Jonathan List

Relationship between excitability, plasticity and thickness of the motor cortex in older adults

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimers Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

Intensive speech and language therapy in patients with chronic aphasia after stroke: a randomised, open-label, blinded-endpoint, controlled trial in a health-care setting

BACKGROUND Treatment guidelines for aphasia recommend intensive speech and language therapy for chronic (≥6 months) aphasia after stroke, but large-scale, class 1 randomised controlled trials on treatment effectiveness are scarce. We aimed to examine whether 3 weeks of intensive speech and language therapy under routine clinical conditions improved verbal communication in daily-life situations in people with chronic aphasia after stroke. METHODS In this multicentre, parallel group, superiority, open-label, blinded-endpoint, randomised controlled trial, patients aged 70 years or younger with aphasia after stroke lasting for 6 months or more were recruited from 19 inpatient or outpatient rehabilitation centres in Germany. An external biostatistician used a computer-generated permuted block randomisation method, stratified by treatment centre, to randomly assign participants to either 3 weeks or more of intensive speech and language therapy (≥10 h per week) or 3 weeks deferral of intensive speech and language therapy. The primary endpoint was between-group difference in the change in verbal communication effectiveness in everyday life scenarios (Amsterdam-Nijmegen Everyday Language Test A-scale) from baseline to immediately after 3 weeks of treatment or treatment deferral. All analyses were done using the modified intention-to-treat population (those who received 1 day or more of intensive treatment or treatment deferral). This study is registered with ClinicalTrials.gov, number NCT01540383. FINDINGS We randomly assigned 158 patients between April 1, 2012, and May 31, 2014. The modified intention-to-treat population comprised 156 patients (78 per group). Verbal communication was significantly improved from baseline to after intensive speech and language treatment (mean difference 2·61 points [SD 4·94]; 95% CI 1·49 to 3·72), but not from baseline to after treatment deferral (-0·03 points [4·04]; -0·94 to 0·88; between-group difference Cohens d 0·58; p=0·0004). Eight patients had adverse events during therapy or treatment deferral (one car accident [in the control group], two common cold [one patient per group], three gastrointestinal or cardiac symptoms [all intervention group], two recurrent stroke [one in intervention group before initiation of treatment, and one before group assignment had occurred]); all were unrelated to study participation. INTERPRETATION 3 weeks of intensive speech and language therapy significantly enhanced verbal communication in people aged 70 years or younger with chronic aphasia after stroke, providing an effective evidence-based treatment approach in this population. Future studies should examine the minimum treatment intensity required for meaningful treatment effects, and determine whether treatment effects cumulate over repeated intervention periods. FUNDING German Federal Ministry of Education and Research and the German Society for Aphasia Research and Treatment.

A new case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

Sir, We read with great interest the recent article published in Brain by Pittock and colleagues (2010) describing eight patients with a previously unrecognized distinct brainstem encephalitis named chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Here, we report on what we believe to be another patient with CLIPPERS, lending further support to the concept that CLIPPERS is a novel, definable, inflammatory CNS disease. The patient provided written informed consent for presentation of her case as a report. A 69-year-old female noticed general weakness, dizziness and abnormal fatigue with subacute onset 16 weeks prior to evaluation at the Department of Neurology, Charite, Universitatsmedizin, Berlin. Eleven weeks prior, the patient developed horizontal diplopia and walking difficulties that gradually worsened so that she became unable to walk without assistance. Additionally, she noticed dysarthria and dysphagia as well as facial tingling and paraesthesia in her fingertips. About 4 weeks prior to admission, she developed hyperacusis and a labile affect with involuntary crying. Her past medical history was unremarkable except for arterial hypertension, which was treated with bisoprolol. Her family history was negative. Neurological examination on admission revealed a cerebellar syndrome with limb, gait and stance ataxia, as well as intention tremor on the left, more than on the right-hand side. She had marked cerebellar dysarthria. Her gait …

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.

Cognitive function and brain structure after recurrent mild traumatic brain injuries in young-to-middle-aged adults

Recurrent mild traumatic brain injuries (mTBIs) are regarded as an independent risk factor for developing dementia in later life. We here aimed to evaluate associations between recurrent mTBIs, cognition, and gray matter volume and microstructure as revealed by structural magnetic resonance imaging (MRI) in the chronic phase after mTBIs in young adulthood. We enrolled 20 young-to-middle-aged subjects, who reported two or more sports-related mTBIs, with the last mTBI > 6 months prior to study enrolment (mTBI group), and 21 age-, sex- and education matched controls with no history of mTBI (control group). All participants received comprehensive neuropsychological testing, and high resolution T1-weighted and diffusion tensor MRI in order to assess cortical thickness (CT) and microstructure, hippocampal volume, and ventricle size. Compared to the control group, subjects of the mTBI group presented with lower CT within the right temporal lobe and left insula using an a priori region of interest approach. Higher number of mTBIs was associated with lower CT in bilateral insula, right middle temporal gyrus and right entorhinal area. Our results suggest persistent detrimental effects of recurrent mTBIs on CT already in young-to-middle-aged adults. If additional structural deterioration occurs during aging, subtle neuropsychological decline may progress to clinically overt dementia earlier than in age-matched controls, a hypothesis to be assessed in future prospective trials.

