Gerhard Schuierer

Neuroplasticity: Changes in grey matter induced by training

Does the structure of an adult human brain alter in response to environmental demands? Here we use whole-brain magnetic-resonance imaging to visualize learning-induced plasticity in the brains of volunteers who have learned to juggle. We find that these individuals show a transient and selective structural change in brain areas that are associated with the processing and storage of complex visual motion. This discovery of a stimulus-dependent alteration in the brains macroscopic structure contradicts the traditionally held view that cortical plasticity is associated with functional rather than anatomical changes.

Specific tonotopic organizations of different areas of the human auditory cortex revealed by simultaneous magnetic and electric recordings

This paper presents data concerning auditory evoked responses in the middle latency range (wave Pam/Pa) and slow latency range (wave N1m/N1) recorded from 12 subjects. It is the first group study to report multi-channel data of both MEG and EEG recordings from the human auditory cortex. The experimental procedure involved potential and current density topographical brain mapping as well as magnetic and electric source analysis. Responses were compared for the following 3 stimulus frequencies: 500, 1000 and 4000 Hz. It was found that two areas of the auditory cortex showed mirrored tonotopic organization; one area, the source of N1m/N1 wave, exhibited higher frequencies at progressively deeper locations, while the second area, the source of the Pam/Pa wave, exhibited higher frequencies at progressively more superficial locations. The Pa tonotopic map was located in the primary auditory cortex anterior to the N1m/N1 mirror map. It is likely that N1m/N1 results from activation of secondary auditory areas. The location of the Pa map in A1, and its N1 mirror image in secondary auditory areas is in agreement with observations from animal studies.

External Carotid Artery Territory Ischemia Impairs Outcome in the Endovascular Filament Model of Middle Cerebral Artery Occlusion in Rats

BACKGROUND AND PURPOSE Middle cerebral artery occlusion (MCAO) by an intraluminal filament is a widely accepted animal model of focal cerebral ischemia. In this procedure, cutting of the external carotid artery (ECA) is a prerequisite for thread insertion. However, the implications of ECA transsection have not yet been described. METHODS After 90 minutes of filament MCAO or sham surgery, rats were evaluated for up to 14 days in terms of body weight development, core temperature, and motor performance. Repeated in vivo MRI of the head and neck was performed for quantification of brain edema and infarct volume. The temporal muscles were histologically analyzed postmortem. RESULTS In 47% of all rats, ischemic tissue damage to the ipsilateral ECA area, including temporal, lingual, and pharyngeal musculature, was detectable by MRI. Histology of temporal muscles confirmed acute ischemic myopathy. Animals with ECA territory ischemia (ECA-I) showed delayed body weight development and poorer recovery of motor function. There was no difference in the extent of brain edema or final cerebral lesion size between ECA-I-affected and unaffected rats. CONCLUSIONS Filament MCAO was complicated by the consequences of ECA ischemia in approximately half of all rats. Impaired mastication and swallowing functions restricted ingestion and resulted in postsurgical body weight loss and worse motor performance. Impaired cerebral microperfusion resulting from dehydration and reduced spontaneous motor activity resulting from reduced food and water uptake might have contributed to poorer neurological recovery in ECA ischemic rats. Thus, adverse effects caused by extracerebral ischemia with potential impact on outcome have to be considered in this stroke model.

White matter abnormalities in patients with treated hyperphenylalaninaemia : magnetic resonance relaxometry and proton spectroscopy findings

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n=8) and/or1H spectroscopy (n=7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6-to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200–450 ms, indicating an increase in free (extracellular) water.1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-&bgr; (A&bgr;) deposition in the blood–brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to A&bgr; compromising the BBB. Methods— We characterized 19 patients with acute stroke with “probable CAA” for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of A&bgr; on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Results— Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. A&bgr;40 decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Conclusions— Our findings indicate that A&bgr; contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that A&bgr; causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Hypothalamic gray matter changes in narcoleptic patients

