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Background and Purpose— Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. Methods— Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. Results— The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group ( t test, P =0.003). Increases were largest for subtest naming ( P =0.002) and tended to be higher for comprehension, token test, and writing ( P t test, P =0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change ( r 2 =0.25; P =0.015). Conclusions— Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.

Background: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported. Methods: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers. Results: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres. Conclusion: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.

Background and Purpose— Although functional imaging studies suggest that recruitment of contralesional areas hinders optimal functional reorganization in patients with aphasic stroke, only limited evidence is available on the efficacy of noninvasive brain stimulation such as repetitive transcranial magnetic stimulation aimed at suppression of contralateral overactivation. Methods— In this randomized, controlled, blinded pilot study, the effect of 1-Hz repetitive transcranial magnetic stimulation over right-hemispheric Broca homolog in subjects with poststroke aphasia in the subacute stage was examined. According to their group allocation, patients received, in addition to conventional speech and language therapy, multiple sessions of repetitive transcranial magnetic stimulation either over the right-hemispheric inferior frontal gyrus (intervention group) or over the vertex (control group). The primary outcome parameter was the change in laterality indices as quantified by activation positron emission tomography before and after the 2-week intervention period. The clinical efficacy was evaluated with the Aachen Aphasia Test. Results— At baseline, no group differences were discovered for age, laterality indices, or mean Aachen Aphasia Test scores. Four patients were lost to follow-up, but none due to side effects of the transcranial magnetic stimulation. Positron emission tomography revealed an activation shift toward the right hemisphere in the control group ( P =0.0165), which was absent in the intervention group. Furthermore, the latter improved significantly clinically by a mean of 19.8 points in the Aachen Aphasia Test total score ( P =0.002), whereas the control group did not. There was however no clear linear relationship between the extent of laterality shift and clinical improvement ( r =0.193, P =nonsignificant). Conclusions— Repetitive transcranial magnetic stimulation might be an effective, safe, and feasible complementary therapy for poststroke aphasia.

For the rehabilitation process, the treatment of patients surviving brain injury in a vegetative state is still a serious challenge. The aim of this study was to investigate patients exhibiting severely disturbed consciousness using functional magnetic resonance imaging. Five cases of posttraumatic vegetative state and one with minimal consciousness close to the vegetative state were studied clinically, electrophysiologically, and by means of functional magnetic resonance imaging. Visual, sensory, and acoustic paradigms were used for stimulation. In three patients examined less than 2 months after trauma, a consistent decrease in blood oxygen level dependent (BOLD) signal ('negative activation') was observed for visual stimulation; one case even showed a decrease in BOLD activation for all three activation paradigms. In the remaining three cases examined more than 6 months after trauma, visual stimulation yielded positive BOLD contrast or no activation. In all cases, sensory stimulation was followed by a decrease in BOLD signal or no activation, whereas auditory stimulation failed to elicit any activation with the exception of one case. Functional magnetic resonance imaging in the vegetative state indicates retained yet abnormal brain function; this abnormality can be attributed to the impairment of cerebral vascular autoregulation or an increase in the energy consumption of activated neocortex in severe traumatic brain injury.

To determine to what extent repetitive transcranial magnetic stimulation (rTMS) combined with speech and language therapy improves functional communication and basic linguistic skills of individuals with subacute aphasia.Randomized, blinded, and sham-controlled study.Neurologic rehabilitation hospital.Participants (N=30) with subacute aphasia after stroke.During a 2-week treatment period, half of the participants received 10 sessions of 20-minute inhibitory 1-Hz rTMS over the right inferior frontal gyrus (Brodmann area 45), and the other half received sham stimulation. Directly thereafter, all the participants underwent 45 minutes of speech and language therapy.Aachen Aphasia Test, Amsterdam-Nijmegen Everyday Language Test (ANELT), a naming screening, and subscales of the FIM, all assessed the day before and the day after treatment period.The participants who received real rTMS significantly improved with respect to all 10 measures of basic linguistic skills and functional communication, whereas sham-treated participants significantly improved in only 6 of 10 measures (paired t tests, P.05). There was a significant difference in the gains made by the 2 groups on 5 of 10 measures including functional communication (ANELT) (repeated-measures analysis of variance, P≤.05).For the first time, this study has demonstrated that basic linguistic skills as well as functional communication are bolstered by combining rTMS and behavioral language therapy in patients with subacute aphasia.

