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Functional recovery of stroke-related deficits is mainly achieved through neural reorganization. Neurorehabilitative approaches, therefore, aim at supporting positive processes while suppressing maladaptive neuronal processes. This review summarizes the main findings of studies using non-invasive and invasive brain stimulation with respect to the benefits of the treatment for motor deficits after stroke. In addition, the article discusses possible approaches to enhance the effectiveness of neuromodulatory approaches and thus improve the outcome of patients.

An essay on regression.

Neuronal plasticity is a core mechanism for learning and memory. Abnormal neuronal plasticity has emerged as a key mechanism in many neurological and neuropediatric diseases.Chances and perspectives of neuromodulation techniques in neurological and neuropediatric diseases with altered neuronal plasticity.Presentation and discussion of own results of neuronal plasticity investigations in patients with neurodevelopmental disorders including RASopathies, autism spectrum disorders (ASD) and Gilles de la Tourette syndrome (GTS).The results of neuronal plasticity studies in patients with RASopathies, ASD and GTS underline the pathophysiological relevance of abnormal neuronal plasticity in these diseases. Transcranial magnetic stimulation (TMS) is a useful tool to examine and also induce neuronal plasticity in these patients.Neuronal plasticity appears to be an important pathophysiological factor in neuronal developmental disorders and can be investigated using TMS. New and innovative techniques may offer novel approaches for individualized TMS applications, particularly in children with neuropediatric conditions.

Bipolar disorders are quite common (lifetime prevalence 1–2 %) and have a substantial genetic risk (total heritability about 80 %). However, the contribution of individual genes to the total genetic risk is very small. Accordingly, no specific genes are known which show a larger contribution. Nevertheless, many of the known genes involved encode for proteins important for neural plasticity, mitochondrial function, dopaminergic neurotransmission and calcium channels. Similarly, the few data about neurobiological alterations in the brains of bipolar patients also point into the same direction. However, these observations are not very specific. A possible exception might be mitochondrial dysfunction seen in bipolar patients, which could integrate several of the other findings into one concept. The pharmacology of the drugs used to treat bipolar disorders is also not pointing to one common mechanism of action. While the mechanisms of action of antidepressants and antipsychotics probably are not different from the mechanisms relevant to treat depression and schizophrenia, the mechanisms of the anticonvulsants used in bipolar disorders (valproic acid, carbamazepine, lamotrigine) are probably different from their mechanism of action as anticonvulsant drugs. More likely, these drugs improve neuronal plasticity similarly to lithium and antidepressants.

Seit Beginn der Beschreibung der Demetia Praecox (später Schizophrenie) Ende des 19. Jahrhunderts hat diese das Interesse neurobiologisch orientierter Forscher auf sich gezogen. Von jeher stand die Frage im Raum, ob dieser Erkrankungsgruppe nicht hirnstrukturelle Veränderungen zugrunde liegen, die neurodegenerativer Natur sein könnten. Aufgrund der Schwere und der ungünstigen Prognose ist dies ein nachvollziehbarer Gedanke, dem allerdings diverse Argumente widersprechen: Erstens scheint es keine Progression von kognitiven Defiziten oder allgemein der Negativsymptomatik mit dem Krankheitsverlauf zu geben, zweitens fehlen Hinweise auf einen klassisch neurodegenerativen Prozess und drittens scheint eine Reversibilität hirnstruktureller Veränderungen vorzuliegen, was alles zusammengenommen dafür spricht, dass der Schizophrenie kein (klassisch) degenerativer Prozess, sondern den hirnstrukturellen und hirnfunktionellen Veränderungen eine Störung regenerativer Prozesse zugrunde liegt.

