Cause or effect: Altered brain and network activity in cervical dystonia is partially normalized by botulinum toxin treatment.

BACKGROUND: Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD. OBJECTIVES: We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function. METHODS: Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months). RESULTS: In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia. CONCLUSION: The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls.

Primary somatosensory contextual modulation is encoded by oscillation frequency change.

OBJECTIVE: This study characterized thalamo-cortical communication by assessing the effect of context-dependent modulation on the very early somatosensory evoked high-frequency oscillations (HF oscillations). METHODS: We applied electrical stimuli to the median nerve together with an auditory oddball paradigm, presenting standard and deviant target tones representing differential cognitive contexts to the constantly repeated electrical stimulation. Median nerve stimulation without auditory stimulation served as unimodal control. RESULTS: A model consisting of one subcortical (near thalamus) and two cortical (Brodmann areas 1 and 3b) dipolar sources explained the measured HF oscillations. Both at subcortical and the cortical levels HF oscillations were significantly smaller during bimodal (somatosensory plus auditory) than unimodal (somatosensory only) stimulation. A delay differential equation model was developed to investigate interactions within the 3-node thalamo-cortical network. Importantly, a significant change in the eigenfrequency of Brodmann area 3b was related to the context-dependent modulation, while there was no change in the network coupling. CONCLUSION: This model strongly suggests cortico-thalamic feedback from both cortical Brodmann areas 1 and 3b to the thalamus. With the 3-node network model, thalamo-cortical feedback could be described. SIGNIFICANCE: Frequency encoding plays an important role in contextual modulation in the somatosensory thalamo-cortical network.

Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location, N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment.

Stimulation of cell proliferation and neurogenesis in the adult dentate gyrus has been observed after focal and global brain ischemia but only little is known about the underlying mechanisms. We here analyzed neurogenesis in the dentate gyrus after small cortical infarcts leaving the hippocampal formation and subcortical regions intact. Using the photothrombosis model in adult rats, focal ischemic infarcts were induced in different cortical areas (sensorimotor forelimb and hindlimb cortex) and proliferating cells were labeled at days 3-14 after infarct induction with bromodeoxyuridine. At 2, 4, and 10 weeks after ischemia, immunocytochemistry was performed with immature neuronal (doublecortin), mature neuronal (neuronal nuclei antigen) and glial (calcium-binding protein beta S100beta) markers. When compared with sham-operated controls, animals with infarcts in the forelimb as well as hindlimb cortex revealed an increase in survival of newborn progenitor cells at four and 10 weeks after the insult with predominance at the ipsilateral side. Triple immunofluorescence and confocal laser scanning microscopy revealed an increase in neurogenesis in all groups that was more pronounced 10 weeks after the infarct. Application of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 during lesion induction significantly enhanced neurogenesis in the dentate gyrus. An even stronger increase in newborn neurons was observed after anti-inflammatory treatment with indomethacine during the first 16 days of the experiment. The present study demonstrates that small cortical infarcts leaving subcortical structures intact increase neurogenesis in the dentate gyrus and that these processes can be stimulated by N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment.

[Cerebral vasospasms with hemodynamic infarctions as a complication of HELLP syndrome]. / Zerebrale Vasospasmen mit hämodynamischen Infarkten als Komplikation eines HELLP-Syndroms.

Sinal thrombosis, intracerebral bleeding, cerebral edema, and cerebral vasospasm are typical neurological complications in pre- and eclampsia. Hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome is a rare, severe complication of pre-eclampsia. We present the case of a 33-year-old woman with HELLP syndrome. After a cesarean section, generalized epileptic seizure occurred and intubation was necessary due to sustained unconsciousness. Despite magnesium therapy, bilateral hemodynamic ischemic infarctions and narrowing of the circle of Willis were visible on MRI, and vasospasm of all large basal cerebral arteries was confirmed by cerebral angiography and transcranial Doppler sonography. During the following 2 weeks, the cerebral vasospasm resolved with application of high-dose methyl prednisolone and nimodipine. After extubation, the patient initially suffered from mild psychosyndrome and ataxia but recovered completely after 3 months. The HELLP syndrome may be complicated by cerebral vasospasm with subsequent hemodynamic strokes. Combined treatment with magnesium, corticosteroids, and nimodipine can be recommended. In our case, this regimen led to resolution of the cerebral vasospasm and complete clinical recovery.

Reorganized cerebral metabolic interactions in temporal lobe epilepsy.

Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood. To explore abnormal patterns of brain functional connections with respect to language processing, we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right- and left-sided temporal lobe epilepsy and controls. Two principal components were expressed differentially among the groups. One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions-corresponding to Broca's and Wernicke's areas, respectively-and right mesial temporal cortex and right thalamus. Functional couplings between these brain regions were abnormally enhanced in the left-sided epilepsy patients. The right thalamic left superior temporal coupling was also abnormally enhanced in the right-sided epilepsy patients, but differentially from that in the left-sided patients. The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex. Although both the right- and left-sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions, a weaker right-left mid prefrontal coupling in the left-sided epilepsy patients best distinguished them from the right-sided patients. The two mutually independent, abnormal metabolic patterns each predicted verbal intelligence deficits in the patients. The findings suggest a site-dependent reorganization of two independent, language-subserving pathways in temporal lobe epilepsy.

Thalamocortical circuits causing remote hypometabolism during focal interictal epilepsy.

The functional circuit causing depression of cerebral glucose metabolism in brain areas remote from an epileptic focus was investigated in experiments on the cortex of the rat. Epileptic activity was induced by direct epicortical application of Na-penicillin onto the motor cortical area Fr1/Fr2. The increased neuronal activity was associated with an increase of metabolism in the focal area and a decrease in somatosensory cortical areas. Metabolism was also massively increased in the thalamus, predominantly in the posterior nucleus. Stereotactic radiofrequency lesioning of this nucleus, 30 days prior to the induction of the epileptic focus, restricted the area with increase of metabolism to the upper cortical laminae, and abolished the cortical hypometabolism in the sensory cortex. It is suggested that the primary functional circuit affected by the acute epileptic focus in the present model consists of the motor cortex, the thalamic nucleus posterior and the somatosensory cortex.

Transient increase of manganese-superoxide dismutase in remote brain areas after focal photothrombotic cortical lesion.

BACKGROUND AND PURPOSE: Free radicals including superoxide are responsible for postlesional cytotoxicity. In contrast to the constitutive CuZn-superoxide dismutases (SODs), manganese-superoxide dismutase (Mn-SOD) is inducible and has the potential to protect neurons by its superoxide dismutating activity. Therefore, we studied the presence and the regional changes in Mn-SOD within the brain after focal cortical ischemia. METHODS: Focal cortical photothrombotic lesions were produced in the hindlimb region of rat brains. Animals were anesthetized and transcardially perfused with Zamboni's fixative. Mn-SOD was immunohistochemically localized using an antiserum against rat-Mn-SOD. Changes in Mn-SOD immunoreactivity were quantified by image analysis. RESULTS: Focal photothrombosis caused a perilesional increase in Mn-SOD after 24 hours, followed by a further significant increase at 48 hours in perilesional cortex, ipsilateral corpus callosum, hippocampus, and thalamus, as well as in a homotopic cortical area within the nonlesioned hemisphere. At day 2, Mn-SOD was present in neurons and astrocytes. Up to day 7, Mn-SOD increased in the entire ipsilateral and contralateral cortex but remained higher elevated in the ipsilateral hippocampus and thalamus. Thereafter, Mn-SOD decreased globally but remained elevated in some cortical neurons up to day 60. CONCLUSIONS: The early transient increase of Mn-SOD in distinct brain regions, which are functionally connected via afferents and efferents, suggests that these regions are affected by the injury. It suggests that Mn-SOD protects the cells in these regions from superoxide-induced damage and therefore may limit the retrograde and anterograde spread of neurotoxicity.

Coupling of cortical and thalamic metabolism in experimentally induced visual and somatosensory focal epilepsy.

Focal epileptic activity induces widespread metabolic disturbances beyond the area of the electroencephalographically detectable focus. In order to find out whether the metabolic coupling between the epileptic focus and other brain regions depends on the localization of the focus, two groups of rats with epileptic foci at different sites were investigated. In the first group acute epileptic activity was induced by application of penicillin to the secondary visual cortex (Oc2), and in the second group to the primary somatosensory cortex (Par1). Metabolism was analyzed using the [14C]deoxyglucose autoradiographic method. In both groups of animals, hypermetabolism in the area of the focus and in specific functionally coupled thalamic nuclei was observed. Focal epileptic activity in the secondary visual cortex induced significant hypometabolism in remote ipsilateral cortical areas. In rats with epileptic foci in the primary somatosensory cortex hypometabolism in extrafocal ipsilateral cortical areas was less prominent. These findings provide further support for the integral involvement of the thalamus in modulating metabolism in remote cortical brain regions during focal epileptic activity. The extent of metabolic alterations may depend on the site of the epileptic focus and the connectivity of the recruited thalamic nuclei.

Systemically administered cycloheximide reduces inhibition in rat neocortical slice preparation.

