Non-affected Hemisphere Research Articles

SURG-19. THE SYNDROME OF THE SUPPLEMENTARY MOTOR AREA: CLINICAL COURSE AND PREDICTORS OF OUTCOME AFTER RESECTION OF PREMOTOR LESIONS

Abstract OBJECTIVE Supplementary motor area (SMA) syndrome frequently occurs after resection of premotor lesions. Interhemispheric connectivity including the contralateral SMA might be crucially involved in its development and recovery. We aimed to identify predictors of outcome by quantifying preoperative structural alterations in the non-affected contralateral hemisphere. METHODS We retrospectively searched our database for patients developing SMA syndrome after resection of premotor lesions between 2013 and 2023. Clinical characteristics and imaging data were collected. Structural network analysis was performed using the previously validated morphometric inverse divergence network. RESULTS 27 patients with a mean age of 39.2 ± 17.7 years developed SMA syndrome, including 13/27 patients (48.1%) with primary brain tumors and 14/27 patients (51.9%) with intractable lesional epilepsy. Postoperative SMA syndrome was commonly characterized by contralateral upper extremity hemiparesis (19/27 patients, 70.4%) and aphasia in case of dominant hemisphere involvement (13/13 patients, 100%). Tumor patients were less likely to fully recover from SMA syndrome after 7 days compared to epilepsy patients (2/13 [15.4%] versus 9/14 [64.3%] patients, p=0.018). Most patients (23/27, 85.2%) experienced full recovery of SMA syndrome after a median follow-up of 5 months (IR 3-16 months), with no difference between patients with tumors or epilepsy (p=0.999). Preoperative contralateral intra-hemispheric connectivity was similar between patients receiving tumor or focal resection (0.183 vs 0.177, p=0.295). However, imaging analyses demonstrated baseline affection of SMA connectivity in patients with brain tumors as characterized by reduced cortical thickness of the contralateral frontal lobe and the cingulate gyrus compared to epilepsy patients. CONCLUSION While full recovery from SMA syndrome is common, SMA syndrome is frequently less severe and more transient in patients with epilepsy. This might be due to affection of the contralateral SMA network in tumor patients due to the infiltrative nature of the disease. Imaging analyses might assist in identifying network affections at baseline.

The role of ventral hippocampal-medial prefrontal glutamatergic pathway on the non-affected side in post-stroke cognitive impairment

Elucidate the pathogenesis mechanism of post-stroke cognitive impairment (PSCI) can help to develop precision interventions. In this study, we established a mouse model of PSCI using the photochemical method, and behavioral tests including Y-maze and Novel object recognition task for accessing cognitive impairment were observed at week 2 post-stroke. Besides, synaptic plasticity, theta nerve oscillatory and the activity of glutamatergic neurons related to the ventral hippocampal-medial prefrontal glutamatergic neural pathway in the non-affected hemisphere (contralateral hemisphere to the lesion site) were observed. The result indicated the cognitive function declined at week 2 post-stroke. Synaptic plasticity, theta nerve oscillatory synchronization and the activity of glutamatergic neurons of the ventral hippocampal-medial prefrontal glutamatergic neural pathway in the non-affected hemisphere was down-regulated in the PSCI group compared to those of the SHAM group. Therefore, we concluded that the declined function of the ventral hippocampal-medial prefrontal glutamatergic pathway in the non-affected hemisphere is a biomarker in the occurrence of cognitive dysfunction after stroke.

Cerebral vasomotor reactivity in the acute phase and after 6 months in non-disabling stroke/TIA: A prospective cohort study

Background and aimCerebral Vasomotor Reactivity (VMR) is a property of cerebral hemodynamics that protects from cerebrovascular disease. We aimed to explore the VMR longitudinal changes in patients with acute non-disabling stroke/Transient Ischemic Attack (TIA) to understand its implication in stroke ethiopatogenesis. MethodsVMR by Transcranial Doppler Breath Holding test was performed at 48-72 h from stroke onset (T1) and after 6 months (T2) on MCA of the non-affected hemisphere and PCA of the affected hemisphere. ResultsWe consecutively enrolled 124 patients with a median age of 66.0 (IQR 54.75-74.25) years with a median NIHSS 2 (IQR 1-3). Both MCA (1.38 %/s SD 0.58) and PCA (1.35 %/s SD 0.75) BHI at T1 did not differ among different stroke subtypes (p=0.067 and p=0.350; N=124). MCA and PCA BHI decreased from T1 to T2 (respectively 1.39 %/s SD 0.56 vs 1.18%/s SD 0.44 and 1.30 %/s SD 0.69 vs 1.20 %/s SD 0.51; N=109) regardless of ethiopatogenesis (respectively p<0.0001 and p=0.111). ConclusionThe VMR is higher in acute phase than at 6 months in patients with non-disabling stroke/TIA, regardless of etiopathogenesis. The higher VMR in acute phase could be sustained by an increased Cerebral Blood Flow due to collateral circulation activation supporting the ischemic zone.