Every year in Europe 1.5 million patients suffer a new stroke. Despite the further developments in acute therapy with nationwide stroke units, thrombolysis, thrombectomy and post-acute neurorehabilitation, only a small proportion of patients recover to a satisfactory degree allowing them to return to their normal social and professional life. This makes stroke the main cause of long-term disability with a corresponding impact on patient lives, socioeconomics and the healthcare system. Thus, the concepts of neurorehabilitation have to be extended to enhance the effects of rehabilitative treatment strategies. To achieve this, an understanding of the prediction of the course of recovery, the mechanisms underlying functional recovery and factors influencing recovery have to be enhanced for the development towards patient-tailored precision medicine approaches. A central point towards this is the understanding of stroke as a disease, which not only influences the damaged area but also the associated network. This is crucial for the understanding of the stroke-induced deficits, for prediction of recovery and options for interventional treatment strategies, which can target different areas in this network (e.g. primary motor cortex and secondary motor regions) based on individual factors of the patient. The present article discusses the importance of network alterations for motor neurorehabilitation after a stroke and which novel options, concepts and consequences could arise from this for neurorehabilitation.

Chronic pain represents a great challenge; according to epidemiological data increasing numbers of patients should be expected. Based on recent advances, a better understanding of the pathophysiology of chronic pain has been achieved and neurologists have made a major contribution to this understanding. Chronic pain is accompanied by substantial maladaptive plastic alterations in both the peripheral and central nervous systems; therefore, neurological knowledge is of paramount importance for pain therapists but this contrasts with the current treatment situation of pain patients in Germany. There are basically too few departments and practices undertaking treatment, and neurologists are an exception in most pain centers. Furthermore, due to economic reasons neurological hospitals are currently experiencing a dearth of inpatients suffering from chronic pain. Diagnostic and/or treatment procedures for neurological pain entities (e.g. headaches or neuropathic pain) are insufficiently represented in the German diagnosis-related groups (DRG) reimbursement system and the obstacles for an efficient pain therapy in neurological practices are too high. Finally, there are too few academic positions for pain medicine in neurological hospitals; therefore, career opportunities for motivated young neurologists with an interest in pain are lacking. In order to address the unmet therapeutic needs of patients with chronic pain there is a high demand for (i) establishment of departments for neurological pain medicine, (ii) modification of the German DRG system and (iii) education of young neurologists with expertise in pain. Pain medicine in particular should be especially appealing to neurologists .

Cluster headaches have an incidence of 1-3 per 10,000 with a 2.5:1 male-to-female gender ratio. Although not life threatening, the impact of the attacks on the individual patient can result in tremendous pain and disability. The pathophysiology of the disease is unclear, but it is known that the hypothalamus, the brainstem, and genetic factors, such as the G1246A polymorphism, play a role. A distinction is made between episodic and chronic cluster headaches. In a controlled setting, we treated 29 patients with cluster headaches (13 with chronic cluster and 16 with the episodic form), who had been refractory to conventional treatments, with a low dose of ketamine (an NMDA receptor antagonist) i.v. over 40 min to one hour every 2 weeks or sooner for up to four times. It was observed that the attacks were completely aborted in 100 % of patients with episodic headaches and in 54 % of patients with chronic cluster headaches for a period of 3-18 months. We postulated neuroplastic brain repair and remodulation as possible mechanisms.

Chronic pain results in structural and functional changes of the brain. However, most of the neurophysiologic and imaging studies have been conducted with small sample sizes, some have been reproduced, but studies on larger populations are lacking. Larger epidemiologic studies are currently being performed to show specific structural changes due to chronic pain. Longitudinal studies using neurophysiologic or imaging methods are very rare and often not feasible. Most methods are very complex, which hampers their application in daily practice. But it is not only the complexity of methods, but also a lack of interaction between researchers and practitioners to formulate joint research topics and targets. This article tries to fill the gap between the practicing pain therapist and the researcher in summarizing neurophysiological and imaging results on neuropathic and chronic pain in a clear and simple manner.