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Local cerebral hemodynamics and oxygen metabolism were measured by positron emission tomography (PET) with the oxygen-15 (15O) steady-state method in baboons, immediately before (TO), 1 (T1), and 3–4 (T2) h after permanent middle cerebral artery occlusion (MCAO). At T1, there was a marked fall in both cerebral blood flow (CBF) and the CBF/cerebral blood volume (CBV) ratio in the occluded territory; these changes were sustained at T2, indicating stable reduction in cerebral perfusion pressure and lack of spontaneous reperfusion within this time range. Compared with preocclusion conditions, the oxygen extraction fraction (OEF) in the occluded territory was elevated at both T1 and T2, indicative of a persistent oligemia/ischemia for up to 3 h after MCAO. At T2, however, this OEF increase had lessened, concomitantly with a decline in cerebral metabolic rate of oxygen (CMRO2). This impairment of oxidative metabolism occurred earlier in the deep, compared with the cortical, MCA territories; in the latter, the CMRO2 was essentially preserved at T1 and only moderately reduced at T2, possibly suggesting prolonged viability. Finally, no significant changes in CBF or CMRO2 were observed in the contralateral MCA territory in this time range after MCAO. Despite methodological limitations (mainly partial volume effects related to PET imaging, which may have resulted in an underestimation of true changes and an overlooking of heterogeneous changes) our study demonstrates the feasibility of the combined PET-MCAO paradigm in baboons; this experimental approach should be valuable in investigating the pathophysiology and therapy of acute stroke.

In baboons with or without regional cerebral ischaemia (achieved by transorbital clip of the middle cerebral artery), cerebral blood flow (CBF) was measured using the intra-arterial Xenon-133 technique during steady-state, slight hypotension, and hypocapnia before and after administration of various doses of the calcium antagonist flunarizine (0.5 mg kg-1, 1.0 mg kg-1, or 10 micrograms kg-1 min-1 over 30 min). In normal baboons flunarizine did not alter CBF significantly, but at reduced blood pressure it increased CBF by 19.9% owing to exaggerated vasodilatory autoregulation. During hypocapnia flunarizine impaired the physiological reduction in CBF owing to reduced vasoconstriction. In baboons with cerebral ischaemia, CBF measurements were stable and comparable with those in a control group using an arterial clip unless flunarizine was added. In a group of five flunarizine-treated animals, mean CBF after positioning of the clip was higher than in the control group. However, the increase in mean CBF varied significantly between animals, indicating that a secondary reduction in CBF due to postischaemic pathophysiological processes was not prevented consistently.

2,3,5-triphenyltetrazoliumchloride (TTC) as an indicator of mitochondrial function in combination with regional cerebral blood flow measurements was used in six baboons 6.9 ±1.2 h after permanent occlusion of the left middle cerebral artery. Staining with TTC was compared with blood flow data obtained during normocapnia using the microsphere method. Five animals showed a focal area of unstained tissue in the left middle cerebral artery territory. Mean blood flow in the unstained area was 28.3 + 15.4 ml min~1100 g~1. Five of 6 animals showed a significant decrease of contralateral cerebellar blood flow in the presence of normal TTC staining. We conclude that at this early stage of infarction contralateral cerebellar diaschisis is caused by functional deactivation. [Neurol Res 1995; 17: 109–112]

To decrease immunogenicity of the rat kidney, grafts were perfused with an anti-MHC class II monoclonal antibody (mAb). How effectively this procedure blocked class II-positive cells, which were mainly dendritic in appearance, was checked by immunostaining renal sections after perfusion and comparing them with in vitro stained sections. Optimum conditions were applied for graft pretreatment before transplantation. This procedure prolonged graft survival, though not satisfactorily from the biological point of view (9.6 +/- 0.8 versus 7.7 +/- 0.5 days in the control group; P less than 0.02). The dendritic cells were not killed but blocked. Several hours after transplantation, the mAb dissociated from these class II-positive cells. It was also shown that donor cells migrate into the recipient's spleen early after transplantation. The number of these cells was smaller when the transplanted organ was perfused with the mAb. Further studies are suggested to deplete the graft of donor dendritic cells more adequately. They should also combine graft perfusion with anti-class II mAb and recipient immunosuppression at reduced doses.

