Jamshid Faraji

Transcranial Direct Current Stimulation in Stroke Rehabilitation: A Review of Recent Advancements

Transcranial direct current stimulation (tDCS) is a promising technique to treat a wide range of neurological conditions including stroke. The pathological processes following stroke may provide an exemplary system to investigate how tDCS promotes neuronal plasticity and functional recovery. Changes in synaptic function after stroke, such as reduced excitability, formation of aberrant connections, and deregulated plastic modifications, have been postulated to impede recovery from stroke. However, if tDCS could counteract these negative changes by influencing the systems neurophysiology, it would contribute to the formation of functionally meaningful connections and the maintenance of existing pathways. This paper is aimed at providing a review of underlying mechanisms of tDCS and its application to stroke. In addition, to maximize the effectiveness of tDCS in stroke rehabilitation, future research needs to determine the optimal stimulation protocols and parameters. We discuss how stimulation parameters could be optimized based on electrophysiological activity. In particular, we propose that cortical synchrony may represent a biomarker of tDCS efficacy to indicate communication between affected areas. Understanding the mechanisms by which tDCS affects the neural substrate after stroke and finding ways to optimize tDCS for each patient are key to effective rehabilitation approaches.

Characterization of spatial performance in male and female Long-Evans rats by means of the Morris water task and the ziggurat task

Sex differences are prominent influences on spatial performance. One of the most common tasks to assess sex differences in spatial navigation in rodents is the Morris water task (MWT). In this task rats swim in a pool of water to locate a hidden platform employing the topographical relationships among the distal visual cues, pool wall, and goal location. Some evidence suggests that male rats display superior performance relative to females in the MWT. It is unknown, however, to what extent the sex difference in rats is task-dependent. This study compared the performance of male and female Long-Evans rats in the wet-land MWT versus the dry-land ziggurat task (ZT). The ZT represents a new dry-land task in which rats explore an arena with 16 ziggurat pyramids to locate food rewards. Several behavioural parameters, including latency, path length, path speed, probe trial performance, errors, and the number of returns were used as indices of spatial learning and memory. While males and females did not display significant differences in the traditional measures of spatial navigation within MWT, they displayed a robust sex difference in all measures of the ZT. These results indicate task-specific sex differences in spatial performance. Our findings suggest that males and females may employ different learning strategies in the MWT and ZT and that the latter task provides a more favourable task for assessing sex differences in rats.

Stress and corticosterone enhance cognitive recovery from hippocampal stroke in rats

When locally infused, the potent vasoconstrictor, endothelin-1 (ET-1) produces partial ischemic damage in many regions of the brain, including the hippocampus. The hippocampus is known for a high density of glucocorticoid receptors and for the potent actions of stress and corticosterone to modulate function. The current experiment evaluates the effects of stress and corticosterone on the severity of memory impairment and anatomical pathology produced by hippocampal mini-stroke. Rats with ET-1-induced mini-stroke were exposed to mild restraint stress (1 h/day) or oral corticosterone (0.5 mg/kg) for 16 consecutive days. Spatial memory was then tested in the Morris water task (MWT) and the ziggurat task (ZT). The groups ET-1+stress and ET-1+corticosterone performed significantly better in both tasks than the ET-1-only group. This suggests that increasing corticosteroid levels alleviates the hippocampal stroke-induced memory deficits. Hippocampal volumetric assessment also revealed that both the post-stroke stress and corticosteroid treatment significantly decreased the volume of hippocampal damage. The findings support the view that elevated levels of corticosterone may exert neuroprotective effects in the hippocampus following stroke.

Sequential bilateral striatal lesions have additive effects on single skilled limb use in rats