MRI Evaluation of Microstructural and Perfusion Changes in Patients with Hemsensory Neurological Syndromes

Background: Hemisensory syndrome is characterized by a nondermatomal sensory deficit involving one half of the body. With the conventional imaging techniques, researches find low diagnostic yield in this condition; however, with the advancements in MRI imaging, there is hope to find the pathophysiological basis of hemisensory symptoms. Objective: To evaluate microstructural and perfusion changes in brain parenchyma in patients with hemisensory syndrome on MRI with diffusion tensor imaging (DTI) and arterial spin labeling (ASL). Material and Methods: A total of 20 patients with hemisensory symptoms and 10 age-matched controls were enrolled and divided in two study groups – a) case vs. control and b) affected vs. nonaffected cerebral hemisphere in cases. Quantification of absolute cerebral blood flow (aCBF), fractional anisotropy (FA), and mean diffusivity (MD) was done in both groups. Results: On ASL, there was significantly increased aCBF in thalamus on the contralateral-affected side. DTI revealed significantly decreased FA in the thalamus and increased FA in corona radiata of the affected side. There was a significant difference for MD of corona radiata between affected and nonaffected hemisphere. The mean value of MD in corona radiata is decreased on the affected side. Conclusion: Changes in advanced neuroimaging techniques like ASL and DTI along the pain processing pathway suggest an alteration in neuronal density and activity at the microstructural level. These findings may provide an insight into the etiopathogenesis of pain syndromes.

Resting-state EEG as Biomarker of Maladaptive Motor Function and Depressive Profile in Stroke Patients.

Objective: Investigate the relationship between resting-state EEG-measured brain oscillations and clinical and demographic measures in Stroke patients. Methods: We performed a cross-sectional analysis of a cohort study (DEFINE cohort), Stroke arm, with 85 patients, considering demographic, clinical, and stroke characteristics. Resting-state EEG relative power from delta, theta, alpha, and beta oscillations were measured from the central region. Multivariate regression models were used for both affected and non-affected hemispheres. Results: Motor function was negatively associated with Delta and Theta oscillations, while positively associated with Alpha oscillations (both hemispheres). Similarly, cognition levels measured were negatively associated with Delta activity. Depression levels were negatively associated with Alpha activity specifically in the affected hemisphere, while positively associated with Beta activity in both hemispheres. Regarding pain measures, no significant association was observed, while CPM measure showed a positive association with Alpha activity in the non-affected hemisphere. Finally, we found that theta/alpha ratio was negatively associated with motor function and CPM scores. Conclusion: The results lead us to propose a framework for brain oscillations in stroke, whereas Delta and Beta would represent disrupted mal-adaptive brain plasticity and Theta and Alpha would represent compensatory and functional brain oscillations for motor and sensory deficits in stroke, respectively.

A Study of Different Frequencies of Repetitive Transcranial Magnetic Stimulation on Upper Extremity Muscle Activity and Hand Function in Chronic Stroke Patients

The purpose of this study was to compare the use of different frequencies of repetitive transcranial magnetic stimulation (rTMS) on the upper extremity muscle activity and hand function of chronic stroke patients. The study subjects comprised 18 chronic stroke patients: the 5 Hz rTMS group (HFG), which included nine patients who received rTMS to the affected cerebral hemisphere, and the 1 Hz low-frequency group (LFG), which had nine patients who received rTMS to the nonaffected cerebral hemisphere. The intervention was conducted three times a week for four weeks. Electromyography was used to check muscle activity, and the stroke upper extremity function test (MFT) and grip strength test were performed to check hand function. Pre- and post-evaluations were performed for both groups. A comparison between the two groups showed a significant difference in the activity of the trapezius anterior and triceps brachii muscle for the muscle activities in the HFG group (p 0.05) as well as a significant difference in the MFT results for hand function (p 0.05). In the LFG group, a significant difference was noted in the triceps brachii muscle for muscle activity (p 0.05), but no significant difference was evident in hand function (p 0.05). The comparison of the two groups showed a significant difference in muscle activity in the triceps brachii muscle (p 0.05) but no significant difference in hand function (p 0.05). This study confirmed that high-frequency rTMS has a positive effect on upper extremity muscle activity and hand function in chronic stroke patients.

