Updating beliefs beyond the here-and-now: the counter-factual self in anosognosia for hemiplegia.

The syndrome of anosognosia for hemiplegia, or the lack of awareness for one's paralysis following right hemisphere stroke, can provide unique insights into the neurocognitive mechanisms of self-awareness. Yet it remains unclear whether anosognosia for hemiplegia is a modality-specific deficit of sensorimotor monitoring, or whether domain-general processes of attention and belief-updating converge to cause anosognosia for hemiplegia. Using a Bayesian learning framework, we formalized and empirically investigated the hypothesis that failures to update anosognosic beliefs can be explained by abnormalities in the relative uncertainty (i.e. precision) ascribed to prior beliefs versus sensory information in different contexts. We designed a new motor belief-updating task that manipulated both the temporal (prospective and retrospective) and spatial (hemispace most affected by inattention and hemispace less affected by inattention) conditions in which beliefs had to be updated, and we validated its sensitivity to anosognosia for hemiplegia in 26 patients with right hemisphere stroke. We then computed and empirically tested two different Bayesian predictors of prospective beliefs using two proxies for precision in anosognosia for hemiplegia patients: (i) standardized, neuropsychological measures of objective attention abilities, i.e. visuospatial neglect scores and (ii) subjective uncertainty reports, i.e. confidence ratings. Our results suggest that while neglect does not affect local, sensorimotor error monitoring, it does seem to affect the degree to which observed errors are used to update more general, prospective beliefs about counterfactual motor abilities in anosognosia for hemiplegia. Difficulties in such 'counterfactual' belief-updating were associated with disruptions in tracts of the ventral attentional network (i.e. superior longitudinal fasciculus connecting the temporo-parietal junction and ventral frontal cortex) and associated lesions to the insula, inferior parietal cortex and superior temporal regions. These results suggest that self-awareness extends beyond local, retrospective monitoring, requiring also salience-based, convergence of beliefs about the self that go beyond the 'here-and-now' of sensorimotor experience.

Exploratory Randomized Double-Blind Placebo-Controlled Trial of Botulinum Therapy on Grasp Release After Stroke (PrOMBiS).

Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain. Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke. Methods. A total of 28 patients, at least 1 month poststroke, were randomized to receive either onabotulinumtoxinA or placebo injections to the affected upper limb followed by standardized upper-limb physiotherapy (10 sessions over 4 weeks). The primary outcome was time to release grasp during a functionally relevant standardized task. Secondary outcomes included measures of wrist and finger spasticity and strength using a customized servomotor, clinical assessments of stiffness (modified Ashworth Scale), arm function (Action Research Arm Test [ARAT], Nine Hole Peg Test), arm use (Arm Measure of Activity), Goal Attainment Scale, and quality of life (EQ5D). Results. There was no significant difference between treatment groups in grasp release time 5 weeks post injection (placebo median = 3.0 s, treatment median = 2.0 s; t(24) = 1.20; P = .24; treatment effect = -0.44, 95% CI = -1.19 to 0.31). None of the secondary measures passed significance after correcting for multiple comparisons. Both groups achieved their treatment goals (placebo = 65%; treatment = 71%), and made improvements on the ARAT (placebo +3, treatment +5) and in active wrist extension (placebo +9°, treatment +11°). Conclusions. In this group of stroke patients with mild to moderate spastic hemiparesis, a single treatment with onabotulinumtoxinA did not augment the improvements seen in grasp release time after a standardized upper-limb physiotherapy program.

Theta burst magnetic stimulation over the pre-supplementary motor area improves motor inhibition.

BACKGROUND: Stopping an ongoing motor response or resolving conflict induced by conflicting stimuli are associated with activation of a right-lateralized network of inferior frontal gyrus (IFG), pre-supplementary motor area (pre-SMA) and subthalamic nucleus (STN). However, the roles of the right IFG and pre-SMA in stopping a movement and in conflict resolution remain unclear. We used continuous theta burst stimulation (cTBS) to examine the involvement of the right IFG and pre-SMA in inhibition and conflict resolution using the conditional stop signal task. METHODS: We measured stop signal reaction time (SSRT, measure of reactive inhibition), response delay effect (RDE, measure of proactive action restraint) and conflict induced slowing (CIS, measure of conflict resolution). RESULTS: Stimulation over the pre-SMA resulted in significantly shorter SSRTs (improved inhibition) compared to sham cTBS. This effect was not observed for CIS, RDE, or any other measures. cTBS over the right IFG had no effect on SSRT, CIS, RDE or on any other measure. CONCLUSIONS: The improvement of SSRT with cTBS over the pre-SMA suggests its critical contribution to stopping ongoing movements.

