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Introduction Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia.Patients and methods Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01–2014/03–2018) and randomized to receive rTMS (N= 20), ctDCS (N= 24) or sham stimulation (N= 19) with ST for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca’s area or not).Results Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/p =.01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca’s area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/p =.062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca’s area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/p =.053) versus NIBS (median = 12.7%/interquartile range = 31.7). Conclusion:We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-stroke aphasia. This intervention may be beneficial only in patients with morphologically intact Broca’s area.

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Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear.

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.

SUMMARY Functional imaging studies suggest that recruitment of contralesional areas hinders optimal functional cortical reorganization in patients with post-stroke aphasia. In this review, imaging data of activation shifts in the course of poststroke aphasia are described and data on transcallosal disinhibition of right-hemispheric homolog speech areas are presented. The activated right-hemispheric regions are the target for inhibitory repetitive transcranial magnetic stimulation (rTMS) as a treatment option for aphasia. Several cases and one small controlled study have reported improved function after rTMS treatment in chronic aphasics. In one controlled feasibility study, rTMS over the right homolog of Brocas area was compared with sham stimulation over the vertex in the subacute stage and demonstrated a reduction of the activation shift to the right hemisphere in the treated group, which was related to a significantly improved outcome in the Aachen Aphasia Test. The clinical application of rTMS as a supportive treatment for poststroke aphasia requires further proof of efficacy in a large multicenter trial.

Cerebrolysin showed neuroprotective and neurotrophic properties in various preclinical models of ischemia and small clinical trials. The aim of this large double-blind, placebo-controlled randomized clinical trial was to test its efficacy and safety in patients with acute ischemic stroke.

Perfusion-weighted imaging maps are used to identify critical hypoperfusion in acute stroke. However, quantification of perfusion may depend on the choice of the arterial input function (AIF). Using quantitative positron emission tomography we evaluated the influence of the AIF location on maps of absolute and relative perfusion-weighted imaging to detect penumbral flow (PF; <20 mL100 gmin on positron emission tomographyCBF) in acute stroke.

Activated microglia is one of the most important cellular components of poststroke neuroinflammation, which occurs early in the area of the infarct but also in remote regions with fiber tract connections to the site of the primary lesion. The development of different radioligands for the translocator protein, a mitochondrial membrane protein expressed in microglial cells when they transform from the resting to the activated state, allows to study the temporal dynamics of this cellular neuroinflammatory component in vivo in animal models and human stroke using positron emission tomography. In this article, we review the advantage and limitations of current and future methods for microglia imaging as well as new results of multimodal imaging approaches in clinical stroke, which try to combine microglia imaging with diffusion tensor imaging to investigate the clinical relevance of remote microglia activation along fiber tracts for poststroke recovery.

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.

Perfusion-weighted imaging-derived maps of time-to-maximum (Tmax) are increasingly used to identify the tissue at risk in clinical stroke studies (eg, DEFUSE and EPITHET). Using quantitative positron emission tomography (PET), we evaluated Tmax to define the penumbral flow threshold in stroke patients and compared its performance to nondeconvolved time-to-peak (TTP) maps.

Perfusion-weighted (PW) MRI is increasingly used to identify the tissue at risk. The adequate PW-MRI map and threshold remain controversial due to a considerable individual variation of values. By comparative positron emission tomography, we evaluated a simple MR-based and positron emission tomography-validated calibration of PW maps.

The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Perfusion-weighted imaging maps are used to identify hypoperfusion in acute ischemic stroke. We evaluated maps of cerebral blood flow (CBF), cerebral blood volume, mean transit time, and time to peak (TTP) in acute stroke by comparison with positron emission tomography.

Perfusion-weighted MRI-based maps of cerebral blood flow (CBFMRI) are considered a good MRI measure of penumbral flow in acute ischemic stroke but are seldom used in clinical routine due to methodical issues. We validated CBFMRIon quantitative CBF measurement by 15O-water positron emission tomography (CBFPET).