Transcranial alternating current stimulation (tACS) is a new technique for the modulation of oscillatory brain activity as measured in the electroencephalogram (EEG). In contrast to well-established stimulation techniques, such as transcranial direct current stimulation and transcranial magnetic stimulation, tACS applies a sinusoidal alternating current at a specific frequency. This enables the modulation of the amplitude and frequency of endogenous brain oscillations as well as related cognitive processes. Therefore, the use of tACS has the possibility to evaluate well-known correlations between brain oscillations and cognitive processes in terms of causality. Such causal relationships have been documented in numerous neurocognitive studies on sensory, motor and perceptual processes; however, the clinical application of tACS is still in its infancy. In principle, any pathology that can reliably be connected with brain oscillations of a defined frequency is treatable. A current main focus of clinical research is on symptoms of Parkinson's disease and to a lesser degree, tinnitus. For an effective application of tACS it is important to choose the electrode positions as well as the frequency, intensity and duration of the stimulation in a theory-based and symptom-related manner. A successful therapeutic intervention requires the persistence of the tACS effect after stimulation has ceased. A mechanism that offers not only an explanation to the origin of persistent tACS effects but is also of high therapeutic benefit is neural plasticity. Therefore, one current focus of research aims at a better understanding of tACS after effects.

In spite of several approved analgesics, the therapy of pain still constitutes a challenge due to the fact that the drugs do not exert sufficient efficacy or are associated with severe side effects. Therefore, the development of new and improved painkillers is still of great importance. A number of highly qualified scientists in Germany are investigating signal transduction pathways in pain, effectivity of new drugs and the so far incompletely investigated mechanisms of well-known analgesics in preclinical and clinical studies. The highlights of pharmacological pain research in Germany are summarized in this article.

This article, without presuming to be comprehensive, gives a brief outline of the development of research on neuropathic pain in Germany. Current clinical research on this subject focusses on the validation of human models, patient phenotyping, mechanism-based classification and treatment as well as on molecular pathomechanisms. This clinical research is based to a large extent on the work of several internationally recognized basic researchers in the 1990s. In particular, findings from system physiology led to the analysis of clinical phenotypes and the underlying pathophysiology. In parallel, basic research achieved international top levels through the development of innovative methods. Close cooperation, building of consortia and European networking made major contributions to the success of this research.

Modern neuroimaging techniques, such as structural and functional magnetic resonance imaging (MRI) and non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) are increasingly used in the neuroscientific research of neurological disorders, such as stroke, tinnitus and movement disorders. These methods offer a non-invasive approach and especially in combination, not only the opportunity to add to the pathophysiological understanding of these disorders but also to provide information about the functional recovery and the natural course of the disease in a predictive way. Based on such knowledge therapeutic approaches can be adapted in a patient-tailored fashion to achieve the best therapeutic effects. Furthermore, these methods might provide additional non-invasive information for neurosurgical interventions reducing perioperative interventional risks.In the present article these aspects will be discussed with a focus on the combination of MRI and TMS especially addressed for the topic of recovery from stroke.

Stroke induces structural and functional changes within the cortical motor network of both hemispheres. Repetitive transcranial magnetic stimulation modulates the excitability of the motor cortex and thereby may facilitate motor function and/or recovery of motor function after stroke. Based on a systematic literature search we identified 33 placebo-controlled trials which examined the effectiveness of repetitive transcranial magnetic stimulation in the treatment of impaired hand function following stroke. Despite limitations, the majority of the studies referred to the interhemispheric competition model after stroke to apply repetitive transcranial magnetic stimulation. In a comparative approach, methodology and effectiveness of (a) inhibition of the unaffected hemisphere, (b) facilitation of the affected hemisphere and (c) combined application of repetitive transcranial magnetic stimulation over the affected and unaffected hemispheres to treat impaired hand function after stroke are presented. Problems and limitations of repetitive transcranial magnetic stimulation in stroke rehabilitation are discussed and visions for future clinical research are presented.

