Impaired Autonomic Responses to Emotional Stimuli in Autoimmune Limbic Encephalitis.

Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular, the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2) antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence, and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala.

Cortical plasticity is preserved in nondemented older individuals with severe ischemic small vessel disease.

Ischemic small vessel disease (SVD) is a common finding on routine scans in older people, but cognitive sequelae vary considerably. To improve understanding of mechanisms underlying decline or preservation of cognitive function in this condition, we assessed cognition and cortical plasticity in 20 elderly subjects with severe SVD and 20 age-matched controls without SVD, as rated on conventional MRI. Cognitive status was determined with a neuropsychological test battery, cortical plasticity induced with a paired associative stimulation protocol. Microstructural white matter changes were further analyzed for fractional anisotrophy using diffusion tensor imaging. We found that cortical plasticity as well as memory functions were preserved in severe SVD, while executive functions showed trendwise or significant decreases. Within the SVD group, lower white matter integrity in parahippocampal regions and posterior parts of the corpus callosum was associated with larger cortical plasticity, an association not seen for prefrontal white matter tracts. Enhanced cortical plasticity in subjects with lower white matter integrity in memory-relevant areas might thus indicate a compensatory mechanism to counteract memory decline in severe SVD.

Reperfusion does not improve impaired rapid-onset cortical plasticity in patients with severe stenosis of the internal carotid artery.

BACKGROUND: Severe stenosis of the internal carotid artery (ICA) has been associated with impaired cognition in patients, but its effect on rapid-onset cortical plasticity is not known. Carotid endarterectomy (CEA) in patients with severe ICA stenosis reduces stroke risk, but the impact on cognition or physiology of the respective hemisphere remains controversial. METHODS/RESULTS: 16 patients with severe stenosis of the ICA and 16 age and sex matched controls were included. Rapid-onset cortical plasticity was assessed using the paired-associative stimulation (PAS) protocol. PAS models long-term synaptic potentiation in human motor cortex, combining repetitive stimulation of the peripheral ulnar nerve with transcranial magnetic stimulation of the contralateral motor cortex. Cognitive status was assessed with a neuropsychological test battery. In patients, verbal learning and rapid-onset cortical plasticity were significantly reduced as compared to controls. Identical follow-up tests in 9 of the 16 patients six months after CEA revealed no improvement of cognitive parameters or cortical plasticity. CONCLUSIONS: Decreased rapid-onset cortical plasticity in patients with severe stenosis of the ICA was not improved by reperfusion. Thus, other strategies known to increase plasticity should be tested for their potential to improve cortical plasticity and subsequently cognition in these patients.

Interaction of BDNF and COMT polymorphisms on paired-associative stimulation-induced cortical plasticity.

The common single-nucleotide polymorphism (SNP) brain-derived neurotrophic factor (BDNF) valine-to-methionine substitution at codon 66 (Val66Met) has been associated with differences in memory functions and cortical plasticity following brain stimulation. Other studies could not confirm these results, though, and potential interactions of BDNF carrier status with other learning-relevant SNPs are largely unknown. The present study aimed to evaluate the effects of BDNF Val66Met genotype on paired associative stimulation (PAS)-induced motor cortex plasticity, while additionally taking catechol-O-methyltransferase (COMT) Val158Met and kidney and brain (KIBRA) rs17070145 carrier status into account. Therefore, a cohort of 2 × 16 age- and education-matched healthy young females underwent transcranial magnetic stimulation using an excitatory PAS(25) protocol to induce cortical plasticity. Cognitive performance was assessed using implicit grammar- and motor-learning tasks and a detailed neuropsychological test battery. While BDNF carrier status alone did not significantly influence PAS-induced cortical plasticity, we found a significant BDNF × COMT interaction, showing higher plasticity immediately following the PAS(25) protocol for the BDNF Val/Val vs Met genotype in COMT Met homozygotes only (ANOVA, p = 0.027). A similar advantage for this group was noted for implicit grammar learning (ANOVA, p = 0.021). Accounting for KIBRA rs17070145 did not explain significant variance. Our findings for the first time demonstrate an interaction of BDNF by COMT on human cortical plasticity. Moreover, they show that genotype-related differences in neurophysiology translate into behavioral differences. These findings might contribute to a better understanding of the mechanisms of interindividual differences in cognition.

