Amyloid pathology and axonal injury after brain trauma.

OBJECTIVE: To image ß-amyloid (Aß) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aß are correlated, and compare the spatial distribution of Aß to Alzheimer disease (AD). METHODS: Patients 11 months to 17 years after moderate-severe TBI underwent (11)C-Pittsburgh compound B ((11)C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of (11)C-PiB, which index Aß plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with (11)C-PiB BPND. RESULTS: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased (11)C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. CONCLUSIONS: Increased Aß burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

The role of the right inferior frontal gyrus in the pathogenesis of post-stroke psychosis.

Psychotic symptoms have previously been reported following right hemisphere brain injury. We sought to identify the specific neuroanatomical basis of delusions following stroke by studying a series of patients with post-stroke psychosis. Lesion overlap analysis was conducted on three individuals with delusions following right hemisphere stroke. These cases were compared with a control group of patients with similar anatomical damage. The main outcome measures were presence of delusions and presence of behavioural susceptibility. The right inferior frontal gyrus and underlying white matter, including the superior longitudinal fasciculus and anterior corona radiata, were involved in all three cases. All three had a preexisting untreated psychiatric disorder. In contrast, only one of nine control cases with equivalent lesions had evidence of previous psychiatric disorder (p = 0.0182, Fisher's exact test), and this was being treated at the time of stroke. We provide clinical evidence from patients with structural brain lesions implicating damage to the right inferior frontal lobe in the generation of persistent psychosis following stroke. We suggest that preexisting psychiatric disease provided a behavioural susceptibility to develop delusions in these individuals.

FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: neural correlates and prognostic indicators.

RATIONALE: Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy. AIMS: To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. DESIGN: Randomized, controlled, observer-blind trial. STUDY: The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks. OUTCOMES AND ANALYSIS: Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain-muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model.

Salience network integrity predicts default mode network function after traumatic brain injury.

Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)--which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae--regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.

Default mode network connectivity predicts sustained attention deficits after traumatic brain injury.

Traumatic brain injury (TBI) frequently produces impairments of attention in humans. These can result in a failure to maintain consistent goal-directed behavior. A predominantly right-lateralized frontoparietal network is often engaged during attentionally demanding tasks. However, lapses of attention have also been associated with increases in activation within the default mode network (DMN). Here, we study TBI patients with sustained attention impairment, defined on the basis of the consistency of their behavioral performance over time. We show that sustained attention impairments in patients are associated with an increase in DMN activation, particularly within the precuneus and posterior cingulate cortex. Furthermore, the interaction of the precuneus with the rest of the DMN at the start of the task, i.e., its functional connectivity, predicts which patients go on to show impairments of attention. Importantly, this predictive information is present before any behavioral evidence of sustained attention impairment, and the relationship is also found in a subgroup of patients without focal brain damage. TBI often results in diffuse axonal injury, which produces cognitive impairment by disconnecting nodes in distributed brain networks. Using diffusion tensor imaging, we demonstrate that structural disconnection within the DMN also correlates with the level of sustained attention. These results show that abnormalities in DMN function are a sensitive marker of impairments of attention and suggest that changes in connectivity within the DMN are central to the development of attentional impairment after TBI.

Inflammation after trauma: microglial activation and traumatic brain injury.

OBJECTIVE: Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. METHODS: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. RESULTS: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. INTERPRETATION: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed.

Human θ burst stimulation enhances subsequent motor learning and increases performance variability.

Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.

Effectiveness of a community-based low intensity exercise programme for ambulatory stroke survivors.

