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.     

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.     

Transcranial direct current stimulation and cognitive training in the rehabilitation of Alzheimer disease: A case study

In the present study we tested the cognitive effects of transcranial direct current stimulation (tDCS) in a case of probable Alzheimer disease (AD). The patient (male, 60?years, mild AD) underwent two cycles of treatments, separated by 2?months. In the first cycle, active stimulation (10 sessions, 2?mA for 20?min; anode over the left dorsolateral prefrontal cortex) was followed by computerised tasks (CTs) specifically chosen to engage the most impaired cognitive processes in the patient (tDCS+CT condition). In the second cycle, which was structured as the first, CTs were administered after placebo stimulation (sham+CT condition). Effects on cognitive performance were evaluated not only by the CTs, but also by neuropsychological tests assessing global cognitive functioning. Statistical analyses revealed that whereas the tDCS+CT condition had few effects on the CTs, it induced a stability of the patient's global cognitive functioning lasting approximately 3?months, which was not achieved when the patient underwent sham+CT condition. Therefore, the synergetic use of tDCS and CTs appeared to slow down the cognitive decline of our patient. This preliminary result, although in need of further confirmation, suggests the potentiality of tDCS as an adjuvant tool for cognitive rehabilitation in AD.     

Chronic antidepressant-like effect of EMD386088, a partial 5-HT6 receptor agonist,in olfactory bulbectomy model may be connected with BDNF and/or CREB signalling pathway

Background

The removal of the olfactory bulbs has been attributed to behavioral changes and neuroplasticity manifesting themselves among others like increases in brain neurotrophin expression and neurogenesis. Earlier data presented that EMD386088, a 5-HT₆ receptor partial agonist, exerts antidepressant-like properties after chronic administration in olfactory bulbectomy (OB) model as was it compared with amitriptyline (AMI). The aim of this study was to compare acute and chronic biochemical effects of EMD386088, administered in its antidepressant active (2.5 mg/kg) and non-active (1.25 mg/kg) doses, found in the open field test in OB rats, with those of AMI (10 mg/kg). The levels of 5-HT₆ receptor protein and selected neurotrophins in prefrontal cortex (PFC) and hippocampus (Hp) of rats have been examined.

BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: Results from a factorial,randomized, sham-controlled trial

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that modifies cortical excitability according to the stimulation parameters. Preclinical and clinical studies in healthy volunteers suggest that tDCS induces neuroplastic alterations of cortical excitability, which might explain its clinical effects in major depressive disorder (MDD). We therefore examined whether tDCS, as compared to the antidepressant sertraline, increases plasma brain-derived neurotrophic factor (BDNF) levels, a neurotrophin associated with neuroplasticity. Patients (n=73) with major depressive disorder were randomized to active/sham tDCS and sertraline/placebo (four groups) in this 6-week, double-blind, placebo-controlled trial. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. Regarding tDCS, BDNF plasma levels might not be a good candidate biomarker to evaluate depression improvement or be a predictor of response in patients treated with tDCS, as our results showed that BDNF increase was not necessary to induce clinical response. Finally, our findings do not support a relationship between BDNF and improvement of depression.