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. Hum Brain Mapp, 2013.

Impact of tDCS on cerebral autoregulation in aging and in patients with cerebrovascular diseases

Following seminal articles on the technique and underlying mechanisms of transcranial direct current stimulation (tDCS) at the turn of this century,1 tDCS has gained special attention in neurorehabilitative research, given its ability to modulate brain function in a polarity-specific manner in stroke patients together with an excellent safety profile.2 However, an important safety concern emerged recently with regard to its impact on cerebral autoregulation, given a report on decreased autoregulation after 15 minutes anodal tDCS (atDCS) over primary motor cortex (M1) in young healthy subjects.3 Cerebral autoregulation, assessed by vasomotor reactivity (VMR), reflects the autonomic ability of cerebral arterioles to dilate following a vasodilatory stimulus. It is consistently decreased in patients with cerebrovascular diseases,4 and has been linked to stroke risk.5 Thus, a decrease of VMR after atDCS may be harmful to patients with already impaired VMR, such as stroke patients.4 Importantly, >40 ongoing trials with stroke patients and atDCS are registered on www.clinicaltrials.gov as of May 2014. Thus, the concerns raised by Vernieri et al.3 may carry important clinical implications.

Effects of Different Analysis Strategies on Paired Associative Stimulation. A Pooled Data Analysis from Three Research Labs.

Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to non-invasively induce synaptic plasticity in the human brain in vivo. Altered PAS-induced plasticity has been demonstrated for several diseases. However, researchers are faced with a high inter- and intra-subject variability of the PAS response. Here, we pooled original data from nine PAS studies from three centers and analyzed the combined dataset of 190 healthy subjects with regard to age dependency, the role of stimulation parameters and the effect of different statistical methods. We observed no main effect of the PAS intervention over all studies (F(2;362) = 0.44; p = 0.644). The rate of subjects showing the expected increase of motor evoked potential (MEP) amplitudes was 53%. The PAS effect differed significantly between studies as shown by a significant interaction effect (F(16;362) = 1.77; p = 0.034) but post-hoc testing did not reveal significant effects after correction for multiple tests. There was a trend toward increased variability of the PAS effect in older subjects. Acquisition parameters differed across studies but without systematically influencing changes in MEP-size. The use of post/baseline quotients systematically indicated stronger PAS effects than post/baseline difference or the logarithm of the post/baseline quotient. The non-significant PAS effects across studies and a wide range of responder rates between studies indicate a high variability of this method. We were thus not able to replicate findings from a previous meta-analysis showing robust effects of PAS. No pattern emerged regarding acquisition parameters that at this point could guide future studies to reduce variability and help increase response rate. For future studies, we propose to report the responder rate and recommend the use of the logarithmized post/baseline quotient for further analyses to better address the possibility that results are driven by few extreme cases.

Cortical Reorganization Due to Impaired Cerebral Autoregulation in Individuals With Occlusive Processes of the Internal Carotid Artery

BACKGROUND AND PURPOSE To study the impact of impaired cerebral autoregulation on cortical neurophysiology, long term potentiation (LTP)-like plasticity, motor learning and brain structure. METHODS 12 patients with unilateral occlusion or severe stenosis of the internal carotid artery were included. Impairment of cerebral autoregulation was determined by vasomotor reactivity in transcranial Doppler sonography. Corticomotor excitability, cortical silent period and LTP-like plasticity were assessed with transcranial magnetic stimulation, motor learning with a force production task, and brain structure with high-resolution MRI of the brain. RESULTS In the affected hemisphere, corticomotor excitability was significantly higher, cortical silent period and LTP-like plasticity significantly lower, compared to the contralateral side. No significant difference emerged for motor learning, cortical thickness and white matter integrity between the hemispheres. CONCLUSION Despite decreased LTP-like plasticity in the affected hemisphere, motor learning was comparable between hemispheres, possibly due to gamma-aminobutyric-acid (GABA)B-mediated corticomotor excitability changes within the affected hemisphere. Our results may help to develop interventions to beneficially modulate cortical physiology in the presence of cerebral hypoperfusion.

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.