Inhibitory theta burst stimulation of affected hemisphere in chronic stroke: a proof of principle, sham-controlled study.

Non-invasive brain stimulation is presently being tested as a potential therapeutic intervention for stroke rehabilitation. Following a model of competitive interactions between the hemispheres, these interventions aim to increase the plasticity of stroke hemisphere by applying either excitatory protocols to the damaged hemisphere or inhibitory protocols to the non-stroke hemisphere. Here we test the safety and feasibility of using an inhibitory protocol on the stroke hemisphere to improve the response to conventional therapy via a homeostatic increase in learning capacity. Twelve chronic stroke patients received TBS to stroke hemisphere (6 patients inhibitory TBS and 6 sham TBS) followed by physical therapy daily for 10 working days. Patients and therapists were blinded to the type of TBS. Action Research Arm Test (ARAT), Nine-Hole Pegboard Test (NHPT) and Jebsen-Taylor Test (JTT) were the primary outcome measures, grip and pinch-grip dynamometry were the secondary outcome measures. All patients improved ARAT and JTT scores for up to 3 months post-treatment. ARAT scores improved significantly in both real and sham groups, but only patients receiving real TBS significantly improved on the JTT: 3 months post-treatment mean execution time was reduced compared to baseline by 141 s for real group and by 65s for the sham group. This small exploratory study suggests that ipsilesional inhibitory TBS is safe and that it has the potential to be used in a larger trial to enhance the gain from a late rehabilitation program in chronic stroke patients.

Theta burst stimulation in the rehabilitation of the upper limb: a semirandomized, placebo-controlled trial in chronic stroke patients.

BACKGROUND: Noninvasive cortical stimulation could represent an add-on treatment to enhance motor recovery after stroke. However, its clinical value, including anticipated size and duration of the treatment effects, remains largely unknown. OBJECTIVE: The authors designed a small semi-randomized clinical trial to explore whether long-lasting clinically important gains can be achieved by adding theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), to a rehabilitation program for the hand. METHODS: A total of 41 chronic stroke patients received excitatory TBS to the ipsilesional hemisphere or inhibitory TBS to the contralesional hemisphere in 2 centers; each active group was compared with a group receiving sham TBS. TBS was followed by physical therapy for 10 working days. Patients and therapists were blinded to the type of TBS. Primary outcome measures (9-hole Peg Test [9HPT], Jebsen Taylor Test [JTT], and grip and pinch-grip dynamometry) were assessed 4, 30, and 90 days post treatment. The clinically important difference was defined as 10% of the maximum score. RESULTS: There were no differences between the active treatment and sham groups in any of the outcome measures. All patients achieved small sustainable improvements--9HPT, 5% of maximum (confidence interval [CI] = 3%-7%); JTT, 5.7% (CI = 3%-8%); and grip strength, 6% (CI = 2%-10%)--all below the defined clinically important level. CONCLUSIONS: Cortical stimulation did not augment the gains from a late rehabilitation program. The effect size anticipated by the authors was overestimated. These results can improve the design of future work on therapeutic uses of TMS.

Age-related changes in causal interactions between cortical motor regions during hand grip.

Brain activity during motor performance becomes more widespread and less lateralized with advancing age in response to ongoing degenerative processes. In this study, we were interested in the mechanism by which this change in the pattern of activity supports motor performance with advancing age. We used both transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) to assess age related changes in motor system connectivity during isometric hand grip. Paired pulse TMS was used to measure the change in interhemispheric inhibition (IHI) from contralateral M1 (cM1) to ipsilateral M1 (iM1) during right hand grip. Dynamic Causal Modelling (DCM) of fMRI data was used to investigate the effect of age on causal interactions throughout the cortical motor network during right hand grip. Bayesian model selection was used to identify the causal model that best explained the data for all subjects. Firstly, we confirmed that the TMS and DCM measures both demonstrated a less inhibitory/more facilitatory influence of cM1 on iM1 during hand grip with advancing age. These values correlated with one another providing face validity for our DCM measures of connectivity. We found increasing reciprocal facilitatory influences with advancing age (i) between all ipsilateral cortical motor areas and (ii) between cortical motor areas of both hemispheres and iM1. There were no differences in the performance of our task with ageing suggesting that the ipsilateral cortical motor areas, in particular iM1, play a central role in maintaining performance levels with ageing through increasingly facilitatory cortico-cortical influences.

A distinctive pattern of cortical excitability in patients with the syndrome of dystonia and cerebellar ataxia.