Interhemispheric differences in time-frequency representation of motor evoked potentials in brain tumor patients

ObjectiveConventional time-series parameters are unreliable descriptors of motor-evoked potentials (MEPs) in brain tumor patients. Frequency domain analysis is suggested to provide additional information about the status of the cortico-spinal motor system. Aim of the present study was to describe the time-frequency representation of MEPs and its relation to the motor performance. MethodsThis study enrolled 17 consecutive brain tumor patients with impaired dexterity. After brain mapping of the affected (AH) and non-affected (NAH) hemisphere, TMS was applied to the hotspots of the abductor pollicis brevis muscles (APB). Using a Morlet wavelet approach, event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) of the MEPs were calculated and compared to the Grooved Pegboard Test (GPT). Additionally, inter- and intra-subject reliability was assessed by the intraclass correlation coefficient (ICC). ResultsMEPs were projecting to a frequency band between 30 and 400 Hz with a local maximum between 100 and 150 Hz. There was a significant ERSP and ITC reduction of the AH in comparison to the NAH. In contrast, no interhemispheric differences were depicted in the conventional time-series analysis. ERSP and ITC values correlated significantly with GPT results (r = 0.35 and r = 0.50). Time-frequency MEP description had good inter-and intra-subject reliability (ICC = 0.63). ConclusionsBrain tumors affect corticospinal transmission resulting in a reduction of temporal and spectral MEP synchronization correlating with the dexterity performance. SignificanceTime-frequency representation of MEPs provide additional information beyond conventional time-domain features.

Abstract P731: Genetic Knockout of Cd38 Protects Mice Against Ischemic Brain Injury

Introduction: CD38 is an ectoenzyme that is present on the cellular membranes of endothelial cells and subtypes of inflammatory cells. We have shown that ischemia/reperfusion (I/R) in the heart triggers CD38 activation that in turns leads to NADPH depletion and endothelial nitric oxide synthase (eNOS) impairment. This cascade results in worsening of ischemic injury secondary to endothelial dysfunction. We hypothesize that a similar paradigm exists in acute ischemic stroke and that loss of CD38 function is protective against cerebral I/R injury. Methods: Middle cerebral artery occlusion (MCAO) was performed for 60 minutes in 15 week-old CD38 knockout mice (KO) n=12 and wild type (WT) mice n=12. Stroke volume was calculated using T2 MRI sequences obtained at 48 hours post MCAO. Percentage of brain infarction volume compensated for swelling (IFV) was calculated by manual segmentation of the stroke area and non-affected cerebral hemisphere. Following brain MRI, H&amp;E staining and immunohistochemistry assessment of superoxide radicals (DHE fluorescence) nitric oxide (NO) (DAF fluorescence), eNOS expression, CD38 expression and microglia activation (Iba1) were performed. (P&lt;0.05) was considered significant in statistical testing. Results: CD38 KO mice had a smaller IFV as % of the normal contralateral hemisphere volume compared to WT (19.6±3 vs 33.5±9, P=0.001). Both western blotting and immunohistology confirmed lack of CD38 expression in CD38 KO mice. CD38 expression was 55% higher in the ipsilateral stroke side compared to the contralateral stroke side in WT mice (P=0.0105). Compared to WT mice, CD38 KO had 45% lower superoxide levels (P&lt;0.001), 50% higher NO levels (P&lt;0.05) and 46% lower Iba-1 expression with more significance in ipsilateral side (P&lt;0.01) than contralateral side (P&lt;0.05). While eNOS expression was 40% lower in WT vs CD38 KO, this did not reach statistical significance. Conclusions: Thus, genetic deletion of CD38 is protective against cerebral ischemia with reduced superoxide production and preserved NO production, likely through the protection conferred against NADPH depletion. These results suggest that inhibition of CD38 could serve as a potent therapeutic approach to protect against acute ischemic stroke and related brain I/R injury.

