Evidence for reactive synaptogenesis in the ventrolateral thalamus and red nucleus of the rat: changes in high affinity glutamate uptake and numbers of corticofugal fiber terminals

Summary High affinity glutamate uptake into corticofugal fiber terminals was measured in the ventrolateral thalamus and red nucleus at varying time intervals after lesions were made by kainic acid in the contralateral interpositus nucleus of the cerebellum in rats. Under similar conditions the density of cortical fiber terminals was estimated using the Fink-Heimer impregnation technique. 1. Glutamate uptake steadily increased in the ventrolateral thalamus up to 60 days after lesions in the contralateral cerebellum. 2. Similar changes were noted in the red nucleus. 3. The changes were dependent on the integrity of corticofugal fibers to the thalamus and red nucleus. 4. No changes in uptake of gammaaminobutyric acid were noted. 5. Saturation curves for glutamate uptake suggested a change in the maximal number of transport sites. 6. Fink-Heimer degeneration studies showed an increase in cortical terminals in the ipsilateral ventrolateral thalamus and in both rostral and caudal regions of the red nucleus following lesions in the contralateral interpositus nucleus. The data are consistent with an increase in the number of cortical fiber terminals in reaction to loss of cerebellar input to the ventrolateral thalamus and red nucleus. This study correlates anatomical and biochemical evidence for collateral sprouting in a model based on electrophysiologic data in the red nucleus and extends the model to include the thalamus.     

Modulation of rodent cortical motor excitability by somatosensory input

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.     

Decreased neuroplasticity in minor burn injury survivors compared to non-injured adults: A pilot study in burn injury survivors aged 45 years and older

ObjectiveNeuroplasticity is the capacity of the brain to change or adapt with experience: brain changes occur with use, disuse, and injury. Repetitive transcranial magnetic stimulation (rTMS) can be used to induce neuroplasticity in the human brain. Here, we examined rTMS-induced neuroplasticity in the primary motor cortex in burns survivors and controls without injury, and whether neuroplasticity is associated with functional recovery in burns survivors.MethodsSixteen burn injury survivors (total body surface area of burn injury <15%) and 13 non-injured control participants were tested. Repetitive TMS (specifically, spaced continuous theta-burst stimulation[cTBS]) was applied to induce neuroplasticity 6 and 12 weeks after injury in burn survivors and in two sessions separated by 6 weeks in controls. Motor evoked potentials (MEPs) elicited by single-pulse TMS were measured before and after rTMS to measure neuroplasticity. Burns survivors completed a functional assessment 12 weeks after injury.ResultsNon-injured controls showed decreased MEP amplitude 15?30 min after spaced cTBS in both experimental sessions. Burn survivors showed a smaller change in MEP amplitude after spaced cTBS compared to controls 6 weeks after burn injury but no difference compared to controls 12 weeks after burn injury. In burn survivors, there was a significant positive association between general health outcome (Short-Form Health Survey) and the change in MEP amplitude after spaced cTBS 12 weeks after injury (r=.73, p = .01).ConclusionsThe current findings suggest that burn survivors have a reduced capacity for neuroplasticity early in the recovery period (6 weeks after injury), which normalizes later in the recovery period (12 weeks after injury). Furthermore, the results provide preliminary evidence to suggest that burn survivors with normalized neuroplasticity 12 weeks after injury recover faster after burn injury.     

Age-related remodeling of glutamic-acid decarboxylase-labeled elements in deafferented piriform cortex of rats

Olfactory bulb (OB) removal has been shown to result in plasticity in the piriform cortex (PC) that is age dependent. We are studying this phenomenon using immunoelectron microscopy of glutamic acid decarboxylase immunoreactivity (GAD, the enzymatic precursor for GABA) at selected postnatal ages and in adults with emphasis on short survival times of 4-7 days after OB ablation. Normally GAD-labeled synaptic terminals form type II symmetric contacts onto unlabeled dendrites and GAD-labeled dendrites receive type I, asymmetric contacts from unlabeled terminals (Westenbroek, et al., 1988a). The OB lesion results in degenerating terminals with type I contacts onto unlabeled and onto GAD-labeled dendrites. Type I postsynaptic sites may be seen partially contacted by or entirely devoid of degenerating terminals and occasionally may be apposed to variable degrees by normal unlabeled or by GAD-positive terminals. Subsequently, some GAD-labeled terminals may form asymmetric type I contacts usually with unlabeled dendrites and rarely with GAD-labeled dendrites. The findings are most common in the youngest subjects and essentially absent in the adult subjects. A sequence of reinnervation of deafferented type I sites by GAD-labeled terminals is suggested for the formation of this "atypical" synapse and the sequelae of this reorganization are discussed.     

Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial

Parkinson disease (PD) patients frequently experience micrographia and difficulty writing, which could potentially impact their quality of life. This study aimed to determine whether handwriting exercise could improve fine manual motor function in PD. The study was a randomized controlled trial assessing the efficacy of a 4-week handwriting exercise using a newly developed handwriting practice book. The primary endpoint was an improvement in the time used to complete the handwriting test. Secondary endpoints were accuracy of the writing performance, patient’s subjective rating scale of their handwriting and a UPDRS part III motor examination. Of a total of 46 subjects, 23 were randomly assigned to the handwriting exercise group. After 4 weeks, the mean time used to complete the test was significantly lower in the exercise group, compared to the control group (143.43 ± 34.02 vs. 175 ± 48.88 s, p = 0.015). Mean time used to complete the handwriting test decreased from the baseline by 16.16% in the exercise group, but increased by 3.63% in the control group (p < 0.001). Significant improvements were also observed by assessing the subjective rating scale and the UPDRS part III scores. The 4-week handwriting exercise using the studied handwriting practice book appears to promote an improvement in writing speed and motor function of hands. The optimal duration and frequency of the exercise, the quantity and characteristic of the letters in the handwriting practice book, and the benefits of the exercise in other languages merit further studies.     

Experimental Referred Pain Extends Toward Previously Injured Location: An Explorative Study

Facilitated pain mechanisms have been demonstrated in musculoskeletal pain, but it is unclear whether a recent painful injury leaves the pain system sensitized. Pain characteristics were assessed in individuals who recently recovered from ankle pain (recovered pain group; n?=?25) and sex-matched control subjects (n?=?25) in response to tonic pressure pain and saline-induced pain applied at the shin muscle. Pain intensity and pain referral patterns were recorded bilaterally after the painful muscle stimulus. Pressure pain thresholds were measured at the lower legs and shoulder. Cuff pressure algometry on the lower leg was used to assess pain detection threshold, pressure evoking 6-cm pain score on a 10-cm visual analog scale, pain tolerance, temporal summation of pain, and conditioned pain modulation. Compared with in control subjects, saline-induced and pressure-induced pain in the shin muscle were more frequently felt as referred pain in the previously painful ankle (P < .05), and the pain area within the previously affected ankle was larger after saline-induced pain (P < .05). In the recovered pain group, conditioned pain modulation responses and the cuff pressure needed to reach a 6-cm pain score on a 10-cm visual analog scale was higher in the previously painful leg compared with in the contralateral leg (P < .05). No group differences were found in pressure pain threshold, pain detection threshold, pain tolerance, and temporal summation of pain.

Understanding heterogeneity in the effects of birth weight on adult cognition and wages

A large economics literature has shown long term impacts of birth weight on adult outcomes, including IQ and earnings that are often robust to sibling or twin fixed effects. We examine potential mechanisms underlying these effects by incorporating findings from the genetics and neuroscience literatures. We use a sample of siblings combined with an “orchids and dandelions hypothesis”, where the IQ of genetic dandelions is not affected by in utero nutrition variation but genetic orchids thrive under advantageous conditions and wilt in poor conditions. Indeed, using variation in three candidate genes related to neuroplasticity (APOE, BDNF, and COMT), we find substantial heterogeneity in the associations between birth weight and adult outcomes, where part of the population (i.e., “dandelions”) is not affected by birth weight variation. Our results help uncover why birth weight affects adult outcomes.     

Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes,BDNF, and astrocytes

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug’s sustained antidepressant-like effects.