To study cerebrovascular autoregulation and its impact on clinical course in patients with impending malignant middle cerebral artery infarction, we used invasive multimodal neuromonitoring, including measurement of cerebral perfusion pressure, tissue oxygen pressure, and microdialysis.

Mild cognitive impairment may be an early clinical manifestation of Alzheimer's disease, but there are also patients who remain stable or remit. In-vivo measurements of cortical acetylcholine esterase activity by positron emission tomography have shown that it is reduced in Alzheimer's disease, and we investigated whether there is also a reduction in mild cognitive impairment. A significant reduction was observed in three of eight patients, and a significant association was found with progression to Alzheimer's disease within 18 months. These results suggest that low cortical acetylcholine esterase activity may be an indicator of impending dementia in patients with mild cognitive impairment.

Neuroimaging studies of language networks in patients with brain lesions of the left language‐dominant hemisphere have shown activation in the right inferior frontal gyrus (IFG). We tested the functional relevance of right IFG activation using neuroimaging‐guided repetitive transcranial magnetic stimulation (rTMS) to disturb language function over bilateral IFG in right‐handed patients with brain tumors and controls. All subjects were susceptible to TMS over the left IFG. In patients, this susceptibility correlated with left‐sided the degree of language lateralization to the left. Those patients with lowest dominance were also susceptible to right‐sided TMS proving relevant language function of the right IFG. Ann Neurol 2005;57:128–131

In a prospective phase I/II clinical study, we treated eight patients suffering from recurrent glioblastoma multiform with stereotactically guided intratumoral convection‐enhanced delivery of an HSV‐1‐tkgene–bearing liposomal vector and systemic ganciclovir. Noninvasive identification of target tissue together with assessment of vector‐distribution volume and the effects of gene therapy were achieved using magnetic resonance imaging and positron emission tomography. The treatment was tolerated well without major side effects. In two of eight patients, we observed a greater than 50% reduction of tumor volume and in six of eight patients focal treatment effects. Intracerebral infusion of contrast medium before vector application displayed substantial inhomogeneity of tissue staining indicating the need of test infusions to monitor the mechanical distribution of vectors. Visualization of therapeutic effects on tumor metabolism and documentation of gene expression using positron emission tomography indicated that molecular imaging technology appears to be essential for the further development of biological treatment strategies.

Background and Purpose—To predict malignant course in patients with large middle cerebral artery (MCA) infarction, we combined PET imaging and neuromonitoring, including microdialysis.

