Translational Value of Skilled Reaching Assessment in Clinical and Preclinical Studies on Motor Recovery After Stroke.

BACKGROUND: Assessment of skilled reaching enables extensive analysis of upper limb function in clinical and preclinical studies on poststroke outcome. However, translational research if often limited by lack of correspondence between tests of human and rodent motor function. OBJECTIVES: To determine (1) the translational value of skilled reaching performance for preclinical research by comparing the behavioral recovery profiles of skilled reaching characteristics between humans and rats recovering from stroke and (2) the relationship between skilled reaching performance and commonly used clinical outcome measures after stroke. METHODS: Twelve patients with ischemic or hemorrhagic stroke and 17 rats with photothrombotic stroke underwent an equivalent skilled reaching test at different time points, representing early to late subacute stages poststroke. Success scores and a movement element rating scale were used to measure the skilled reaching performance. The Fugl-Meyer Upper Extremity (FM-UE) assessment and the Action Research Arm Test (ARAT) were used as clinical outcome measures. RESULTS: Both species had muscle flaccidity at the early subacute stage after stroke and showed motor recovery following a proximal-distal principle toward the early subacute stage, albeit for rats within a shorter time course. Human skilled reaching scores and FM-UE and ARAT scores in the first 3 months poststroke were significantly correlated (P < .05). CONCLUSIONS: Our study demonstrates that poststroke changes in skilled reaching performance are highly similar between rats and humans and correspond with standard clinical outcome measures. Skilled reaching testing therefore offers an effective and highly translational means for assessment of motor recovery in experimental and clinical stroke settings.

Activation response and functional connectivity change in rat cortex after bilateral transcranial direct current stimulation-An exploratory study.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique implicated as a promising adjunct therapy to improve motor function through the neuromodulation of brain networks. Particularly bilateral tDCS, which affects both hemispheres, may yield stronger effects on motor learning than unilateral stimulation. Therefore, the aim of this exploratory study was to develop an experimental model for simultaneous magnetic resonance imaging (MRI) and bilateral tDCS in rats, to measure instant and resultant effects of tDCS on network activity and connectivity. Naïve, male Sprague-Dawley rats were divided into a tDCS (n = 7) and sham stimulation group (n = 6). Functional MRI data were collected during concurrent bilateral tDCS over the sensorimotor cortex, while resting-state functional MRI and perfusion MRI were acquired directly before and after stimulation. Bilateral tDCS induced a hemodynamic activation response, reflected by a bilateral increase in blood oxygenation level-dependent signal in different cortical areas, including the sensorimotor regions. Resting-state functional connectivity within the cortical sensorimotor network decreased after a first stimulation session but increased after a second session, suggesting an interaction between multiple tDCS sessions. Perfusion MRI revealed no significant changes in cerebral blood flow after tDCS. Our exploratory study demonstrates successful application of an MRI-compatible bilateral tDCS setup in an animal model. Our results indicate that bilateral tDCS can locally modulate neuronal activity and connectivity, which may underlie its therapeutic potential.

Design and Evaluation of a Rodent-Specific Transcranial Magnetic Stimulation Coil: An In Silico and In Vivo Validation Study.

BACKGROUND: Rodent models are fundamental in unraveling cellular and molecular mechanisms of transcranial magnetic stimulation (TMS)-induced effects on the brain. However, proper translation of human TMS protocols to animal models have been restricted by the lack of rodent-specific focal TMS coils. OBJECTIVE: We aimed to improve TMS focalization in rodent brain with a novel small, cooled, and rodent-specific TMS coil. METHODS: A rodent-specific 25-mm figure-of-eight TMS coil was developed. Stimulation focalization was simulated in silico for the rodent coil and a commercial human 50-mm figure-of-eight TMS coil. Both coils were also compared in vivo by electromyography measurements of brachialis motor evoked potential (MEP) responses to TMS at different brain sites in anesthetized rats (n = 6). Focalization was determined from the coils' level of stimulation laterality. Differences in MEPs were statistically analyzed with repeated-measures, within-subjects, ANOVA. RESULTS: In silico simulation results deemed the human coil insufficient for unilateral stimulation of the rat motor cortex, whereas lateralized electrical field induction was projected attainable with the rodent coil. Cortical, in vivo MEP amplitude measurements from multiple points in each hemisphere, revealed unilateral activation of the contralateral brachialis muscle, in absence of ipsilateral brachialis activation, with both coils. CONCLUSION: Computer simulations motivated the design of a smaller rodent-specific TMS coil, but came short in explaining the capability of a larger commercial human coil to induce unilateral MEPs in vivo. Lateralized TMS, as demonstrated for both TMS coils, corroborates their use in translational rodent studies, to elucidate mechanisms of action of therapeutic TMS protocols.

Noninvasive Brain Stimulation to Enhance Functional Recovery After Stroke: Studies in Animal Models.

