Catharina Korsukewitz

High impact running improves learning

Regular physical exercise improves cognitive functions and lowers the risk for age-related cognitive decline. Since little is known about the nature and the timing of the underlying mechanisms, we probed whether exercise also has immediate beneficial effects on cognition. Learning performance was assessed directly after high impact anaerobic sprints, low impact aerobic running, or a period of rest in 27 healthy subjects in a randomized cross-over design. Dependent variables comprised learning speed as well as immediate (1 week) and long-term (>8 months) overall success in acquiring a novel vocabulary. Peripheral levels of brain-derived neurotrophic factor (BDNF) and catecholamines (dopamine, epinephrine, norepinephrine) were assessed prior to and after the interventions as well as after learning. We found that vocabulary learning was 20 percent faster after intense physical exercise as compared to the other two conditions. This condition also elicited the strongest increases in BDNF and catecholamine levels. More sustained BDNF levels during learning after intense exercise were related to better short-term learning success, whereas absolute dopamine and epinephrine levels were related to better intermediate (dopamine) and long-term (epinephrine) retentions of the novel vocabulary. Thus, BDNF and two of the catecholamines seem to be mediators by which physical exercise improves learning.

Tonic Dopaminergic Stimulation Impairs Associative Learning in Healthy Subjects

Endogenous dopamine plays a central role in salience coding during associative learning. Administration of the dopamine precursor levodopa enhances learning in healthy subjects and stroke patients. Because levodopa increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating dopamine-receptor agonist pergolide (0.1 mg) vs placebo 120 min before training on each training day. The dopamine agonist significantly impaired novel word learning compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group. The extent of ‘flattened’ affect with pergolide was related to the degree of learning inhibition. These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals. Thus, phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and stroke patients.

A shift of paradigm: From noradrenergic to dopaminergic modulation of learning?

d-Amphetamine coupled with behavioral training has been effective for improving functional recovery after stroke. d-amphetamine acts on multiple brain transmitter systems, but the recovery enhancing effect has been attributed to its noradrenergic actions. Another potent modulator of learning is dopamine, which may also enhance stroke recovery in humans. Based on data from previous studies of our group, we compared the learning enhancing effects of d-amphetamine with a more selective dopaminergic substance (levodopa) in identical protocols. Using a prospective, randomized, double-blind, placebo-controlled design, we had taught 60 male healthy subjects a miniature lexicon of 50 concrete nouns over the course of five consecutive training days using an associative learning principle. Subjects had received either d-amphetamine (0.25 mg/kg), levodopa/carbidopa (fixed dose of 100/25 mg), or placebo 90 min prior to training on each of the 5 days. Novel word learning was significantly enhanced in both the d-amphetamine and levodopa groups as compared to the placebo group. The learning superiority was maintained at the two re-assessments (1 week and 1 month post training). Both d-amphetamine and levodopa are thus potent drugs in enhancing learning in humans. We here discuss why the efficiency of both d-amphetamine and levodopa may be related to dopaminergic rather than noradrenergic actions.

Executive Performance is Related to Regional Gray Matter Volume in Healthy Older Individuals

Individual differences in executive functioning and brain morphology are considerable. In this study, we investigated their interrelation in a large sample of healthy older individuals. Digit span, trail‐making, and Stroop tasks were used to assess different executive subfunctions in 367 nondemented community‐dwelling individuals (50–81 years). Task performance was analyzed relative to brain structure using voxel‐based morphometry, corrected for age and sex. Improved task performance was associated with increased local gray matter volume in task‐specific patterns that showed partial, but not complete overlap with known task‐specific functional imaging patterns. While all three tasks showed associations with prefrontal gray matter volume as expected for executive functioning, the strongest overlap between the three tasks was found in insular cortex, suggesting that it has a previously underestimated role for executive functions. The association between the insular cortex and executive functioning was corroborated using stereological region‐of‐interest measurement of insular volume in a subgroup of 93 subjects. Quantitatively, the volume of the single most strongly related region explained 2.4 ± 1.1% of the variance in executive performance over and above the variance explained by age, which amounted to 7.4 ± 4.1%. The age‐independent peak associations between executive performance and gray matter described here occurred in regions that were also strongly affected by age‐related gray matter atrophy, consistent with the hypothesis that age‐related regional brain volume loss and age‐related cognitive changes are linked. Hum Brain Mapp 34:3333–3346, 2013.

L-dopa does not add to the success of high-intensity language training in aphasia.

PURPOSE L-dopa has been shown to improve outcome of moderate-intensity language training after stroke in acute aphasia. Given the critical role of training intensity we probed the effect of l-dopa in combination with high-intensity language training in chronic post-stroke aphasia. METHODS In this prospective, randomized, placebo-controlled, double-blind study, aphasia patients (>1 year post stroke) were administered 100/25 mg of l-dopa/carbidopa or placebo daily prior to four hours of language training for two weeks. Conditions were crossed-over after a wash-out period of 4 weeks. RESULTS An a-priori planned interim analysis (n = 10) showed that naming performance and verbal communication improved significantly and persistently for at least 6 months in every patient, but l-dopa had no incremental effect to intensive training. CONCLUSION High-intensity language training in chronic aphasia may take learning to a ceiling that precludes additive benefits from l-dopa. Effects of l-dopa on post-stroke recovery during less intense treatment in chronic aphasia remain to be evaluated.

Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets

Background: Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). Objective: To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. Methods: Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. Results: Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony-stimulating factor (GM-CSF) producing TH1 cells or interleukin (IL)-17-producing TH17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22-producing lymphoid tissue inducer (LTi), the innate counterpart of TH17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. Conclusions: Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.

