Cornelius Weiller

Treatment-Induced Cortical Reorganization After Stroke in Humans

BACKGROUND AND PURPOSE Injury-induced cortical reorganization is a widely recognized phenomenon. In contrast, there is almost no information on treatment-induced plastic changes in the human brain. The aim of the present study was to evaluate reorganization in the motor cortex of stroke patients that was induced with an efficacious rehabilitation treatment. METHODS We used focal transcranial magnetic stimulation to map the cortical motor output area of a hand muscle on both sides in 13 stroke patients in the chronic stage of their illness before and after a 12-day-period of constraint-induced movement therapy. RESULTS Before treatment, the cortical representation area of the affected hand muscle was significantly smaller than the contralateral side. After treatment, the muscle output area size in the affected hemisphere was significantly enlarged, corresponding to a greatly improved motor performance of the paretic limb. Shifts of the center of the output map in the affected hemisphere suggested the recruitment of adjacent brain areas. In follow-up examinations up to 6 months after treatment, motor performance remained at a high level, whereas the cortical area sizes in the 2 hemispheres became almost identical, representing a return of the balance of excitability between the 2 hemispheres toward a normal condition. CONCLUSIONS This is the first demonstration in humans of a long-term alteration in brain function associated with a therapy-induced improvement in the rehabilitation of movement after neurological injury.

Ventral and dorsal pathways for language

Built on an analogy between the visual and auditory systems, the following dual stream model for language processing was suggested recently: a dorsal stream is involved in mapping sound to articulation, and a ventral stream in mapping sound to meaning. The goal of the study presented here was to test the neuroanatomical basis of this model. Combining functional magnetic resonance imaging (fMRI) with a novel diffusion tensor imaging (DTI)-based tractography method we were able to identify the most probable anatomical pathways connecting brain regions activated during two prototypical language tasks. Sublexical repetition of speech is subserved by a dorsal pathway, connecting the superior temporal lobe and premotor cortices in the frontal lobe via the arcuate and superior longitudinal fascicle. In contrast, higher-level language comprehension is mediated by a ventral pathway connecting the middle temporal lobe and the ventrolateral prefrontal cortex via the extreme capsule. Thus, according to our findings, the function of the dorsal route, traditionally considered to be the major language pathway, is mainly restricted to sensory-motor mapping of sound to articulation, whereas linguistic processing of sound to meaning requires temporofrontal interaction transmitted via the ventral route.

Motor cortex plasticity during constraint-induced movement therapy in stroke patients

Stroke patients in the chronic phase received constraint-induced (CI) movement therapy. The motor cortex was spatially mapped using focal transcranial magnetic stimulation (TMS) before and after 2 weeks of treatment. Motor-output areas of the abductor pollicis brevis muscle, motor evoked potential (MEP) amplitudes and location of centre of gravity (CoG) of motor cortex output were studied. After CI therapy, motor performance improved substantially in all patients. There was also an increase of motor output area size and MEP amplitudes, indicating enhanced neuronal excitability in the damaged hemisphere for the target muscles. The mean centre of gravity of the motor output maps was shifted considerably after the rehabilitation, indicating the recruitment of motor areas adjacent to the original location. Thus, even in chronic stroke patients, reduced motor cortex representations of an affected body part can be enlarged and increased in level of excitability by an effective rehabilitation procedure. The data therefore demonstrate a CNS correlate of therapy-induced recovery of function after nervous system damage in humans.

Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.

Abstract Placebo analgesia is one of the most striking examples of the cognitive modulation of pain perception and the underlying mechanisms are finally beginning to be understood. According to pharmacological studies, the endogenous opioid system is essential for placebo analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate cortex (rACC) represents a crucial cortical area for this type of endogenous pain control. We therefore hypothesized that placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC with these brain areas mediate opioid‐dependent endogenous antinociception as part of a top–down mechanism. Nineteen healthy subjects received and rated painful laser stimuli to the dorsum of both hands, one of them treated with a fake analgesic cream (placebo). Painful stimulation was preceded by an auditory cue, indicating the side of the next laser stimulation. BOLD‐responses to the painful laser‐stimulation during the placebo and no‐placebo condition were assessed using event‐related fMRI. After having confirmed placebo related activity in the rACC, a connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray (PAG). This finding supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.

Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization

We evaluated the influence of time of recanalization or degree of initial leptomeningeal collateral blood flow in cardioembolic or arterio-arterial middle cerebral artery (MCA) occlusion on infarct size and clinical outcome in a series of 34 consecutive acute stroke patients with main stem (N = 31) or major branch (N = 3) occlusions using CT, initial cerebral arteriography (N = 21), repetitive close-meshed transcranial Doppler ultrasonography, and a neurologic stroke scale. We treated 15 patients with tissue plasminogen activator intravenously within the first 6 hours. The type and size of infarction depended on the location of the occluding lesions within the MCA trunk. Proximal MCA occlusion always led to infarction involving the striatum and internal capsule. Sixty-five percent of patients showed recanalization of the occluded MCA within 1 week. Following MCA recanalization, hyperperfusion was present in 38 to 44% of cases. There was a marginally significant relation between size of infarction on CT and recanalization time within the first 24 hours. The more rapidly recanalization occurred, the smaller the size of the infarct. When recanalization time was greater than 8 hours, the lesions always extended to the cortex. An additional good leptomeningeal collateral blood flow significantly reduced the size of the infarct and improved clinical outcome after 17 days and after 10 months. Early recanalization of embolic MCA occlusions within up to 8 hours, in conjunction with good transcortical collateralization, has a favorable impact on infarct size and outcome and may constitute the therapeutic window of opportunity.