Unilateral dopamine depletion in rats induced by injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal system causes permanent impairments in limb use. The disturbances in limb use, including impairments in skilled reaching, are most severe on the side contralateral to the lesion. A number of studies, however, have also described ipsilateral deficits in skilled reaching. The purpose of this study was to investigate the effects of sequential bilateral striatal 6-OHDA lesions on skilled reaching movements in rats to compare the contribution of contra- versus ipsilateral motor control. Rats were trained in a reaching task to grasp food pellets with their preferred paw prior to receiving an intrastriatal 6-OHDA injection on the side contralateral to the preferred paw. The lesion significantly reduced reaching success along with qualitative impairments in limb use. In addition, animals displayed asymmetry in limb use and contraversive rotation bias after an apomorphine challenge. Three weeks later, animals received a second lesion induced by intrastriatal 6-OHDA injection into the hemisphere ipsilateral to the preferred paw. This lesion exaggerated the previous impairments in limb use and further reduced reaching success of the preferred paw. In the ladder rung walking task, additional impairments were found only in the forelimb ipsilateral to the first lesion. The findings of additive effects of sequential bilateral lesions suggest that both the contra- and ipsilateral striatum control single limb use. This supports the notion of bilateral control of skilled forelimb use by the mesostriatal dopaminergic system.

Rats with hippocampal lesion show impaired learning and memory in the ziggurat task: a new task to evaluate spatial behavior.

Spatial tasks are widely used to determine the function of limbic system structures in rats. The present study used a new task designed to evaluate spatial behavior, the ziggurat task (ZT), to examine the performance of rats with widespread hippocampal damage induced by N-methyl-d-aspartic acid (NMDA). The task consisted of an open field containing 16 identical ziggurats (pyramid shaped towers) arranged at equal distances. One of the ziggurats was baited with a food reward. The task required rats to navigate through the open field by using a combination of distal and/or proximal cues in order to locate the food reward. The ability to acquire and recall the location of the goal (baited) ziggurat was tested in consecutive training sessions of eight trials per day for 10 days. The location of the goal ziggurat was changed every second day, requiring the rats to learn a total of five different locations. Several parameters, including latency to find the target, distance traveled, the number of visits to non-baited ziggurats (errors), and the number of returns were used as indices of learning and memory. Control rats showed a significant decrease in distance traveled and reduced latency in locating the goal ziggurat across trials and days, suggesting that they learned and remembered the location of the goal ziggurat. Interestingly, the hippocampal-damaged group moved significantly faster, and traveled longer distances compared to the control group. Significant differences were observed between these groups with respect to the number of errors and returns on test days. Day 11 served as probe day, in which no food reward was given. The controls spent more time searching for the food in the previous training quadrant compared to the hippocampal group. The findings demonstrate that the ZT is a sensitive and efficient dry task for measuring hippocampus-dependent spatial performance in rats requiring little training and not associated with some of the disadvantages of water tasks.

Stress after hippocampal stroke enhances spatial performance in rats.

The nature of stress-related cognitive changes is still a matter of debate. Stress is often considered to be deleterious to cognitive function, despite many instances in which beneficial effects are evident in neural structure and cognition. Moreover, in some neuropathological conditions such as focal ischemia, stress exaggerates loss of cognitive function. The present experiments set out to investigate the effects of repeated restraint stress on spatial cognition in rats, and on recovery from a focal stroke induced by injection of endothelin-1 (ET-1) into the hippocampus (HPC). We did not observe a deleterious effect of stress on performance in the Morris water task (MWT). The HPC focal stroke induced by ET-1 produced lasting spatial learning impairments. Importantly, rats in the HPC stroke+stress group exhibited superior performance in the MWT compared with the HPC stroke-only group. No between-group structural difference was observed related to stress. These findings confirm that corticosterone-related experiences may be key factors influencing cognitive performance after HPC focal ischemic stroke.

Chronic stress prior to hippocampal stroke enhances post-stroke spatial deficits in the ziggurat task.

Stress is one of the most important variables to determine recovery following stroke. We have previously reported that post-stroke exposure to either stress or corticosterone (CORT) alleviates hippocampal ischemic outcome. The present experiment expands previous findings by investigating the influence of exposure to stress prior to ischemic event. Rats received either daily restraint stress (1h/day; 16 consecutive days) or CORT (0.5mg/kg; 16 consecutive days) prior to focal ischemic stroke in the hippocampus induced by bilateral injection of endothelin-1 (ET-1). All experimental groups were then tested in the ziggurat task, a new task for spatial cognition. The stress+stroke group showed significant deficits in both hippocampal structure and function. No deleterious effect of pre-stroke exposure to CORT was found in the CORT+stroke group. Our results indicate that a history of chronic stress sensitizes hippocampal cells to the damaging consequences of focal ischemia. The opposing effects of CORT-related experiences in this study not only reflect the diversity of glucocorticoid actions in the stress response, but also provide evidence that elevated CORT in the absence of emotional disturbance is not sufficient to produce hippocampal deficit.