Dysfunction of anterior insula in the non- affected hemisphere in patients with post- stroke depression: A resting-state fMRI study

BACKGROUND: Post-stroke depression (PSD) is a consequential neuropsychiatric sequela that occurs after stroke. However, the pathophysiology of PSD are not well understood yet.OBJECTIVE: To explore alterations in functional connectivity (FC) between anterior insula and fronto-cortical and other subcortical regions in the non-affected hemisphere in patients with PSD compared to without PSD and healthy control.METHODS: Resting-state FC was estimated between the anterior insula and cortical and subcortical brain regions in the non-affected hemisphere in 13 patients with PSD, 12 patients without PSD, and 13 healthy controls. The severity of depressive mood was measured by the Beck Depression Inventory (BDI)-II.RESULTS: Patients with PSD showed significant differences in FC scores between the anterior insula and the superior frontal, middle frontal, and orbitofrontal gyrus in the non-affected hemisphere than healthy control or patients without PSD ( 0.05). In post-hoc, patients with PSD showed higher FC scores between the anterior insula and the superior frontal region than patients without PSD ( 0.05). Furthermore, alterations in FC of the superior frontal, middle frontal, and orbitofrontal gyrus were positively correlated with depression severity, as measured with the BDI-II ( 0.001).

Understanding intracortical excitability in phantom limb pain: A multivariate analysis from a multicenter randomized clinical trial

ObjectivesTo explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP). MethodsAncillary study using baseline and longitudinal data from a large multicenter randomized trial that investigated the effects of non-invasive brain stimulation combined with sensorimotor training on PLP. Multivariate regression modeling analyses were used to investigate the association of intracortical excitability, measured by percentages of intracortical inhibition (ICI) and facilitation (ICF) with clinical variables. ResultsNinety-eight subjects were included. Phantom sensation of itching was positively associated with ICI changes and at baseline in the affected hemisphere (contralateral to PLP). However, in the non-affected hemisphere (ipsilateral to PLP), the phantom sensation of warmth and PLP intensity were negatively associated with ICI (both models). For the ICF, PLP intensity (baseline model only) and age (longitudinal model) were negatively associated, while time since amputation and amputation level (both for longitudinal model only) were positively associated in the affected hemisphere. Additionally, use of antidepressants led to lower ICF in the non-affected hemisphere for the baseline model while higher amputation level also led to less changes in the ICF. ConclusionResults revealed clear associations of clinical variables and cortical excitability in a large chronic pain sample. ICI and ICF changes appear not to be mainly explained by PLP intensity. Instead, other variables associated with duration of neuroplasticity changes (such as age and duration of amputation) and compensatory mechanisms (such as itching and phantom limb sensation) seem to be more important in explaining these variables.

Intracortical Inhibition in the Affected Hemisphere in Limb Amputation.

Phantom limb pain (PLP) affects up to 80% of amputees. Despite the lack of consensus about the etiology and pathophysiology of phantom experiences, previous evidence pointed out the role of changes in motor cortex excitability as an important factor associated with amputation and PLP. In this systematic review, we investigated changes in intracortical inhibition as indexed by transcranial magnetic stimulation (TMS) in amputees and its relationship to pain. Four electronic databases were screened to identify studies using TMS to measure cortical inhibition, such as short intracortical inhibition (SICI), long intracortical inhibition (LICI) and cortical silent period (CSP). Seven articles were included and evaluated cortical excitability comparing the affected hemisphere with the non-affected hemisphere or with healthy controls. None of them correlated cortical disinhibition and clinical parameters, such as the presence or intensity of PLP. However, most studies showed decreased SICI in amputees affected hemisphere. These results highlight that although SICI seems to be changed in the affected hemisphere in amputees, most of the studies did not investigate its clinical correlation. Thus, the question of whether they are a valid diagnostic marker remains unanswered. Also, the results were highly variable for both measurements due to the heterogeneity of study designs and group comparisons in each study. Although these results underscore the role of inhibitory networks after amputation, more studies are needed to investigate the role of a decreased inhibitory drive in the motor cortex to the cause and maintenance of PLP.