Diffusion tensor imaging detects early Wallerian degeneration of the pyramidal tract after ischemic stroke

We used diffusion tensor imaging (DTI) to assess Wallerian degeneration of the pyramidal tract within the first 2 weeks after ischemic stroke, and correlated the extent of Wallerian degeneration with the motor deficit. Nine patients with middle cerebral artery stroke were examined 2-16 days after stroke by DTI and T2-weighted MRI. We measured fractional anisotropy (FA), averaged diffusivity (Dav), eigenvalues of the diffusion tensor and T2-weighted signal in the cerebral peduncle and compared these values between the affected and the unaffected side and between patients and six controls. FA was significantly reduced on the affected side compared to the unaffected side and compared to the control group. The largest eigenvalue was reduced, whereas the smallest eigenvalue was elevated on the affected side. There was no significant difference in T2-weighted signal and Dav. The decrease of anisotropy correlated positively with the motor deficit at the time of DTI study and 90 days after stroke. The reduction of anisotropy mirrors the disintegration of axonal structures, as it occurs in the early phase of Wallerian degeneration. DTI detects changes of water diffusion related to beginning pyramidal tract degeneration within the first 2 weeks after stroke that are not yet visible in conventional T2-weighted or orientationally averaged diffusion weighted MRI. We demonstrated for the first time a correlation of early DTI findings of pyramidal tract damage with the motor deficit. DTI can help prognosing recovery of motor function after stroke within the early subacute phase.

Brain representation of active and passive movements

During active and passive (driven by a torque motor) flexion and extension of the right elbow, regional cerebral blood flow (rCBF) was measured in six healthy, male volunteers using positron emission tomography and the standard H2(15)O injection technique. During active as well as during passive movements of the right elbow there were strong increases in rCBF, identical in location, amount, and extent in the contralateral sensorimotor cortex. There were activations during both conditions in the supplementary motor area (stronger and more inferior in the active condition) and inferior parietal cortex (on the convexity during active movements and in the depth of the central sulcus during passive movements). During active movements only, activations of the basal ganglia and the cingulate gyrus were found. Brain activations during motor tasks are largely related to the processing of afferent information.

Experimental cranial pain elicited by capsaicin: a PET study

&NA; Using a positron emission tomography (PET) study it was shown recently that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so called ‘migraine generator’. To test this hypothesis we performed an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as in the migraine patients. A small amount of capsaicin was administered subcutaneously in the right forehead to evoke a burning painful sensation in the first division of the trigeminal nerve. Increases of regional cerebral blood flow (rCBF) were found bilaterally in the insula, in the anterior cingulate cortex, the cavernous sinus and the cerebellum. Using the same stereotactic space limits as in the above mentioned migraine study no brain stem activation was found in the acute pain state compared to the pain free state. The increase of activation in the region of the cavernous sinus however, suggests that this structure is more likely to be involved in trigeminal transmitted pain as such, rather than in a specific type of headache as was suggested for cluster headache.

Outcome and Symptomatic Bleeding Complications of Intravenous Thrombolysis Within 6 Hours in MRI-Selected Stroke Patients: Comparison of a German Multicenter Study With the Pooled Data of ATLANTIS, ECASS, and NINDS tPA Trials

Background and Purpose— We compared outcome and symptomatic bleeding complications of intravenous tissue plasminogen activator (IV-tPA) within 6 hours of symptom onset in MRI-selected patients with acute middle cerebral artery infarction with the pooled data of the large stroke tPA trials. Methods— Patients were examined by perfusion-weighted and diffusion-weighted imaging ≤6 hours. Within 3 hours, patients were treated according to Second European-Australasian Acute Stroke Study (ECASS II) criteria. After 3 to 6 hours, treatment with IV-tPA was performed based on MRI findings. Favorable outcome was assessed after 90 days using a dichotomized modified Rankin scale score of 0 to 1. Intracerebral bleeding complications were assessed on follow-up MRI or computed tomography. Data were compared with the pooled placebo and pooled tPA patients of the ATLANTIS, ECASS, and National Institute of Neurological Disorders and Stroke (NINDS) tPA trials. Results— From 174 MRI-selected tPA patients, 62% (n=108) were treated in ≤3 hours and 38% (n=66) after 3 to 6 hours. Favorable outcome was more frequent in MRI-selected tPA patients (48% [95% CI, 39 to 54]) compared with pooled placebo (33% [95% CI, 31 to 36]; P<0.001) and pooled tPA patients (40% [95% CI, 37 to 42]; P=0.046). Odds ratios for favorable outcome in the MRI-selected tPA group were 1.82 (1.32 to 2.51) compared with the pooled placebo and 1.39 (1.01 to 1.92) compared with the pooled tPA group. The rate of symptomatic intracerebral hemorrhage in MRI-selected tPA patients (3% [95% CI, 0 to 5]) was lower than in the pooled tPA group (8% [95% CI, 7 to 10]; P=0.012) and comparable to the pooled placebo group (2% [95% CI, 1 to 3]; P=0.392). Conclusions— This study supports that it is safe and effective to expand the time window for IV-tPA up to 6 hours in patients with tissue at risk as defined by MRI.

Subcortical structures involved in pain processing: evidence from single-trial fMRI

&NA; Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single‐trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium–YAG (yttrium–aluminum–granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right‐ and left‐sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.