poststroke at the apraxia assessment = 7 days, range 1-44 days) had lesions confined to subcortical regions (gray and white matter). Eleven patients showed apraxic deficits when imitating gestures or pantomiming object use. Region-wise statistical lesion comparison (controlled for lesion size) revealed a more significant proportion of damage ('lesion load') in the caudate nucleus in apraxic stroke patients (mean difference = 6.9%, 95% CI 0.4-13.3, p = 0.038, η p 2 = 0.11). By contrast, apraxic patients had lower lesion load in the globus pallidus (mean difference = 9.9%, 95% CI 0.1-19.8, p = 0.048, η p 2 = 0.10), whereas the lesion load in other subcortical structures (putamen, thalamus, and adjacent white matter tracts) did not differ significantly between the apraxic and nonapraxic patients. DISCUSSION: These findings provide new insights into the subcortical anatomy of apraxia after LH stroke, suggesting a specific contribution of caudate nucleus lesions to apraxic deficits.

Gesture meaning modulates the neural correlates of effector-specific imitation deficits in left hemisphere stroke.

BACKGROUND: Previous studies on left hemisphere (LH) stroke patients reported effector-specific (hand, fingers, bucco-facial) differences in imitation performance. Furthermore, imitation performance differed between meaningless (ML) and meaningful (MF) gestures. Recent work suggests that a gesture's meaning impacts the body-part specificity of gesture imitation. METHODS: We tested the hypothesis that the gesture's meaning (ML vs MF) affects the lesion correlates of effector-specific imitation deficits (here: bucco-facial vs arm/hand gestures) using behavioural data and support vector regression-based lesion-symptom mapping (SVR-LSM) in a large sample of 194 sub-acute LH stroke patients. RESULTS: Behavioural data revealed a significant interaction between the effector used for imitation and the meaning of the imitated gesture. SVR-LSM analyses revealed shared lesion correlates for impaired imitation independent of effector or gesture meaning in the left supramarginal (SMG) and superior temporal gyri (STG). Besides, within the territory of the left middle cerebral artery, impaired imitation of bucco-facial gestures was associated with more anterior lesions, while arm/hand imitation deficits were associated with more posterior lesions. MF gestures were specifically associated with lesions in the left inferior frontal gyrus and the left insular region. Notably, an interaction of effector-specificity and gesture meaning was also present at the lesion level: A more pronounced difference in imitation performance between the effectors for ML (versus MF) gestures was associated with left-hemispheric lesions in the STG, SMG, putamen, precentral gyrus and white matter tracts. CONCLUSION: The current behavioural data show that ML gestures are particularly sensitive in assessing effector-specific imitation deficits in LH stroke patients. Moreover, a gesture's meaning modulated the effector-specific lesion correlates of bucco-facial and arm/hand gesture imitation. Hence, it is crucial to consider gesture meaning in apraxia assessments.

MRI correlates of motoneuron loss in SMA.

BACKGROUND: Magnetic resonance imaging (MRI) is currently explored as supplemental tool to monitor disease progression and treatment response in various neuromuscular disorders. We here assessed the utility of a multi-parametric magnetic resonance imaging (MRI) protocol including quantitative water T2 mapping, Dixon-based proton density fat fraction (PDFF) estimation and diffusion tensor imaging (DTI) to detect loss of spinal motor neurons and subsequent muscle damage in adult SMA patients. METHODS: Sixteen SMA patients and 13 age-matched controls were enrolled in this prospective, longitudinal study. All participants underwent MRI imaging including measurements of Dixon-based PDFF and DTI of the sciatic nerve. SMA patients furthermore underwent measurements of muscle water T2 (T2w) of the biceps femoris muscle (BFM) and quadriceps femoris muscle (QFM). Ten participants returned for a second scan six months later. MRI parameter were correlated with clinical data. All patients were on nusinersen treatment. RESULTS: There were significantly higher intramuscular fat fractions in the BFM and QFM of SMA patients compared to healthy controls at baseline and after 6 months. Furthermore, T2 values significantly correlated positively with intramuscular fat fractions. The Hammersmith functional motor scale significantly correlated with the QFM's intramuscular fat fractions. DTI scans of the sciatic nerve were not significantly different between the two groups. CONCLUSION: This study demonstrates that, water T2 mapping and Dixon-based PDFF estimation may distinguish between adult SMA patients and controls, due to massive intramuscular fat accumulation in SMA. More extensive long-term studies are warranted to further evaluate these two modalities as surrogate markers in SMA patients during treatment.

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.

Differential perception of sharp pain in patients with borderline personality disorder.