Age affects chunk-based, but not rule-based learning in artificial grammar acquisition.

Explicit learning is well known to decline with age, but divergent results have been reported for implicit learning. Here, we assessed the effect of aging on implicit vs. explicit learning within the same task. Fifty-five young (mean 32 years) and 55 elderly (mean 64 years) individuals were exposed to letter strings generated by an artificial grammar. Subsequently, participants classified novel strings as grammatical or nongrammatical. Acquisition of superficial ("chunk-based") and structural ("rule-based") features of the grammar were analyzed separately. We found that overall classification accuracy was diminished in the elderly, driven by decreased performance on items that required chunk-based knowledge. Performance on items requiring rule-based knowledge was comparable between groups. Results indicate that rule-based and chunk-based learning are differentially affected by age: while rule-based learning, reflecting implicit learning, is preserved, chunk-based learning, which contains at least some explicit learning aspects, declines with age. Our findings may explain divergent results on implicit learning tasks in previous studies on aging. They may also help to better understand compensatory mechanisms during the aging process.

Non-invasive brain stimulation improves object-location learning in the elderly.

Remembering the location of objects, an integral part of everyday life, is known to decline with advancing age and early in the course of neurodegenerative dementia. Here, we aimed to test if object-location learning and its retention could be modified by noninvasive brain stimulation. In a group of 20 elderly (mean age 62.1 years) right-handed individuals, we applied transcranial direct current stimulation (tDCS; 20 minutes, 1 mA) over the right temporoparietal cortex, while subjects acquired the correct position of buildings on a street map using an associative learning paradigm. Each subject participated in a randomized and balanced order in 1 session of anodal tDCS and 1 session of sham stimulation, in a double-blind design with 2 parallel versions of the task. Outcome measures were learning success at the end of each session, and immediate as well as delayed (1 week) free recall. We found that subjects performed comparably in the learning task in the 2 conditions, but showed improved recall 1 week after learning with anodal tDCS compared with learning with sham stimulation. In conclusion, retention of object-location learning in the elderly may be modulated by noninvasive brain stimulation, a finding of potential relevance not only for normal aging but also for memory deficits in pathological aging.

Enhanced rapid-onset cortical plasticity in CADASIL as a possible mechanism of preserved cognition.

Ischemic small vessel disease (SVD) may lead to cognitive impairment, but cognitive deficits with a given burden of SVD vary significantly. The underlying mechanisms of impaired or preserved cognition are unknown. Here, we investigated the impact of ischemic SVD on rapid-onset cortical plasticity, as induced with a paired-associative stimulation protocol. To exclude concomitant effects of aging, we examined 12 middle-aged patients (48.3 ± 8.3 years) with cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) who suffered from severe ischemic SVD and a group of 12 age-matched controls (49.9 ± 8.3 years). Cognitive status, motor performance and learning, and motor cortex excitability in response to cathodal transcranial direct current stimulation (ctDCS) were assessed. White matter integrity was analyzed by conventional magnetic resonance imaging and diffusion tensor imaging. We found that cognitive and motor functions were largely preserved in CADASIL patients, while rapid-onset cortical plasticity was significantly higher in the CADASIL group compared with controls (repeated measures analysis of variance [group × time] interaction: P = 0.03). This finding was even more pronounced in patients with higher white matter lesion load. ctDCS revealed no evidence of cortical dysplasticity. We conclude that increased rapid-onset cortical plasticity may contribute to largely preserved cognitive and motor function despite extensive ischemic SVD.