Prothrombin and factor X are elevated in multiple sclerosis patients

Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls. Individuals suffering from relapsing–remitting and secondary progressive MS had significantly higher prothrombin and factor X levels than healthy donors, whereas levels were unchanged in primary progressive MS and neuromyelitis optica patients. Our study demonstrates that coagulation factors may be key mediators in neuroinflammation and may therefore provide future targets for therapeutic strategies. Ann Neurol 2016;80:946–951

Behr syndrome with homozygous C19ORF12 mutation

OBJECTIVE Behr syndrome, first described in 1909 by the ophthalmologist Carl Behr, is a clinical entity characterised by a progressive optic atrophy, ataxia, pyramidal signs and mental retardation. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder. METHODS We present the long-term observation of two Turkish sisters with Behr syndrome. We performed neurophysiological, imaging and molecular genetic studies to identify the underlying genetic cause in our patients. RESULTS Magnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis. Molecular genetic studies revealed a homozygous mutation in the C19ORF12 gene which has been previously reported in patients with a subtype of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). CONCLUSION We expand the spectrum of genetic causes of Behr syndrome. Genetic testing of patients presenting with Behr syndrome should include C19ORF12 mutation screening.

Present status and future possibilities of adjuvant pharmacotherapy for aphasia

ZusammenfassungEine Aphasie zählt zu den häufigsten und subjektiv schwerwiegendsten Folgen eines Schlaganfalls. Angesichts einer geringen Spontanerholung und der beschränkten Wirksamkeit konventioneller Sprachtherapie stellt sich die Frage nach Möglichkeiten der Therapieverbesserung. Neben einer Steigerung der Trainingsfrequenz — mit täglichen, mehrstündigen Einheiten und einer hohen Wiederholungsrate des Sprachmaterials („massiertes Training“) — bietet sich die Möglichkeit einer adjuvanten Pharmakotherapie. Hier beleuchten wir das Potenzial monoaminerger (Bromocriptin, Levodopa, d-Amphetamin) und cholinerger (Donepezil) Medikamente bei Aphasie. Eine abschließende Wirksamkeitsbewertung einer Kombinationsbehandlung aus massiertem Sprachtraining und pharmakologischer Zusatzbehandlung kann jedoch erst durch Etablierung von Verbundstrukturen und Durchführung hinreichend großer randomisierter, plazebokontrollierter klinischer Studien erfolgen. Neben diesen medikamentösen Strategien erwecken tierexperimentelle Ergebnisse zur Funktionserholung nach Gehirnschädigungen die Hoffnung, dass mittelfristig auch neurotrophe Faktoren oder Stammzellen in der adjuvanten Therapie von Aphasie einen Platz finden werden.SummaryAphasia is one of the most frequent and disabling consequences of stroke. Poor spontaneous recovery and the limited success of conventional speech therapy bring up the question of how current treatment approaches can be improved. Besides increasing training frequency—with daily sessions lasting several hours and high repetition rates of language materials (“massed training”)—adjuvant drug therapy may help to increase therapy efficacy. In this article, we illuminate the potential of monoaminergic (bromocriptine, levodopa, d-amphetamine) and cholinergic (donepezil) substances for treating aphasia. For a final evaluation of combined massed training and adjuvant pharmacotherapy, randomized, placebo-controlled (multicenter) clinical trials with sufficient numbers of patients are needed. Furthermore, results of experimental animal studies of functional recovery in brain damage raise hopes that neurotrophic factors or stem cells might find a place in recovery from aphasia in the intermediate future.

Pharmakologische Zusatzbehandlung in der Aphasietherapie

ZusammenfassungEine Aphasie zählt zu den häufigsten und subjektiv schwerwiegendsten Folgen eines Schlaganfalls. Angesichts einer geringen Spontanerholung und der beschränkten Wirksamkeit konventioneller Sprachtherapie stellt sich die Frage nach Möglichkeiten der Therapieverbesserung. Neben einer Steigerung der Trainingsfrequenz — mit täglichen, mehrstündigen Einheiten und einer hohen Wiederholungsrate des Sprachmaterials („massiertes Training“) — bietet sich die Möglichkeit einer adjuvanten Pharmakotherapie. Hier beleuchten wir das Potenzial monoaminerger (Bromocriptin, Levodopa, d-Amphetamin) und cholinerger (Donepezil) Medikamente bei Aphasie. Eine abschließende Wirksamkeitsbewertung einer Kombinationsbehandlung aus massiertem Sprachtraining und pharmakologischer Zusatzbehandlung kann jedoch erst durch Etablierung von Verbundstrukturen und Durchführung hinreichend großer randomisierter, plazebokontrollierter klinischer Studien erfolgen. Neben diesen medikamentösen Strategien erwecken tierexperimentelle Ergebnisse zur Funktionserholung nach Gehirnschädigungen die Hoffnung, dass mittelfristig auch neurotrophe Faktoren oder Stammzellen in der adjuvanten Therapie von Aphasie einen Platz finden werden.SummaryAphasia is one of the most frequent and disabling consequences of stroke. Poor spontaneous recovery and the limited success of conventional speech therapy bring up the question of how current treatment approaches can be improved. Besides increasing training frequency—with daily sessions lasting several hours and high repetition rates of language materials (“massed training”)—adjuvant drug therapy may help to increase therapy efficacy. In this article, we illuminate the potential of monoaminergic (bromocriptine, levodopa, d-amphetamine) and cholinergic (donepezil) substances for treating aphasia. For a final evaluation of combined massed training and adjuvant pharmacotherapy, randomized, placebo-controlled (multicenter) clinical trials with sufficient numbers of patients are needed. Furthermore, results of experimental animal studies of functional recovery in brain damage raise hopes that neurotrophic factors or stem cells might find a place in recovery from aphasia in the intermediate future.