Low-intensity contralesional electrical theta burst stimulation modulates ipsilesional excitability and enhances stroke recovery.

Targeting interhemispheric inhibition using brain stimulation has shown potential for enhancing stroke recovery. Following stroke, increased inhibition originating from the contralesional hemisphere impairs motor activation in ipsilesional areas. We have previously reported that low-intensity electrical theta burst stimulation (TBS) applied to an implanted electrode in the contralesional rat motor cortex reduces interhemispheric inhibition, and improves functional recovery when commenced three days after cortical injury. Here we apply this approach at more clinically relevant later time points and measure recovery from photothrombotic stroke, following three weeks of low-intensity intermittent TBS (iTBS), continuous TBS (cTBS) or sham stimulation applied to the contralesional motor cortex. Interhemispheric inhibition and cellular excitability were measured in the same rats from single pyramidal neurons in the peri-infarct area, using in vivo intracellular recording. A minimal dose of iTBS did not enhance motor function when applied beginning one month after stroke. However both a high and a low dose of iTBS improved recovery to a similar degree when applied 10 days after stroke, with the degree of recovery positively correlated with ipsilesional excitability. The final level of interhemispheric inhibition was negatively correlated with excitability, but did not independently correlate with functional recovery. In contrast, contralesional cTBS left recovery unaltered, but decreased ipsilesional excitability. These data support focal contralesional iTBS and not cTBS as an intervention for enhancing stroke recovery and suggest that there is a complex relationship between functional recovery and interhemispheric inhibition, with both independently associated with ipsilesional excitability.

A behavioral task for investigating action discovery, selection and switching: comparison between types of reinforcer.

Action discovery and selection are critical cognitive processes that are understudied at the cellular and systems neuroscience levels. Presented here is a new rodent joystick task suitable to test these processes due to the range of action possibilities that can be learnt while performing the task. Rats learned to manipulate a joystick while progressing through task milestones that required increasing degrees of movement accuracy. In a switching phase designed to measure action discovery, rats were repeatedly required to discover new target positions to meet changing task demands. Behavior was compared using both food and electrical brain stimulation reward (BSR) of the substantia nigra as reinforcement. Rats reinforced with food and those with BSR performed similarly overall, although BSR-treated rats exhibited greater vigor in responding. In the switching phase, rats learnt new actions to adapt to changing task demands, reflecting action discovery processes. Because subjects are required to learn different goal-directed actions, this task could be employed in further investigations of the cellular mechanisms of action discovery and selection. Additionally, this task could be used to assess the behavioral flexibility impairments seen in conditions such as Parkinson's disease and obsessive-compulsive disorder. The versatility of the task will enable cross-species investigations of these impairments.

Utility of intracerebral theta burst electrical stimulation to attenuate interhemispheric inhibition and to promote motor recovery after cortical injury in an animal model.

Following a cerebral cortex injury such as stroke, excessive inhibition around the core of the injury is thought to reduce the potential for new motor learning. In part, this may be caused by an imbalance of interhemispheric inhibition (IHI); therefore, treatments that relieve the inhibitory drive from the healthy hemisphere to the peri-lesional area may enhance motor recovery. Theta burst stimulation delivered by transcranial magnetic stimulation has been tested as a means of normalizing IHI, but clinical results have been variable. Here we use a new rat model of synaptic IHI to demonstrate that electrical intracranial theta burst stimulation causes long-lasting changes in motor cortex excitability. Further, we show that contralateral intermittent theta burst stimulation (iTBS) blocks IHI via a mechanism involving cannabinoid receptors. Finally, we show that contralesional iTBS applied during recovery from cortical injury in rats improves the recovery of motor function. These findings suggest that theta burst stimulation delivered through implanted electrodes may be a promising avenue to explore for augmenting rehabilitation from brain injury.

Cell cycle genes PEDF and CDKN1C in growing deer antlers.

Deer antlers are the only mammalian appendage to display an annual cycle of full regeneration. The growth phase in antler involves the rapid proliferation of several tissues types, including epidermis, dermis, cartilage, bone, blood vessels, and nerves. Antlers thus provide an excellent model to study the developmental regulation of these tissues. We describe here the identification of two genes, pigment epithelium-derived factor (PEDF) and cyclin-dependent kinase inhibitor 1C (CDKN1C), both of which are known to be involved in cell proliferation and differentiation. These genes were identified as the result of screening an expressed sequence tag database derived from a cDNA library enriched for sequences from the growing antler tip. PEDF mRNA was detected in developing skin, cartilage, and bone during endochondral ossification. PEDF mRNA was not detected within endothelial cells that exhibited positive immunoreactivity to a CD146 antibody. CDKN1C mRNA was expressed by only the immature chondrocytes within the precartilage region. These results suggested that PEDF and CDKN1C are important genes involved in cell proliferation and differentiation during antler growth.