BACKGROUND: Stroke is the leading cause of adult disability, but treatment options remain limited, leaving most patients with incomplete recovery. Patient and animal studies have shown potential of noninvasive brain stimulation (NIBS) strategies to improve function after stroke. However, mechanisms underlying therapeutic effects of NIBS are unclear and there is no consensus on which NIBS protocols are most effective. OBJECTIVE: Provide a review of articles that assessed effects and mechanisms of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in animal stroke models. METHODS: Articles were searched in PubMed, including cross-references. RESULTS: Nineteen eligible studies reporting effects of rTMS or tDCS after stroke in small rodents were identified. Seventeen of those described improved functional recovery or neuroprotection compared with untreated control or sham-stimulated groups. The effects of rTMS could be related to molecular mechanisms associated with ischemic tolerance, neuroprotection, anti-apoptosis, neurogenesis, angiogenesis, or neuroplasticity. Favorable outcome appeared most effectively when using high-frequency (>5 Hz) rTMS or intermittent theta burst stimulation of the ipsilesional hemisphere. tDCS effects were strongly dependent on stimulation polarity and onset time. Although these findings are promising, most studies did not meet Good Laboratory Practice assessment criteria. CONCLUSIONS: Despite limited data availability, animal stroke model studies demonstrate potential of NIBS to promote stroke recovery through different working mechanisms. Future studies in animal stroke models should adhere to Good Laboratory Practice guidelines and aim to further develop clinically applicable treatment protocols by identifying most favorable stimulation parameters, treatment onset, adjuvant therapies, and underlying modes of action.

The effects of nicotine on cognition are dependent on baseline performance.

Since cholinergic neurotransmission plays a major role in cognition, stimulation of the nicotinic acetylcholine receptor may be a target for cognitive enhancement. While nicotine improves performance on several cognitive domains, results of individual studies vary. A possible explanation for these findings is that the effect of nicotine administration may be dependent on baseline cognitive function, where subjects with a suboptimal cognitive performance may benefit from nicotine, while subjects who already perform optimally may show a decline in performance after nicotinic stimulation. We conducted a double-blind randomised placebo-controlled crossover trial, examining the effects of placebo, 1, and 2mg of nicotine on cognition in young (n=16, age 18-30 years) and healthy elderly (n=16, age 60-75 years) subjects. We hypothesised that the elderly would benefit more from nicotine compared to young subjects, as normal ageing is associated with decreases in cognitive function. Attention, working memory, visual memory, information-processing speed, psychomotor function, stereotypy, and emotion recognition were assessed. Compared to the young volunteers, the elderly performed significantly worse on psychomotor function and emotion recognition in the placebo condition. Nicotine had no effect in the young volunteers and decreased performance on working memory and visual memory in the elderly. Contrary to our hypothesis, the effect of nicotine was dependent on baseline performance in both the groups, with subjects with lower baseline performance benefiting from nicotine administration, while those with higher baseline performance performed worse after nicotine administration. This suggests that subjects with lower cognitive performance, irrespective of age, may benefit from nicotine.

Comparative gastrointestinal morphology of three small mammalian insectivores: Acomys spinosissimus (Rodentia), Crocidura cyanea (Eulipotyphla), and Amblysomus hottentotus (Afrosoricida).

The gastrointestinal morphology was investigated in three mammalian insectivorous species, namely Acomys spinosissimus, Crocidura cyanea, and Amblysomus hottentotus. The aim of the study was to provide a comprehensive morphological comparison between the different species and to explore whether anatomical gastrointestinal adaptations are associated with the insectivorous diet of these species. The shape, proportional length, and proportional surface areas of the different gastrointestinal regions were recorded and compared in the three insectivores. Hematoxylin and Eosin (H&E) and Alcian Blue/Periodic Acid Schiff (AB/PAS) were used for morphological assessment. In all three species, the stomach was simple and uncompartmentalized. The internal aspect of the stomach in A. spinosissimus was hemi-glandular, containing stratified squamous epithelium in the fundus, with glandular epithelium in the body and pyloric region. However, C. cyanea and A. hottentotus had wholly glandular stomachs. Paneth cells were not observed in the intestinal tracts of C. cyanea and A. hottentotus. Acomys spinosissimus was the only species studied that had a cecum. The proximal colonic region of A. spinosissimus had V-shaped mucosal folds. Histologically, C. cyanea had villi throughout the entire gastrointestinal tract (GIT), whereas for A. hottentotus villi were not present in the most distal gastrointestinal regions. In both C. cyanea and A. hottentotus, longitudinal mucosal folds were present in the distal part of the colon. The GITs of C. cyanea and A. hottentotus showed little morphological differentiation namely, a simple, glandular stomach and the lack of a cecum.

A comparative histochemical study of the distribution of mucins in the gastrointestinal tracts of three insectivorous mammals.

The distribution of mucous secreting goblet cells was examined in the gastrointestinal tracts of three insectivores namely: Acomys spinosissimus (Southern African spiny mouse), Crocidura cyanea (Reddish gray musk shrew) and Amblysomus hottentotus (Hottentot golden mole) in order to improve our understanding of the quality and composition of the protective intestinal biofilm. Intestinal tracts were fixed and processed to wax for histology. Serial transverse sections were stained using alcian blue-periodic acid Schiff, alcian blue-aldehyde fuchsin and alcian blue-high iron diamine techniques. Photomicrographs of the stained sections were analyzed by quantifying the number of goblet cells containing mucins per mm(2) in the surface epithelial or crypt areas. Neutral mucins predominated in the gastric epithelium of all three insectivores, while sialomucins were absent in the stomach of C. cyanea. In all three species, goblet cells producing a mixture of neutral and acid mucins were most abundant throughout the intestinal tract as were cells secreting a mixture of sulfomucins and sialomucins. However, differences between the insectivore species were observed in the qualitative expression and distribution of mucins throughout the intestinal tract. Similarities between the insectivores of this study and other distantly related species suggest that mixed mucin goblet cells are essential for the formation of the biofilm, irrespective of their diet or taxonomy.