globally activate the stress response (data not shown), although the Lewy body–like inclusions immunolabel for Hsp70 (ref. 5). As 3 μg/ml prevents dopaminergic cell loss due to α-synuclein toxicity, it is possible that only a modest change in or redistribution of molecular chaperones is sufficient for neuroprotection. Current anti-PD agents, including levodopa, dopamine receptor agonists (such as bromocriptine), and monoamine oxidase B inhibitors (such as deprenyl), are designed to relieve the symptoms of PD by restoring dopamine levels in the basal ganglia. Our studies define a potential drug class that promotes the survival of dopaminergic neurons. Although we suggest that geldanamycin is acting by upregulating or otherwise modulating molecular chaperone activity, the drug may also be modulating other pathways regulated by Hsp90. Regardless, these studies have revealed a drug that can fully protect against the toxicity of α-synuclein to dopaminergic neurons in Drosophila. Geldanamycin and its derivatives warrant further exploration as cytoprotective agents for the treatment of neurodegenerative diseases involving α-synuclein toxicity, including PD.

Long‐term course and mutational spectrum of spatacsin‐linked spastic paraplegia

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13‐21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long‐term course and the mutational spectrum of spatacsin‐associated ARHSP with TCC.

Cerebral ischemia-reperfusion injury in rats--a 3 T MRI study on biphasic blood-brain barrier opening and the dynamics of edema formation.

Serial magnetic resonance imaging (MRI) was performed to investigate the temporal and spatial relationship between the biphasic nature of blood–brain barrier (BBB) opening and, in parallel, edema formation after ischemia–reperfusion (I/R) injury in rats. T2-weighted imaging combined with T2-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T1-weighted imaging was performed before and after gadolinium contrast at the last three time points to assess BBB integrity. The biphasic course of BBB opening with a significant reduction in BBB permeability at 24 h after reperfusion, associated with a progressive expansion of leaky BBB volume, was accompanied by a peak ipsilateral edema formation. In addition, at 4 h after reperfusion, edema formation could also be detected at the contralateral striatum as determined by the elevated T2-values that persisted to varying degrees, indicative of widespread effects of I/R injury. The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation. Stroke therapy aimed at vasogenic edema and drug delivery for neuroprotection may also be guided according to the functional status of the BBB, and these findings have to be confirmed in human stroke.

Intracranial vascular stenosis and occlusion: comparison of 3D time-of-flight and 3D phase-contrast MR angiography

Abstract We compared the value of 3D time-of-flight (TOF) and phase-contrast (PC) MR angiography (MRA) for detection and grading of intracranial vascular steno-occlusive disease. Unenhanced 3D-TOF MRA and 3D-PC MRA (30–60 cm/s velocity encoding) were performed at the level of the circle of Willis in 18 patients, mean age 56 ± 10 years. Postprocessed images using a maximum-intensity projection reconstruction with multiple targetted projections were analysed. A total of 126 vessels was assessed by PC MRA and 143 by TOF MRA, with digital subtraction angiography (DSA) in 15 patients and/or transcranial Doppler sonography (TCD) in 18 as a standard. Two blinded readers reviewed the MRA, DSA and TCD examinations retrospectively. On DSA and/or TCD the two observers found 32 and 28 steno-occlusive lesions. 3D-TOF MRA was more sensitive than 3D-PC MRA (87 % and 86 % vs. 65 % and 60 %) and had a higher negative predictive value (96 % vs. 89 %). Correct grading of stenoses was achieved in 78 % by 3D-TOF and 65 % by 3D-PC MRA.

Craniocervical artery dissection: MR imaging and MR angiographic findings

Abstract. Dissection of the carotid and vertebral arteries is a not so uncommon cause of stroke and has to be considered as a differential diagnosis especially in younger patients. Therapeutic and prognostic implications are different from those in extracranial atherosclerotic disease. Dissection results from hemorrhage into the vessel wall usually between the layers of the media. Digital subtraction angiography (DSA) depicts the resulting luminal compromise that may reveal some typical, but not specific, findings. The same is true for non-invasive angiographic techniques such as time-of-flight magnetic resonance angiography (MRA) and computed tomography angiography (CTA), which have shown accurate results compared with DSA. The main advantage of these techniques is the direct visualization of the vessel wall confirming the intramural hematoma. This is achieved best with MR imaging due to the high signal of blood degradation products on T1- and T2-weighted images. Therefore, MRI in combination with MRA is presently the method of choice for initial diagnosis and follow-up of craniocervical artery dissection (CCAD). In some questionable cases, CTA is a non-invasive alternative that is independent of flow phenomena.