Stress inhibits psychomotor performance differently in simple and complex open field environments

Stress affects psychomotor profiles and exploratory behavior in response to environmental features. Here we investigated psychomotor and exploratory patterns induced by stress in a simple open-field arena and a complex, multi-featured environment. Groups of rats underwent seven days of restraint stress or no-stress conditions and were individually tested in three versions of the ziggurat task (ZT) that varied according to environmental complexity. The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis due to stress procedure was evaluated by the pre- and post-stress levels of circulating corticosterone (CORT). Horizontal activity, exploration, and motivation were measured by the number of fields entered, the time spent in the central fields, path length and speed, and stop duration. In addition, vertical exploratory behavior was measured by the times rats climbed onto ziggurats. Stress-induced psychomotor changes were indicated by reduced path length and path speed and increased duration of stops only within the complex arena of the ZT. Rats in stress groups also showed a significant decline in the vertical movements as measured by the number of climbing onto ziggurats. No stress-induced changes were revealed by the simple open-field arena. The exploratory patterns of stressed animals suggest psychomotor inhibition and reduced novelty-seeking behaviors in an environment-dependent manner. Thus, multi-featured arenas that require complex behavioral strategies are ideally suited to reveal the inhibitory effects of stress on psychomotor capabilities in rodents.

Beyond the silence: bilateral somatosensory stimulation enhances skilled movement quality and neural density in intact behaving rats.

It is thought that a close dialogue between the primary motor (M1) and somatosensory (S1) cortices is necessary for skilled motor learning. The extent of the relative S1 contribution in producing skilled reaching movements, however, is still unclear. Here we used anodal transcranial direct current stimulation (tDCS), which is able to alter polarity-specific excitability in the S1, to facilitate skilled movement in intact behaving rats. We hypothesized that the critical role of S1 in reaching performance can be enhanced by bilateral tDCS. Pretrained rats were assigned to control or stimulation conditions: (1) UnAno: the unilateral application of an anodal current to the side contralateral to the paw preferred for reaching; (2) BiAno1: bilateral anodal current; (3) BiAno2: a bilateral anodal current with additional 30ms of 65μA pulses every 5s. Rats received tDCS (65μA; 10min/rat) to the S1 during skilled reach training for 20 days (online-effect phase). After-effect assessment occurred for the next ten days in the absence of electrical stimulation. Quantitative and qualitative analyses of online-effects of tDCS showed that UnAno and BiAno1 somatosensory stimulation significantly improve skilled reaching performance. Bilateral BiAno1 stimulation was associated with greater qualitative functional improvement than unilateral UnAno stimulation. tDCS-induced improvements were not observed in the after-effects phase. Quantitative cytoarchitectonic analysis revealed that somatosensory tDCS bilaterally increases cortical neural density. The findings emphasize the central role of bilateral somatosensory feedback in skill acquisition through modulation of cortico-motor excitability.

Concurrent silent strokes impair motor function by limiting behavioral compensation

Silent strokes occur more frequently than classic strokes; however, symptoms may go unreported in spite of lasting tissue damage. A silent stroke may indicate elevated susceptibility to recurrent stroke, which may eventually result in apparent and lasting impairments. Here we investigated if multiple silent strokes to the motor system challenge the compensatory capacity of the brain to cumulatively result in permanent functional deficits. Adult male rats with focal ischemia received single focal ischemic mini-lesions in the sensorimotor cortex (SMC) or the dorsolateral striatum (DLS), or multiple lesions affecting both SMC and DLS. The time course and outcome of motor compensation and recovery were determined by quantitative and qualitative assessment of skilled reaching and skilled walking. Rats with SMC or DLS lesion alone did not show behavioral deficits in either task. However, the combination of focal ischemic lesions in SMC and DLS perturbed skilled reaching accuracy and disrupted forelimb placement in the ladder rung walking task. These observations suggest that multiple focal infarcts, each resembling a silent stroke, gradually compromise the plastic capacity of the motor system to cause permanent motor deficits. Moreover, these findings support the notion that cortical and subcortical motor systems cooperate when adopting beneficial compensatory movement strategies.