Position-Cortical Coherence as a Marker of Afferent Pathway Integrity Early Poststroke: A Prospective Cohort Study

Background. Addressing the role of somatosensory impairment, that is, afferent pathway integrity, in poststroke motor recovery may require neurophysiological assessment. Objective. We investigated the longitudinal construct validity of position-cortical coherence (PCC), that is, the agreement between mechanically evoked wrist perturbations and electroencephalography (EEG), as a measure of afferent pathway integrity. Methods. PCC was measured serially in 48 patients after a first-ever ischemic stroke in addition to Fugl-Meyer motor assessment of the upper extremity (FM-UE) and Nottingham Sensory Assessment hand-finger subscores (EmNSA-HF, within 3 and at 5, 12, and 26 weeks poststroke. Changes in PCC over time, represented by percentage presence of PCC (%PCC), mean amplitude of PCC over the affected (Amp-A) and nonaffected hemisphere (Amp-N) and a lateralization index (L-index), were analyzed, as well as their association with FM-UE and EmNSA-HF. Patients were retrospectively categorized based on FM-UE score at baseline and 26 weeks poststroke into high- and low-baseline recoverers and non-recoverers. Results. %PCC increased from baseline to 12 weeks poststroke (β = 1.6%, CI = 0.32% to 2.86%, P = .01), which was no longer significant after adjusting for EmNSA-HF and FM-UE. A significant positive association was found between %PCC, Amp-A, and EmNSA-HF. Low-baseline recoverers (n = 8) showed longitudinally significantly higher %PCC than high-baseline recoverers (n = 23). Conclusions. We demonstrated the longitudinal construct validity of %PCC and Amp-A as a measure of afferent pathway integrity. A high %PCC in low-baseline recoverers suggests that this measure also contains information on cortical excitability. Use of PCC as an EEG-based measure to address the role of somatosensory integrity to motor recovery poststroke requires further attention.

Abstract TP61: Could Fazekas Score Serve as a Predictor of Functional Outcomes in ELVO Patients Undergoing Mechanical Thrombectomy?

Objective: To evaluate the association between cerebral small vessel disease (CSVD) burden and degree of disability based on modified Rankin Score at 90 days, in patients presenting with emergent large vessel occlusion (ELVO) within 6 hours of last known well. Methods: We conducted a retrospective analysis of all patients presenting with an ELVO between May 2016 and July 2018. Patients with a TICI score of 2b or 3 were included and evaluated for CSVD burden as quantified by white matter hyperintensities in the non-affected hemisphere, on T2-FLAIR MRI using the Fazekas score (0-3). 90-day modified Rankin Scale scores (mRS, range 0-6) and patient information was collected from the Houston Methodist Hospital Outcomes Based Prospective Endpoints in Stroke (HOPES) registry. Results: 138 patients were evaluated, TICI 2b/3 was achieved in 114, and 84 patients were able to undergo MRI. Factors excluding patients from MRI included: medical instability, implantable devices, and death. All 84 patients were successfully re-evaluated at 90 days and divided into two cohorts, functionally independent (mRS 0-2) and functional dependent/deceased (mRS 3-6). Among the 84 patients, 37 (mean age 69.4y [SD, 14.5]; 54% female) were determined to be functionally independent (14, mRS 0; 19, mRS 1; 4, mRS 2) with the average Fazekas score for each subclass and the cohort; (mRS 0, 1.07; mRS 1, 0.89; mRS 2, 1; 0.97). The remaining 47 patients (mean age 71.1y [SD, 15.8]; 55% female) were determined to have a significant degree of disability, or were deceased (8, mRS 3; 10, mRS 4; 15, mRS 5; 14, mRS 6). Average Fazekas scores were (mRS 3, 1.75; mRS 4, 1.90; mRS 5, 2.13; mRS 6, 1.93; 1.96). Potentially confounding variables, including the use of intravenous alteplase (78% vs. 76%), and door to groin puncture time (204m [SD, 74m] vs. 206m [SD, 54m]) were found to be non-significant contributors. Conclusion: Based on our analytical cohort of ELVO patients undergoing thrombectomy, CSVD burden, classified by Fazekas score on T2-FLAIR MRI, was found to correlate with worse 90-day mRS. These results may be explained by potentially poor cerebrovascular reserve and diminished collateral blood flow in patients with greater CVSD burden.