PURPOSE: To establish the feasibility and effectiveness of a community-based exercise programme for ambulatory patients with stroke discharged from rehabilitation. METHOD: Eighteen participants were recruited 3-12 months after onset of first stroke. Using a time series experimental design, the group completed a baseline period of 4 weeks (A1), a group exercise programme of low-intensity progressive resistive exercise and functional tasks for lower limb muscles (B) and repeat assessment after cessation of exercise (A2). Fitness instructors delivered sessions at Leisure Centres twice weekly for 14 weeks with physiotherapy support and the minimum attendance requirement was 16 sessions. Measures included muscle strength, gait velocity, Berg Balance Scale and Nottingham Extended Activities of Daily Living. RESULTS: Lower limb muscle strength improved after training (ANOVA, p < 0.02). Paretic knee extension strength increased from 43.4 + or - 5.9 to 60.4 + or - 6.8 Nm after 16 exercise sessions. Walking velocity increased significantly (ANOVA, p < 0.001), from 0.54 + or - 0.07 to 0.75 + or - 0.08 m/s (t = -3.31, p < 0.01). Balance and everyday function were also significantly improved (p < 0.003). There were marked individual variation in the response to training, and those who completed additional training did not show benefit. CONCLUSIONS: This community-based exercise programme was feasible and delivered positive improvements in physical function for participants. Further issues raised for investigation include the individual response to training and the benefits of extended training.

The facilitatory effects of intermittent theta burst stimulation on corticospinal excitability are enhanced by nicotine.

OBJECTIVE: Intermittent theta burst stimulation (iTBS) is increasingly widely used as a means of facilitating corticospinal excitability in the human primary motor cortex. This form of facilitatory plasticity within the stimulated cortex may occur by induction of long term potentiation (LTP). In animal models, agonists of nicotinic acetylcholine receptors have been shown to modulate or induce LTP; we thus sought to test whether nicotine may modulate the effects of iTBS on corticospinal excitability in humans. METHODS: A double-blind placebo-controlled cross-over design study was conducted with 10 healthy subjects. iTBS was delivered 60min after subjects took either 4mg nicotine or placebo lozenges, and motor-evoked potentials (MEPs) were then recorded for 40min after the end of stimulation. RESULTS: In the placebo arm, iTBS produced an increase in the amplitudes of MEPs which lasted for 5min. In the nicotine arm, iTBS produced a more pronounced facilitation of MEPs that was still present at 40min. In a control experiment, nicotine alone had no effect on MEP amplitudes when given in the absence of iTBS. CONCLUSIONS: These data indicate that the effects of iTBS can be enhanced and prolonged by nicotine. SIGNIFICANCE: These results are consistent with animal models demonstrating nicotinic modulation of facilitatory plasticity, and will be of interest to investigators seeking to enhance artificially induced changes in cortical excitability.

Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology.

Reorganization of motor circuits in the cerebral cortex is thought to contribute to recovery following stroke. These can be examined with transcranial magnetic stimulation (TMS) using measures of corticospinal tract integrity and intracortical excitability. However, little is known about how these changes develop during the important early period post-stroke and their influence on recovery. We used TMS to obtain multiple measures bilaterally in a group of 10 patients during the early days and weeks and up to 6 months post-stroke, in order to examine correlations with tests of hand function. Ten age-matched healthy subjects were also studied. After stroke, day-to-day variation in performance was unrelated to physiological measures in the first 3 weeks. Measures of corticospinal integrity averaged over the same period correlated well with hand function, but this relationship became weaker at 3 months. In contrast, most intracortical excitability measures did not correlate acutely but did so strongly at 3 months. Thus in the acute stage, patients' performance is limited by damage to corticospinal output. Improved performance at 3 months may depend on reorganization in alternative cortical networks to maximize the efficiency of remaining corticospinal pathways--intracortical disinhibition may aid recovery by promoting access to these networks.

Recurrent stroke: where do we stand with the secondary prevention of noncardioembolic ischaemic strokes?

Strokes recur in 6-20% of the patients, most commonly within the first year; after a TIA or minor stroke; most recurrences will occur within the first 90 days. Our ability to identify patients at high risk is poor and most recurrent strokes cannot be explained by traditional risk factors. In 30-45% of the cases the second stroke will be of a different subtype. Moreover, patients are faced with other risks, like cardiac events and cognitive decline. With the population aging, the need for timely and effective secondary prevention strategies is more pressing than ever. This paper summarizes recent advances in pharmacological secondary prevention after a non-cardioembolic ischaemic stroke, and highlights critical questions still in need of answers.

The relationship between brain activity and peak grip force is modulated by corticospinal system integrity after subcortical stroke.