The components of vasogenic oedema associated with brain tumours were investigated in human biopsy material sampled from tumour and peritumoural tissue intraoperatively. Sixty patients with glioblastomas, gliomas, meningiomas and metastases, which had been treated with dexamethasone prior to surgery were employed for tissue measurements of water, electrolyte, haemoglobin, serum protein and dexamethasone concentrations. The quantification of serum proteins was achieved with the method described by Bodsch et al. Accordingly, serum proteins in the brain tissue and the blood were determined with 125 J labelled antihuman antibody. Taking into account brain haematocrit and blood-volume, quantitative measurements of the so-called oedema proteins as a measure of tumour oedema were performed. With the exception of metastases positive correlations were obtained between water and both serum proteins and sodium contents in tumours and peritumoural tissue. The serum protein content varied considerably being high in glioblastomas and low in peritumoural tissue surrounding metastases. However water and serum protein contents decreased with increasing dexamethasone concentrations in glioblastomas, while this effect was virtually absent in gliomas and meningiomas. Our results suggest a previously unknown selectivity among tumour types for the reduction of water content and serum proteins in corticosteroid treated oedematous tissue.

✓ The components of vasogenic edema associated with brain tumors were investigated in human biopsy material sampled from tumor and peritumoral tissue during neurosurgical operations. Tissue from 60 patients with glioblastomas, gliomas, meningiomas, and metastases who had been treated with dexamethasone prior to surgery was used for measurement of water, electrolyte, hemoglobin, serum protein, and dexamethasone concentrations. In all samples except metastases, positive correlations were obtained between water content and both serum protein levels and sodium content in tumors and peritumoral edema, suggesting that these components simultaneously determine forces for extravasation of plasma-derived edema fluid. However, the mean serum protein content varied considerably, being high in glioblastomas (16 mg/ml) and low in peritumoral edema surrounding metastases (4 mg/ml). The mean cerebral blood volume in all samples, as calculated from the tissue hemoglobin content, was 2.5 ml/100 gm wet weight in tumor tissue and 1.6 to 2.0 ml/100 gm wet weight in peritumoral tissue. Sodium concentrations were not significantly different among the tumor types. Both water and serum protein content decreased with increasing dexamethasone concentrations in glioblastomas, while this effect was virtually absent in gliomas and meningiomas. A therapeutic threshold of dexamethasone at 500 mg/gm wet weight was obtained for tumoral and peritumoral tissue of glioblastomas and was effective in a dose-dependent manner as long as the water content and the serum protein concentration remained below 6 ml/gm dry weight and 30 mg/gm dry weight, respectively. These results suggest a previously unknown selectivity among tumor types for the reduction of both water content and serum proteins in corticosteroid-treated edematous tissue.

2,3,5-triphenyltetrazolium chloride (TTC) is commonly applied in rodents and cats as a marker of infarcted tissue as early as 20 min after the onset of focal ischaemia. At this stage it is suggested that it reflects hypoperfusion rather than failure of respiratory chain. Immersion of brain slices in TTC solution is preferable in comparison to perfusion with TTC in order to ensure, that enough TTC enters the post-occlusion tissue. We compared immersion technique versus perfusion technique 6 h after permanent occlusion of the left middle cerebral artery in 18 baboons. In addition, we assessed the function of the respiratory chain enzymes of stained and unstained tissue in three baboons. The immersion technique revealed an absence of TTC staining limited to subcortical structures in two animals. In seven experiments TTC indicated involvement of almost the entire MCA territory. The extent of the ischaemic lesion indicated by the perfusion technique was very similar. Tissue samples from the presumed infarcted areas revealed normal mitochondrial function. We conclude that perfusion and immersion technique do not cause significant different ischaemic delineation 6 h after middle cerebral artery occlusion. TTC staining appears to be a reliable method of evaluating volume of infarction in primates. Furthermore, absence of TTC staining 6 h after stroke onset is caused by energy or oxygen depletion rather than by mitochondrial injury.