Neurophysiological effects of mirror visual feedback in stroke patients with unilateral hemispheric damage

Background and ObjectiveMirror visual feedback (MVF; the illusory perception of movement in one hand upon viewing the moving opposite hand in a midsagittal mirror) is thought to facilitate restoration of mal-adaptive neurophysiological processes underlying conditions like complex regional pain syndrome and phantom limb pain, and to have a positive effect on brain plasticity processes underlying motor recovery after stroke. However, its exact mode of action remains unclear. The aim of the current study was to explore the immediate neurophysiological effects of MVF in patients with stroke-related hemiparesis. We also investigated how these effects relate to lesion location and extent. MethodEEG and EMG data were obtained from 14 first-event sub-acute stroke patients (8 with right-, 6 with left-hemiparesis) during repeated wrist extension movements of the Non-paretic Upper-Limb (NUL), without (NUL/M-) and with (NUL/M+) a midsagittal mirror, as well as during bilateral movements with a mirror (Bil/M+). EEG data was correlated with normalized lesion data obtained from follow-up CT scans. ResultsNUL movement was accompanied by an asymmetric event-related de-synchronization (ERD) of low-beta EEG oscillations, with a more conspicuous ERD in the non-affected hemisphere. In the mirror condition, ERD magnitude was attenuated in both hemispheres. Stronger attenuation in the non-affected hemisphere abolished the hemispheric asymmetry. ERD attenuation by the mirror was affected by lesion side, the severity of hemiparesis and by lesion location and extent. ConclusionFollowing hemispheric stroke, the magnitude of low-beta ERD accompanying unilateral movement of the non-involved upper limb, and its hemispheric asymmetry, are both reduced by MVF. Low-beta ERD dynamics may serve as a marker of neurophysiological response to MVF in research aimed to elucidate the factors influencing patients’ clinical gain from this treatment.

Effects of Navigated Repetitive Transcranial Magnetic Stimulation After Stroke.

The purpose of this study was to test the effects of navigated repetitive transcranial magnetic stimulation, delivered in different modes, on motor impairments and functional limitations after stroke. The study sample included 42 patients (58.5 ± 10.7 years; 26 males) who experienced a single unilateral stroke (1-12 months previously) in the area of the middle cerebral artery. Patients completed a course of conventional rehabilitation, together with 10 sessions of navigated repetitive transcranial magnetic stimulation or sham stimulation. Stimulation was scheduled five times a week over two consecutive weeks in an inpatient clinical setting. Patients were randomly assigned to one of four groups and received sham stimulation (n = 10), low-frequency (1-Hz) stimulation of the nonaffected hemisphere (n = 11), high-frequency (10-Hz) stimulation of the affected hemisphere (n = 13), or sequential combination of low- and high-frequency stimulations (n = 8). Participants were evaluated before and after stimulation with clinical tests, including the arm and hand section of the Fugl-Meyer Assessment Scale, modified Ashworth Scale of Muscle Spasticity, and Barthel Index of Activities of Daily Living. Participants in the three groups receiving navigated repetitive transcranial magnetic stimulation showed improvements in arm and hand functions on the Fugl-Meyer Stroke Assessment Scale. Ashworth Scale of Muscle Spasticity and Barthel Index scores were significantly reduced in groups receiving low- or high-frequency stimulation alone. Including navigated repetitive transcranial magnetic stimulation in a conventional rehabilitation program positively influenced motor and functional recovery in study participants, demonstrating the clinical potential of the method. The results of this study will be used for designing a large-scale clinical trial.

A high-resolution computational localization method for transcranial magnetic stimulation mapping