In healthy human subjects, the relative contribution of cortical regions to motor performance varies with the task parameters. Additionally, after stroke, recruitment of cortical areas during a simple motor task varies with corticospinal system integrity. We investigated whether the pattern of motor system recruitment in a task involving increasingly forceful hand grips is influenced by the degree of corticospinal system damage. Nine chronic subcortical stroke patients and nine age-matched controls underwent functional magnetic brain imaging whilst performing repetitive isometric hand grips. Target grip forces were varied between 15% and 45% of individual maximum grip force. Corticospinal system functional integrity was assessed with transcranial magnetic stimulation. Averaged across all forces, there was more task-related activation compared with rest in the secondary motor areas of patients with greater corticospinal system damage, confirming previous reports. However, here we were primarily interested in regional brain activation, which covaried with the amount of force generated, implying a prominent executive role in force production. We found that in control subjects and patients with lesser corticospinal system damage, signal change increased linearly with increasing force output in contralateral primary motor cortex, supplementary motor area and ipsilateral cerebellum. In contrast, in patients with greater corticospinal system damage, force-related signal changes were seen mainly in contralesional dorsolateral premotor cortex, bilateral ventrolateral premotor cortices and contralesional cerebellum, but not ipsilesional primary motor cortex. These findings suggest that the premotor cortices might play a new and functionally relevant role in controlling force production in patients with more severe corticospinal system disruption.

A method for quantifying directional strength and motor control of the trunk.

We describe a new apparatus for studying trunk motor control. Quasi-isometric trunk forces are exerted in any horizontal direction while seated, with or without the pelvis stabilised. Trunk force magnitude and direction are measured using a novel transducing system. In addition, reaction forces between the buttocks and the seat and between each foot and the ground are measured with three force plates. Twenty-four healthy subjects exerted maximal forces in eight directions, with and without pelvis fixation. Accuracy of trunk force measurements was assessed by comparing them with reaction force measurements. The agreement analysis showed a small mean bias of the new system of -3.0 N for force magnitude and 0.72 degrees for force direction. The trunk force measurement system was sensitive enough to detect effects of movement direction and pelvis fixation on maximum force magnitude. When subjects repeated the test at a later date there were no significant differences between the two sessions. In conclusion, the new device allows measurement of static and dynamic aspects of voluntary trunk activation in multiple directions while seated and provides reproducible measurements for application to longitudinal studies. The method should prove useful for quantifying deficits and recovery of trunk motor control following neurological damage.

Motor system activation after subcortical stroke depends on corticospinal system integrity.

Movement-related brain activation patterns after subcortical stroke are characterized by relative overactivations in cortical motor areas compared with controls. In patients able to perform a motor task, overactivations are greater in those with more motor impairment. We hypothesized that recruitment of motor regions would shift from primary to secondary motor networks in response to impaired functional integrity of the corticospinal system (CSS). We measured the magnitude of brain activation using functional MRI during a motor task in eight chronic subcortical stroke patients. CSS functional integrity was assessed using transcranial magnetic stimulation to obtain stimulus/response curves for the affected first dorsal interosseus muscle, with a shallower gradient representing increasing disruption of CSS functional integrity. A negative correlation between the gradient of stimulus/response curve and magnitude of task-related brain activation was found in several motor-related regions, including ipsilesional posterior primary motor cortex [Brodmann area (BA) 4p], contralesional anterior primary motor cortex (BA 4a), bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral prefrontal cortex and contralesional superior cingulate sulcus. There were no significant positive correlations in any brain region. These results suggest that impaired functional integrity of the CSS is associated with recruitment of secondary motor networks in both hemispheres in an attempt to generate motor output to spinal cord motoneurons. Secondary motor regions are less efficient at generating motor output so this reorganization can only be considered partially successful in reducing motor impairment after stroke.

Observations on the human rejection behaviour syndrome: Denny-Brown revisited.

The parietal avoiding-rejection behaviour syndrome, first described by Denny-Brown in the rhesus monkey, has been reported only rarely in humans. Here, we describe a patient with rejection behaviour in the setting of progressive cognitive decline accompanied by cortical myoclonus.