For the development of efficient and safe gene therapy protocols for clinical application it is desirable to determine the tissue dose of vector-mediated therapeutic gene expression noninvasively in vivo. The herpes simplex virus type 1 thymidine kinase gene (HSV-1-tk) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET). Using bicistronic or multicistronic gene-expressing cassettes with tk as the PET marker gene, the quantitative analysis of tk gene expression may indirectly indicate the distribution and the level of expression of linked and proportionally coexpressed genes. Here, we describe the construction and functional evaluation of HSV-1 amplicon vectors mediating proportional coexpression of HSV-1-tk as PET marker gene and the enhanced green fluorescent protein gene (gfp) as proof of principle and cell culture marker gene and the Escherichia coli cytosine deaminase (cd) as therapeutic gene. Several double-/triple-gene constructs expressing HSV-1-tk, gfp, and E. coli cd were engineered based on gene fusion or the use of an internal ribosome entry site (IRES). Functional analysis in cell culture (green fluorescent protein [GFP] fluorescence and sensitivity to the prodrugs ganciclovir [GCV] and 5-fluorocytosine [5-FC]) and Western blots were carried out after infection of proliferating rat 9L gliosarcoma and human Gli36 glioma cells with helper virus-free packaged HSV-1 amplicon vectors. To study the ability of PET to differentiate various levels of tk expression noninvasively in vivo, retrovirally transduced and selected populations of rat F98 and human Gli36dEGFR glioma cells with defined levels of proportionally coexpressed tk and gfp genes were grown as subcutaneous tumors in nude rats and nude mice, and tk imaging by PET was performed. To study HSV-1 amplicon vector-mediated gene coexpression in vivo, HSV-1 amplicon vectors bearing coexpression constructs were injected (4 × 107 to 1 × 108 transducing units) into subcutaneously growing Gli36dEGFR gliomas in nude animals, and tk imaging was performed 24 hr later. All vector constructs mediated GFP expression and sensitized 9L and Gli36 cells toward GCV- and 5-FC-mediated cell killing in a drug dose-dependent manner, respectively. The levels of gene expression varied depending on the location of the genes within the constructs indicating the influence of the IRES on the level of expression of the second gene. Moreover, functional proportional coexpression of the PET marker gene HSV-1-tk and the linked therapeutic E. coli cd gene was observed. In selected tumor cell populations, subtle IRES-dependent differences of tk gene expression could be noninvasively distinguished by PET with good correlation between quantitative assays for IRES-dependent attenuated GFP and TK expression in culture and in vivo. After infection of subcutaneously growing gliomas with HSV-1 amplicon vectors, various levels of TK expression were found ranging from 0.011-0.062 percentage injected dose per gram (%ID/g). These values were 4.0- to 5.7-fold lower than positive control tumor cells. TK expression could be imaged by PET in vivo even with the tk gene located at the weak position downstream from the IRES. In conclusion, these HSV-1 amplicon vectors carrying HSV-1-tk as PET marker gene and any linked therapeutic gene will serve an indirect noninvasive assessment of the distribution of therapeutic gene expression by PET. Monitoring the correlation between primary transduction and therapeutic efficiency of a given vector is highly desirable for the development of safe and efficient gene therapy and vector application protocols in clinical applications.

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) has become an effective treatment option in advanced Parkinson's disease (PD). Recent animal studies showed an increase of neuronal firing in dopaminergic neurons under effective STN‐DBS. Increased striatal dopamine levels may also contribute to the stimulation's mechanism of action in humans. We investigated the striatal dopamine release in 6 patients with advanced PD under effective bilateral STN‐DBS with positron emission tomography (PET) of the reversible dopamine‐D2/3‐receptor ligand [11C]raclopride (RACLO). Although STN‐DBS proved to be a highly effective treatment in these subjects, we found no significant difference of the striatal RACLO binding between the STN‐DBS–on and –off condition. The changes of radioligand binding did not correlate with the patients' improvement in clinical rating scales or with the stimulation amplitudes. Therefore, our PET data in living parkinsonian humans do not provide evidence for an increased striatal dopamine concentration under effective STN‐DBS. We conclude that the modulation of dopaminergic activity does not seem to play a crucial role for the stimulation's mechanisms of action in parkinsonian humans. © 2002 Movement Disorder Society

Brain ischemia causes rapid energy depletion resulting prominent ion shifts which are responsible for tissue damage. In the present study, we measured extracellular concentrations of ions and adenosine, a determinant of ATP degradation, in gray and white matter during global ischemia. In eight cats, global ischemia was induced by extracranial arteries occlusion. Extracellular levels of Na, K, Ca and pH were measured with microelectrodes, and levels of adenosine were determined by microdialysis-HPLC in gray and white matter. After the arterial occlusion, extracellular K concentration ([K]o) increased, [Na]o and pH decreased. Except for [Ca]o, changes of ion concentrations in white matter were comparable to those in gray matter, although the speed and the magnitude of change were much slower and smaller. In gray matter, [Ca]o started to decrease at 1 min after and reaching minimum at 15 min. [Ca]o in white matter was increased during initial 30 min, and reached minimum at 120 min. In both regions, extracellular adenosine levels increased significantly, however, the peak in white matter was delayed by 20 min compared to that in gray matter. The present study demonstrated slower and smaller ion shifts and ATP breakdown in white matter ischemia than those in gray matter ischemia.