BackgroundTranscranial magnetic stimulation (TMS) is used for the mapping of brain motor functions. The complexity of the brain deters determining the exact localization of the stimulation site using simplified methods (e.g., the region below the center of the TMS coil) or conventional computational approaches. ObjectiveThis study aimed to present a high-precision localization method for a specific motor area by synthesizing computed non-uniform current distributions in the brain for multiple sessions of TMS. MethodsPeritumoral mapping by TMS was conducted on patients who had intra-axial brain neoplasms located within or close to the motor speech area. The electric field induced by TMS was computed using realistic head models constructed from magnetic resonance images of patients. A post-processing method was implemented to determine a TMS hotspot by combining the computed electric fields for the coil orientations and positions that delivered high motor-evoked potentials during peritumoral mapping. The method was compared to the stimulation site localized via intraoperative direct brain stimulation and navigated TMS. ResultsFour main results were obtained: 1) the dependence of the computed hotspot area on the number of peritumoral measurements was evaluated; 2) the estimated localization of the hand motor area in eight non-affected hemispheres was in good agreement with the position of a so-called “hand-knob”; 3) the estimated hotspot areas were not sensitive to variations in tissue conductivity; and 4) the hand motor areas estimated by this proposal and direct electric stimulation (DES) were in good agreement in the ipsilateral hemisphere of four glioma patients. Conclusion(s)The TMS localization method was validated by well-known positions of the “hand-knob” in brains for the non-affected hemisphere, and by a hotspot localized via DES during awake craniotomy for the tumor-containing hemisphere.

Towards standardization of 18F-FET PET imaging: do we need a consistent method of background activity assessment?

BackgroundPET with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical 18F-FET PET reading.The background activity of 20 18F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans.ResultsCompared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more.ConclusionsThe commonly applied methods for background activity assessment show different variability which might hamper 18F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.

Abolished perineuronal nets and altered parvalbumin-immunoreactivity in the nucleus reticularis thalami of wildtype and 3xTg mice after experimental stroke

Treatment strategies for ischemic stroke are still limited, since numerous attempts were successful only in preclinical research but failed under clinical condition. To overcome this translational roadblock, clinical relevant stroke models should consider co-morbidities, age-related effects and the complex neurovascular unit (NVU) concept. The NVU includes neurons, vessels and glial cells with astrocytic endfeet in close relation to the extracellular matrix (ECM). However, the role of the ECM after stroke-related tissue damage is poorly understood and mostly neglected for treatment strategies. This study is focused on alterations of perineuronal nets (PNs) as ECM constituents and parvalbumin-containing GABAergic neurons in mice with emphasis on the nucleus reticularis thalami (NRT) in close proximity to the ischemic lesion as induced by a filament-based stroke model. One day after ischemia onset, immunofluorescence-based quantitative analyses revealed drastically declined PNs in the ischemia-affected NRT from 3- and 12-month-old wildtype and co-morbid triple-transgenic (3xTg) mice with Alzheimer-like alterations. Parvalbumin-positive cells decreased numerically in the ischemia-affected NRT, while staining intensity did not differ between the affected and non-affected hemisphere. Additional qualitative analyses demonstrated ischemia-induced loss of PNs and allocated neuropil ECM immunoreactive for aggrecan and neurocan, and impaired immunoreactivity for calbindin, the potassium channel subunit Kv3.1b and the glutamate decarboxylase isoforms GAD65 and GAD67 in the NRT. In conclusion, these data confirm PNs as highly sensitive constituents of the ECM along with impaired neuronal integrity of GABAergic neurons. Therefore, specific targeting of ECM components might appear as a promising strategy for future treatment strategies in stroke.

Repetitive transcranial magnetic stimulation for rehabilitation of poststroke dysphagia: A randomized, double-blind clinical trial

ObjectiveThis randomized, sham-controlled, double-blind study was conducted to investigate the effects of high-frequency versus low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with poststroke dysphagia during early rehabilitation. MethodsForty patients with poststroke dysphagia were randomized to receive five daily sessions of sham, 3-Hz ipsilesional, or 1-Hz contralesional rTMS. Swallowing function, the severity of stroke and functional disability, and cortical excitability were examined before, immediately after five daily sessions, as well as the first, second, and third month after the last session. ResultsAt baseline, no significant differences between groups were observed in terms of demographic and clinical rating scales. However, a significantly greater improvement in swallowing function as well as functional disability was observed after real rTMS when compared with sham rTMS, which remained 3months after the end of the treatment sessions. In addition, 1-Hz rTMS increased cortical excitability of the affected hemisphere and decreased that of the non-affected hemisphere; however, 3-Hz rTMS only increased cortical excitability of the affected hemisphere. ConclusionrTMS (both high and low frequency) improved swallowing recovery in patients with poststroke dysphagia, and the effects lasted for at least 3months. SignificancerTMS appears to be a beneficial therapeutic modality for patients with dysphagia during the early phase of stroke.