OBJECTIVE: The syndrome of dystonia and cerebellar ataxia (DYTCA) is a recently described condition where cervical dystonia and mild cerebellar ataxia are the major clinical features. Here we attempted to explore the pathophysiology of this condition by comparing measurements of cortical excitability between patients with DYTCA, typical primary dystonia and healthy controls. METHODS: Motor threshold, active MEP recruitment and CSP duration were measured and the excitability of the intracortical inhibitory and excitatory circuits was assessed at rest using a paired pulse protocol. RESULTS: We identified a distinctive pattern of cortical excitability in DYTCA patients different from that found in primary dystonia, namely hyperexcitable short-interval intracortical inhibition. CONCLUSION: DYTCA patients have a noticeably dissimilar excitability profile from patients with primary dystonia. SIGNIFICANCE: A tendency for increased SICI has been previously described in cerebellar syndromes and the altered excitability profile seen in these patients is therefore possibly a consequence of the cerebellar dysfunction in DYTCA. A direct link between reduced intracortical inhibition and dystonia has recently been questioned and our results additionally suggest that reduced motor cortex inhibition is not a prerequisite for dystonia to occur.

Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: a clinical and electrophysiological study.

Approximately 10% of patients diagnosed clinically with early Parkinson's disease (PD) have normal dopaminergic functional imaging (Scans Without Evidence of Dopaminergic Deficit [SWEDDs]). An important subgroup of SWEDDs are those with asymmetric rest tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help to distinguish SWEDDs from PD have not been explored. We therefore studied clinical details including non-motor symptoms in 25 tremulous SWEDDs patients in comparison to 25 tremor-dominant PD patients. Blinded video rating was used to compare examination findings. Electrophysiological tremor parameters and also response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in 9 patients with SWEDDs, 9 with tremor-dominant PD (with abnormal dopamine transporter single photon emission computed tomography findings), 8 with segmental dystonia, and 8 with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favored a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs, and presence of non-motor symptoms favored PD. A single tremor parameter could not differentiate between groups, but the combination of re-emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an abnormal exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help to distinguish between PD and SWEDDs which may be useful in clinical practice. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia.

Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease.

BACKGROUND: Cognition is affected early in Huntington disease (HD), and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. The authors investigated whether there is any evidence for abnormal synaptic plasticity using the human motor cortex-rTMS model and, if so, if there is any difference between premanifest HD gene carriers and very early manifest HD patients or any relationship with ratings of the severity of motor signs. METHODS: Fifteen HD gene carriers (seven premanifest, eight very early manifest) and 14 control participants were given a continuous train of 100 bursts of theta burst stimulation (cTBS: three pulses at 50 Hz and 80% AMT repeated every 200 ms). The size of the motor-evoked potential was measured at regular intervals until 21 min after cTBS. RESULTS: HD gene carriers and controls responded differently to theta burst stimulation (F(4.9,131.9)=1.37, p=0.048) with controls having more inhibition than HD gene carriers (F(1,27)=13.3, p=0.001). Across all time points, mean inhibition differed between the groups (F(2,26)=6.32, p=0.006); controls had more inhibition than either HD gene carrier subgroup (p=0.006 for premanifest and p=0.009 for early symptomatic), whereas there was no difference between premanifest and early symptomatic HD gene carriers. The measure of cortical plasticity was not associated with any clinical ratings (Unified Huntington Disease Rating Scale motor score, estimate of age at onset). CONCLUSIONS: Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD.

A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS.

The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Motor cortical physiology in patients and asymptomatic carriers of parkin gene mutations.

Autosomal recessive parkin (PARK2) gene-related parkinsonism may be phenotypically and pathophysiologically distinct from idiopathic Parkinson's disease (PD). Furthermore, asymptomatic subjects carrying a single parkin mutation ("parkin carriers") may show striatal dopaminergic dysfunction and increased cortical movement-related activation. Here, we used transcranial magnetic stimulation (TMS) to study corticospinal and intracortical excitability in manifesting parkin patients and asymptomatic carriers. We studied resting and active motor thresholds (RMT/AMT), central motor conduction time (CMCT), active recruitment curves, short-interval intracortical inhibition (SICI) and facilitation (ICF), SICI recruitment curve, and cortical silent period (CSP) in 8 patients "off" medication, 7 carriers, and two groups of age-matched controls (n = 21). Patients had longer CMCTs compared to controls with a significant negative correlation between CMCT duration and onset age (r = -0.83, P = 0.04). Carriers had increased RMT/AMT; the time course of SICI/ICF and the duration of CSP were normal in both patients and carriers; however slight abnormalities in the recruitment of SICI were found in the carriers. Prolonged CMCT and normal cortical inhibitory mechanisms in parkin patients may be of value in the differentiation from idiopathic PD. The subclinical electrophysiological abnormalities found in carriers may represent underlying compensatory mechanisms.

Clinical applications of transcranial magnetic stimulation in patients with movement disorders.