Intrakranielle Blutungen, zu denen die intrazerebrale Blutung (ICB), die Subarachnoidalblutung (SAB) und das chronische Subduralhämatom (cSDH) gehören, verlaufen häufig tödlich. Überlebende Patienten weisen oft kognitive Beeinträchtigungen auf. Ziel dieser Arbeit war es, die kognitiven Fähigkeiten im langfristigen Verlauf nach ICB, SAB und cSDH zu überprüfen und dabei vorhandene Entwicklungstendenzen zu bewerten. Es wurden insgesamt 41 Patienten sechs und zwölf Monate nach der Blutung mithilfe einer umfassenden neuropsychologischen Testbatterie untersucht. Bei den ICB-Patienten zeigte sich, dass in verschiedenen Bereichen Defizite vorlagen. Dabei waren vorrangig die Konzentration, die Tempoarbeit und das Gedächtnis betroffen. In den meisten Bereichen kam es zwischen der ersten und zweiten Testung zu Verbesserungen der gezeigten Leistung im Sinne vorhandener kognitiver Plastizität, jedoch blieben manche schlechten Leistungen auch beim zweiten Termin bestehen. Bei der Untersuchung von Faktoren, die die Testergebnisse der ICB-Patienten beeinflussen, fiel auf, dass Patienten mit Hirnstammblutungen insgesamt besser abschnitten als Patienten mit anderen Blutungslokalisationen. Patienten mit arterieller Hypertonie schnitten schlechter ab als Patienten ohne erhöhten Blutdruck. Bei den untersuchten Scores zeigte sich vor allem ein initialer Glasgow-Coma-Score

Lesions of the nervous systems often result in difficult to treat pain syndromes. Neuropathic pain has increasingly gained attention from clinicians as a result of a better understanding of the underlying mechanisms and the development of proven analgesic therapies. This article provides an update on the diagnosis and treatment of neuropathic pain.

Complex regional pain syndrome (CRPS) constitutes an enigmatic post-traumatic pain disorder.The paper provides state of the art knowledge about CRPS.The typical constellation of symptoms of CRPS includes pain, sensory disturbances, motor symptoms, disturbances of the autonomic control of the limbs and trophic changes. These symptoms generalize distally and go beyond single nerve innervation territories. Diagnosis is made based on clinical findings. Three-phase bone scintigraphy may be the best supporting technical investigation. Symptoms typically change during the course of CRPS. In the acute stage inflammatory symptoms prevail and during chronic stages the most expressed findings are related to central neuroplasticity. These findings include hyperalgesia, sensory loss, CRPS movement disorder, body perception disturbances and autonomic symptoms. Medical treatment with anti-inflammatory agents (steroids) or bisphosphonates is most effective in the early stages and DMSO cream might also be beneficial. Administration of i.v. ketamine has been proven effective against CRPS pain and physical therapy with behavioral components, such as pain exposure helps to overcome central reorganization and functional impairment. Psychotherapy should be offered if there are significant comorbidities. All other forms of treatment are more or less empirical. Invasive treatment should be restricted to selected cases and should only be offered in specialized centers.If these recommendations are followed the prognosis for CRPS is not as poor as commonly assumed. Whether this means a return to the previous quality of life is unclear and often depends on very personal factors.

Invasion and metastatic dissemination of tumor cells defines the prognosis of patients with colorectal cancer (CRC). The Abelson interactor 1 (Abi1), a 65 kD substrate of the eponymous Abelson tyrosine kinase, interacts with phosphatidylinositol-3-kinase (PI3K) and heterogeneous nuclear ribonucleoprotein K (hnRNP K) and is a key regulator of cytoskeletal reorganization during synaptic maturation and cellular migration.The aim of this study was the analysis of Abi1 expression patterns and to elucidate the role in cytoskeletal reorganization in colorectal carcinoma cells.The methods used in this study were immunohistochemistry; immunofluorescence microscopy; liposomal transfection and protein analysis by Western blotting.The results showed that Abi1 is expressed at the invasive front of colorectal carcinomas and localizes to the leading edge of lamellipodia in cultured colorectal carcinoma cells. A phosphorylated isoform of Abi1 that stains positively in these microcompartments disappears after treatment with the tyrosine kinase inhibitor STI571 (Glivec®). The RNA interference (RNAi) approach knockdown of Abi1 as well as treatment with STI571 induce a shift in cellular morphology from broad lamellipodia-like to thin filopodia-like cellular protrusions.The initial results support a central role for phosphorylated Abi1 in the formation of lamellipodia-like cellular protrusions as a prerequisite for cellular migration of colorectal carcinoma cells. As phosphorylation of Abi1 could be pharmaceutically targeted with STI571, this indicates a possible therapeutic option to prevent the gain of a metastatic phenotype in colorectal cancer. This possibility will be further evaluated in ongoing research.