Stroke and Cognitive Decline

Stroke and cognitive impairment are common among older persons.1 It is estimated that the lifetime risk for stroke is approximately 1 in 5 for women and 1 in 6 for men,2 and almost one-third of persons with stroke, which typically may involve motor, sensory, or other deficits, may have a significant degree of cognitive impairment within several months of the event.1 Furthermore, silent strokes are more common than clinically manifest stroke events but pose significant danger because they are harbingers of both future stroke and cognitive dysfunction.3 It is estimated that as many as 1 in 10 adults experience a silent stroke by their early 60s.3,4 Stroke and loss of cognitive vitality remain a substantial challenge, as there is a need to better understand the cellular and molecular mechanisms underlying cognitive impairment, course, and phenotypic manifestations of cognitive decline as well as the means to prevent this potentially devastating complication. In this issue of JAMA, Levine and colleagues5 track trajectory of cognitive decline before and after incident stroke. In their analysis of data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) prospective cohort study, the authors obtained longitudinal but limited telephone cognitive testing in more than 23 000 study participants 45 years or older without baseline cognitive impairment. The primary outcome was change in global cognition as measured by the Six-Item Screener (SIS), a 3-item recall and 3-item temporal orientation test (score range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning [score range, 0-30]), verbal memory (Word List Delayed Recall [score range, 0-10]), and executive function (Animal Fluency Test [number of animals named in 1 minute]). Incident strokes were adjudicated by a team of experts, and a complex statistical analysis was carried out and included but was not limited to linear mixedeffects models.5 Comparisons were made between those with and without incident stroke. During a median follow-up of 6.1 years, there were 515 incident strokes, of which 91%were ischemic, including 2.1% (n = 306 events) in white participants and 2.3% (n = 209 events) in black participants.5 As might be expected, those who experienced stroke were older men with more vascular risk factors, lower socioeconomic indicators, worse health status, and lower prestroke SIS scores. The main findings were that stroke was associated with an acute decline in global cognition (0.10 points [95% CI, 0.04-0.17]), new learning (1.80 points [95% CI, 0.73-2.86]), and verbal memory (0.60 points [95% CI, 0.13-1.07]), whereas executive function was not consistently shown to decline acutely. In addition, participants with incident stroke had statistically significantly faster declines in global cognition (0.06 points per year faster) and executive function (0.63 points per year faster) but not in new learning and verbal memory when compared with prestroke slopes (ie, rates). The poststroke rate of incident cognitive impairment occurred significantly faster when compared with the prestroke rate. Thus, acute cognitive decline was associated with incident stroke and accelerated and persisted over the approximately 6-year follow-up period. This studybyLevineandcolleaguesdemonstrates that incident stroke is associatedwith an acutedecline in global cognitive function based on a screening test (SIS) aswell as acute decline in new learning and memory. A novel feature of the study is that its prospective design allowed for prestroke cognition tobe trackedandprovides ratesofcognitivechangeprior to incident stroke.Thedisplaysof the slopesof cognitive function (Figure 2 in the article) are a powerful tool to help understand the findings and explainwhatmayhappen to cognition before andafter stroke. Such figuresmayhave relevance as an educational tool for a lay audience. Even though someof the results of the statistical analysis showonlymodest, average cognitive loss, these findingsmay be interpreted as clinically meaningful because few persons can afford to lose any cognitive capacity over time. As the authors suggest, adeclineof at least0.5 standarddeviations from baseline has been defined as clinically meaningful. A goal of large observational epidemiologic studies is to serve as a catalyst for future targeted investigations. In this case, suchastudy could identify which stroke subgroups show themost extensive cognitive decline. However, the report by Levine et al does not provide information about the mechanism whereby stroke was associated with continued cognitive decline, the possible role of stroke and cardiovascular risk factors, possible interactions with neurodegenerative disease, and the means to prevent suchdecline.1,6Aprior longitudinalclinical-neuropsychologicalneuroradiological correlativestudyofpatientswithstrokewith and without cognitive impairment found little cognitive decline after the acute stroke period and up to 7 years among persons with stroke but without dementia at study entry.7 However, unlike the study by Levine and colleagues,5 the temporal point of comparison in the previous study was not prestroke cognition. Furthermore, in another study that featured magnetic resonance diffusion tensor imaging, there were dynamic changes of the white matter in either the affected or nonaffected brain hemisphere after stroke for up Related article page 41 Opinion