BACKGROUND: Cutting is the most common method of non-suicidal self-injury (NSSI) to reduce inner tension in patients with Borderline Personality Disorder (BPD). Aim of this study was to compare pain perception induced by an incision and by application of a surrogate model for sharp mechanical pain (a non-invasive "blade") in BPD. METHODS: 22 female patients and 20 healthy controls (HC) received a small incision into the volar forearm, a 7s-blade application on the same side, and non-invasive phasic stimuli (pinprick, blade, laser, tactile). Pain intensity as well as affective versus sensory components were assessed. RESULTS: Incision was rated similarly by both groups (BPD: 28.6 ± 5.5 vs. HC: 33.9 ± 6.6; mean maximum pain ± SEM; p > 0.8), without significant difference for "7-s-blade" (BPD: 18.1 ± 3.8 vs. HC: 25.3 ± 3.6; mean maximum pain ± SEM; p > 0.17) or between "7-s-blade" and incision (BPD: p > 0.12; HC: p > 0.84). However, patients' intensity ratings returned significantly faster to baseline after incision (BPD: 38.9 ± 12.6 s vs. HC: 74.52 ± 11.5 s; p < 0.05), and patients evaluated "blade" and incision without any affective and with different sensory descriptors, indicating an altered evaluation of NSSI-like stimulation with qualitative in addition to quantitative differences-especially for the sharp pain component. CONCLUSIONS: The reduced perception of suprathreshold nociceptive stimuli is based on a missing affective component and specific loss of the perception of "sharpness" as part of the sensory component of pain. The results further demonstrate the usefulness of the "blade" for the perception of sharpness in patients. SIGNIFICANCE: Patients with Borderline Personality Disorder (BPD) who engage in non-suicidal self-injury (NSSI) report less pain in response to phasic nociceptive stimuli. In comparing an invasive pain stimulus to phasic nociceptive stimuli in BPD patients, the "blade" as non-invasive surrogate model for sharp mechanical pain in psychiatric patients is used. In contrast to healthy volunteers, BPD patients do not report significant affective ratings and specifically display a reduced sensory component for sharpness.

Posterior Insular GABA Levels Inversely Correlate with the Intensity of Experimental Mechanical Pain in Healthy Subjects.

This study aimed to investigate the relation of GABA and glutamate levels in the posterior insula and mechanical pain sensitivity in healthy subjects. Nineteen healthy female individuals underwent single voxel magnetic resonance spectroscopy (MRS) at 3 T. Metabolites were measured in the right posterior insula using MEGA-PRESS spectral editing. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli on a numeric rating scale. Ratings of perceived intensity of 256 mN and 512 mN pinprick stimuli were negatively correlated with GABA levels and positively with glutamate levels in the posterior insula. Pinprick pain ratings were also positively correlated with the glutamate/GABA ratio. No significant correlation for pinprick stimuli of lower forces than 256 mN was observed. The results of our study support the hypothesis that excitatory and inhibitory neurotransmitter levels and/or the ratio of glutamate/GABA levels in the posterior insula are related to individual differences in pain sensitivity. These results are in line with chronic pain studies, where elevated glutamate/GABA ratios in the insular cortex of patients with chronic pain syndromes were observed.

A novel human surrogate model of noninjurious sharp mechanical pain.

We propose a blade as a noninjurious nociceptive stimulus modeling sharp mechanical pain and yielding acute pain and hyperalgesia responses with closer proximity to incision-induced pain/hyperalgesia than punctate or blunt pressure mechanical pain models. Twenty-six healthy men and women were investigated to compare a small incision in the left forearm with noninvasive stimuli of different shapes and modalities to the right forearm. The magnitude and time course of incisional and blade-induced pain were assessed by numerical rating scales. Affective vs sensory components of pain experience were differentiated using a pain sensation questionnaire. The magnitude and time course of the axon reflex vasodilator response and of secondary hyperalgesia following a 7-second blade application were assessed. The maximum blade or incisional pain was similar (visual analogue scale [mean ± SD]: 32.9 ± 22.5 [blade] vs. 33.6 ± 29.8 [incision]), and both time courses matched closely in the first 10 seconds (paired t test; P = 0.5-1.0), whereas incision but not blade was followed by a second phase of pain, probably related to the tissue injury (decrease to half maximum pain 8 ± 2 vs. 33 ± 35 seconds; P < 0.01). Affective pain scores were significantly lower than sensory scores for all stimuli (P < 0.001). Comparing blade and incision, patterns of affective and sensory pain descriptors exhibited a remarkably similar pattern. Hence, we suggest the blade as novel model of sharp mechanical pain, which will be useful in investigating postoperative/mechanical pain and the role of self-injurious behavior in, eg, patients with borderline personality disorder.