Transcranial magnetic stimulation (TMS) is a method of non-invasive brain stimulation that affects the cerebral cortex but not deep structures. In patients with movement disorders the most common application of TMS has been to test the excitability of connections within and among motor areas of the cortex, which has provided useful information on pathophysiology; however, inter-individual variability in the responses has resulted in difficulties in translating this method into a clinically applicable diagnostic use. Repeated stimulation (eg, 1 Hz for 20 min) can result in long-term plastic changes in the motor system, which has led to increased interest in possible therapeutic applications. In this Review, we describe the theoretical background to TMS techniques and discuss the uses of TMS as a potential diagnostic tool in movement disorders. The difficulties in bringing the technique into regular clinical diagnostic practice will be discussed and the evidence for the potential of repetitive TMS as a therapeutic tool in patients with movement disorders will be reviewed.

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.

Recurrent stroke: the role of common carotid artery intima-media thickness.

The etiology of recurrent stroke is probably multifactorial and many recurrences remain unexplained by conventional risk factors. The purpose of this study is to investigate if common carotid artery intima-media thickness (CCA-IMT), an established vascular risk factor, can predict recurrence in first-ever stroke survivors. Two hundred and eighty-four consecutive patients with a first-ever ischemic stroke were investigated with carotid ultrasonography and were screened for the first recurrent stroke up to 12 months. Sixteen (5.6%, 95% CI: 3.5-9.0%) recurrent ischemic strokes were recorded. Among demographic data, conventional vascular risk factors, presenting stroke features and ultrasonographic measurements, CCA-IMT was the only parameter that differed significantly between those who suffered a recurrent stroke and those who did not. Cox's regression analysis adjusted for confounding factors, showed that CCA-IMT was the only independent predictor of stroke recurrence (HR 1.65; 95% CI: 1.11-2.46%). We propose that CCA-IMT measurements may help to identify stroke patients at higher risk for recurrence and to plan secondary prevention strategies.

Does brain stimulation after stroke have a future?

PURPOSE OF REVIEW: Transcranial methods of cortical stimulation can induce long-term changes in excitability of the cerebral cortex in humans and may be useful as therapeutic interventions in stroke rehabilitation. RECENT FINDINGS: Two approaches have been tested: (1) increasing excitability of the cortex in the stroke hemisphere and (2) suppression of the non-stroke hemisphere to reduce potential interference with function of the stroke hemisphere. The interventions have been transcranial direct current stimulation, transcranial magnetic stimulation and implanted epidural stimulation. All have been reported to give 10-20% functional improvement in small numbers of patients in single-session studies as well as in a small number of longer-term therapeutic trials. Preliminary experiments in aphasic patients using transcranial magnetic stimulation in an interference design show, however, that stimulation of the nonstroke hemisphere can in some patients reduce verbal fluency, questioning the general applicability of the second approach. SUMMARY: Cortical stimulation appears to be a safe and promising intervention for stroke patients. More studies are needed to assess its long-term benefits on substantial numbers of patients. We need to know what type of intervention is best, which patients are likely to benefit, the optimum time to intervene and the duration of any benefits.

F wave study in amyotrophic lateral sclerosis: assessment of balance between upper and lower motor neuron involvement.

OBJECTIVE: We sought to record significant F wave variable changes in ALS patients having no advanced disease. Furthermore, an interpretation of these F wave abnormalities in the context of upper (UMN) and lower motor neuron (LMN) dysfunction was attempted. METHODS: Standard motor and sensory conduction study was performed to the ulnar nerves of 23 patients with ALS (13 males and 10 females with mean age 67.2+/-5.3 years), having a clinically predominant LMN syndrome. A series of 40 electrical stimuli were also delivered to both their ulnar nerves in order to obtain F waves. The following F wave variables were estimated: F persistence, F wave latency, amplitude, duration and F chronodispersion. Twenty-three, age-and gender-matched healthy volunteers served as controls. RESULTS: Both the distal and proximal ulnar a-CMAPs (P=0.001) and the MCV (P=0.014) values were significantly decreased in patients, than the controls. The sensory conduction study was normal. The ulnar F wave persistence in the ALS patients was significantly lower than that of the controls (P=0.0007). The mean (P=0.0001), minimal (P=0.0001) and maximal (P=0.0001) F wave latencies were significantly prolonged, the F wave amplitudes (P=0.0001) were significantly higher and the F wave chronodispersion (P=0.014) was significantly increased in the patients than the controls. CONCLUSIONS: Significant F wave abnormalities occur in patients with ALS, even those patients having no advanced disease. Increased F wave amplitudes combined with low persistence is a pattern consistent with ALS. SIGNIFICANCE: Our results show that patients with ALS having predominantly LMN involvement also have electrophysiological UMN dysfunction.