Global cerebral ischemia leads to long lasting hyperexcitability and a reduced protein synthesis in non-infarcted tissue surrounding the lesion. In this study we investigated whether protein synthesis inhibition by pharmacological means itself changes neocortical excitability. Two hours after the last of three i.p. injections with the protein synthesis inhibitor cycloheximide (12 h interval, 1.5 mg/kg body weight) we observed a widespread reduction of neocortical inhibition. The study indicates that inhibition of protein synthesis may contribute to the altered brain excitability following ischemia.

Afterpotentials of penicillin-induced epileptiform neuronal discharges in the motor cortex of the rat in vivo.

Interictal spikes and sharp waves in the EEG are followed by intervals in which the excitability of the brain seems to be normal or decreased. Often interictal spikes even appear in rhythmical patterns with intervals in the order of 0.5-2 s. These observations suggest that intrinsic and synaptic inhibitory and excitatory processes are activated which outlast the duration of the interictal discharge. In the present study such afterpotentials were analyzed in penicillin foci of the rat motor cortex in vivo using intracellular recording techniques. Paroxysmal depolarizations (PDS) of neurons within the focus were followed by afterpotentials comprising several components. Fast afterpotentials with a duration of 640 ms were associated with a sevenfold increase in membrane conductance. The fast afterpotentials were depolarizing in the majority of recordings and had an average equilibrium potential of -62 mV. This equilibrium potential was Cl(-)-dependent and was not affected by intracellular EGTA or Cs+. It is suggested that these afterpotentials represent GABAA responses. In 38% of the neurons slow afterhyperpolarizations with a twofold increase in membrane conductance and a duration of 2 s were observed. These afterhyperpolarizations had a reversal potential of -79 mV, were blocked by intracellular Cs+, were reduced in duration and amplitude by intracellular EGTA, and are suggested to present a combination of a GABAB response and a calcium-dependent potassium current. In addition, slow afterdepolarizations with a duration of about 1900 ms were registered in 16% of the recordings. It is concluded that afterpotentials with several intrinsic and synaptic components follow penicillin-induced PDS. Among these are giant Cl(-)-dependent potentials which probably represent GABAA responses, GABAB responses and a slow calcium-dependent potassium current. It is suggested that the depolarizing equilibrium potential of the Cl(-)-dependent component is due to intracellular Cl- accumulation which might favor transition to ictal discharges.

Separation of different types of afterpotentials following penicillin-induced paroxysmal depolarization shifts of neurons in the motor cortex of the rat.

Afterpotentials of penicillin-induced paroxysmal depolarization shifts (PDS) of neurones in the motor cortex of the rat in vivo were investigated with intracellular recordings. Following the PDS, 4 different types of afterpotentials were observed: fast afterhyperpolarizations with an average duration of 600 ms, fast afterdepolarizations with an average duration of 700 ms, slow afterhyperpolarizations with an average duration of 1.9 s and slow afterdepolarizations with an average duration of 1.8 s. The fast and slow afterpotentials could occur in various combinations with the exception of a fast afterhyperpolarization followed by a slow afterdepolarization. Neurones displaying afterdepolarizations had higher resting membrane potentials than those displaying afterhyperolarizations, i.e. the polarity of the afterpotential depended on membrane potential. Experiments with intracellular Cl- injection indicated that the fast but not the slow afterpotentials are associated with an increase in membrane Cl- conductance. The slow afterhyperpolarizations are suggested to result from a calcium-dependent or a synaptically generated potassium current.

Motor cortical epileptic foci in vivo: actions of a calcium channel blocker on paroxysmal neuronal depolarizations.

Focal epileptiform activity was induced by local application of penicillin to the surface of the rat motor cortex. Neurons located within the epileptic focus displayed typical paroxysmal depolarization shifts (PDS). The participation of membrane calcium currents in the generation of PDS was examined by injecting the quaternized calcium entry blocker D890 into single neurons by iontophoresis or by pressure pulses. After intracellular injections of D890, PDS were depressed in amplitude by up to 55%. In a few cases the depression of PDS following intracellular application of D890 was preceded by a transient increase. Similar increases of PDS amplitude were obtained by injections of the calcium chelator EGTA. Control experiments in preparations without epileptic activity revealed that excitatory potentials elicited by thalamic stimulation and Cl(-)-dependent inhibitory postsynaptic potentials evoked by epicortical stimulation were not affected by intracellular D890. In these experiments successful intracellular drug application was verified by monitoring the transient shift of the Cl(-)-equilibrium potential induced by injection of KCl together with D890. It is concluded that in the penicillin-induced epileptic focus of the motor cortex Ca2+ inward currents participate in the generation of neuronal PDS.