Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Repetitive transcranial magnetic stimulation (rTMS) noninvasively modulates brain excitability in humans and influences mediators of plasticity in animals. When applied in humans in the months to years after stroke, potentiation of motor recovery has been limited. Recently, investigators have shifted rTMS administration into the early weeks following stroke, when injury-induced plasticity could be maximally engaged. This article provides an overview of basic mechanisms of rTMS, consideration of its interaction with various forms of neuroplasticity, and a summary of the highest quality clinical evidence for rTMS given early after stroke. RECENT FINDINGS/RESULTS:Studies of repetitive magnetic stimulation in vitro and in vivo have found modulation of excitatory and inhibitory neurotransmission and induction of cellular mechanisms supporting plasticity. A handful of clinical studies have shown sustained improvements in grip strength and UE motor impairment when rTMS is delivered in the first weeks after stroke. Though in its infancy, recent research suggests a plasticity-enhancing influence and modest motor recovery potentiation when rTMS is delivered early after stroke.

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.

BACKGROUND:Studies demonstrate that most arm motor recovery occurs within three months after stroke, when measured with standard clinical scales. Improvements on these measures, however, reflect a combination of recovery in motor control, increases in strength, and acquisition of compensatory strategies. OBJECTIVE:To isolate and characterize the time course of recovery of arm motor control over the first year poststroke. METHODS:Longitudinal study of 18 participants with acute ischemic stroke. Motor control was evaluated using a global kinematic measure derived from a 2-dimensional reaching task designed to minimize the need for antigravity strength and prevent compensation. Arm impairment was evaluated with the Fugl-Meyer Assessment of the upper extremity (FMA-UE), activity limitation with the Action Research Arm Test (ARAT), and strength with biceps dynamometry. Assessments were conducted at: 1.5, 5, 14, 27, and 54 weeks poststroke. RESULTS:Motor control in the paretic arm improved up to week 5, with no further improvement beyond this time point. In contrast, improvements in the FMA-UE, ARAT, and biceps dynamometry continued beyond 5 weeks, with a similar magnitude of improvement between weeks 5 and 54 as the one observed between weeks 1.5 and 5. CONCLUSIONS:Recovery after stroke plateaued much earlier for arm motor control, isolated with a global kinematic measure, compared to motor function assessed with clinical scales. This dissociation between the time courses of kinematic and clinical measures of recovery may be due to the contribution of strength improvement to the latter. Novel interventions, focused on the first month poststroke, will be required to exploit the narrower window of spontaneous recovery for motor control.

BACKGROUND: Reducing inhibitory neurotransmission with pharmacological agents is a potential approach for augmenting plasticity after stroke. Previous work in healthy subjects showed diminished intracortical inhibition after administration of theophylline. OBJECTIVE: We assessed the effect of single-dose theophylline on intracortical and interhemispheric inhibition in patients with chronic stroke, in a double-blind, placebo-controlled, cross-over study. METHODS: Eighteen subjects were randomly administered 300 mg of extended-release theophylline or placebo. Immediately and 5 hours following administration, transcranial magnetic stimulation was used to assess bihemispheric resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, and interhemispheric inhibition. Adverse effects on cardiovascular, neurological, and motor performance outcomes were also surveilled. Change between morning and afternoon sessions were compared across conditions. One week later, patients underwent the same assessments after crossing over to the opposite experimental condition. Subjects and investigators were blinded to the experimental condition during data acquisition and analysis. RESULTS: For both hemispheres, changes in intracortical or interhemispheric neurophysiology were comparable under theophylline and placebo conditions. Theophylline induced no adverse neurological, cardiovascular, or motor performance effects. For both conditions and hemipsheres, the baseline level of inhibition inversely correlated with its change between sessions: less baseline inhibition (i.e. disinhibition) was associated with a strengthening in inhibition over the day, and vice versa. CONCLUSION: A single dose of theophylline is well-tolerated by patients with chronic stroke, but does not alter cortical excitability. The inverse relationship between baseline inhibition and its change suggests the existence of a homeostatic process. The lack of effect on cortical inhibition may be related to an insufficiently long exposure to theophylline, or to differential responsiveness of disinhibited neural circuitry in patients with stroke.

About half of patients survive intracerebral hemorrhage (ICH), but most are left with significant disability. Rehabilitation after ICH is the mainstay of treatment to reduce impairment, improve independence in activities, and return patients to meaningful participation in the community. The authors discuss the neuroplastic mechanisms underlying recovery in ICH, preclinical and clinical interventional studies to augment recovery, and the rehabilitative and medical management of post-ICH patients.

Human and animal studies show significant delays in neurobehavioral development in offspring after prolonged prenatal exposure to moderate and high ethanol doses resulting in high blood alcohol concentration (BECs). However, none have investigated the effects of lower ethanol doses given acutely during specific developmental time periods. Here, we sought to create a mouse model for modest and circumscribed human drinking during the 3rd and 4th weeks of pregnancy. We acutely treated mice during embryo gastrulation on gestational day (GD) 7 or neurulation on GD8 with a low or moderate ethanol dose given via gavage that resulted in BECs of 107 and 177 mg/dl, respectively. We assessed neonatal physical development (pinnae unfolding, and eye opening); weight gain from postnatal day (PD) 3-65; and neurobehavioral maturation (pivoting, walking, cliff aversion, surface righting, vertical screen grasp, and rope balance) from PD3 to 17. We used a multiple linear regression model to determine the effects of dose, sex, day of treatment and birth in animals dosed during gastrulation or neurulation, relative to their vehicle controls. We found that ethanol exposure during both time points (GD7 and GD8) resulted in some delays of physical development and significant sensorimotor delays of pivoting, walking, and thick rope balance, as well as additional significant delays in cliff aversion and surface righting after GD8 treatment. We also found that treatment with the low ethanol dose more frequently affected neurobehavioral development of the surviving pups than treatment with the moderate ethanol dose, possibly due to a loss of severely affected offspring. Finally, mice born prematurely were delayed in their physical and sensorimotor development. Importantly, we showed that brief exposure to low dose ethanol, if administered during vulnerable periods of neuroanatomical development, results in significant neurobehavioral delays in neonatal mice. We thus expand concerns about alcohol consumption during the 3rd and 4th weeks of human pregnancy to include occasional light to moderate drinking.

The reliability of transcranial magnetic stimulation (TMS) measures in healthy older adults and stroke patients has been insufficiently characterized. We determined whether common TMS measures could reliably evaluate change in individuals and in groups using the smallest detectable change (SDC), or could tell subjects apart using the intraclass correlation coefficient (ICC). We used a single-rater test-retest design in older healthy, subacute stroke, and chronic stroke subjects. At twice daily sessions on two consecutive days, we recorded resting motor threshold, test stimulus intensity, recruitment curves, short-interval intracortical inhibition, and facilitation, and long-interval intracortical inhibition. Using variances estimated from a random effects model, we calculated the SDC and ICC for each TMS measure. For all TMS measures in all groups, SDCs for single subjects were large; only with modest group sizes did the SDCs become low. Thus, while these TMS measures cannot be reliably used as a biomarker to detect individual change, they can reliably detect change exceeding measurement noise in moderate-sized groups. For several of the TMS measures, ICCs were universally high, suggesting that they can reliably discriminate between subjects. TMS measures should be used based on their reliability in particular contexts. More work establishing their validity, responsiveness, and clinical relevance is still needed.