Nonlesioned Cortex Research Articles

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

Abstract TMP43: Differential Cortical Effect Modulated by Anodal, Cathodal and Bihemispheric Transcranial Direct Current Stimulation (tDCS) in Patients With Ischemic Stroke

Introduction: The differential brain modulatory effects across hemispheres from different montages in stroke patients is not well established. We aimed to investigate the cortical excitability on lesional and contra-lesional hemisphere modulated by anodal, cathodal and bihemispheric montage at 4 mA tDCS strengths. Hypothesis: Bihemispheric tDCS montage induces more cortical excitability on the lesional hemisphere. Methods: Eighteen aging stroke patients with unilateral ischemic stroke of 6 or more months and inducible motor evoked potentials (MEP) underwent 3 sessions of 30 minutes 4 mA tDCS combined with occupational therapy. Each session was at least 2 days apart and consisted of one of the 3 different montages: anodal (Anode: lesional C3/C4, Cathode: non-lesional FP1/FP2), cathodal (Anode: lesional FP1/FP2, Cathode: non-lesional C3/C4), or bihemispheric (Anode: lesional C3/C4, Cathode: non-lesional C3/C4). We collected MEP size, short intracortical inhibition (SICI, 3 ms) and intracortical facilitation (ICF, 15 ms) on bilateral abductor pollicis brevis (APB) muscles using single or paired pulse TMS at 5 timepoints (baseline and four post-tDCS 12 minutes apart sessions). Results: All 18 subjects had comparable resting motor threshold (rMT) across 3 montages (see A). Bihemispheric tDCS montage offered significantly larger peak-to-peak MEP responses on the lesioned cortex (ANOVA, F=8.97, P&lt;0.01) but not on the non-lesioned cortex (ANOVA, F=0.86, P=0.42). These differences were apparent in single pulse, SICI and ICF (see B). Conclusion: Our findings support that bihemispheric montage is better suited in post-stroke motor recovery tDCS applications.

Early expressions of hypoxia-inducible factor 1alpha and vascular endothelial growth factor increase the neuronal plasticity of activated endogenous neural stem cells after focal cerebral ischemia.

Endogenous neural stem cells become “activated” after neuronal injury, but the activation sequence and fate of endogenous neural stem cells in focal cerebral ischemia model are little known. We evaluated the relationships between neural stem cells and hypoxia-inducible factor-1α and vascular endothelial growth factor expression in a photothromobotic rat stroke model using immunohistochemistry and western blot analysis. We also evaluated the chronological changes of neural stem cells by 5-bromo-2′-deoxyuridine (BrdU) incorporation. Hypoxia-inducible factor-1α expression was initially increased from 1 hour after ischemic injury, followed by vascular endothelial growth factor expression. Hypoxia-inducible factor-1α immunoreactivity was detected in the ipsilateral cortical neurons of the infarct core and peri-infarct area. Vascular endothelial growth factor immunoreactivity was detected in bilateral cortex, but ipsilateral cortex staining intensity and numbers were greater than the contralateral cortex. Vascular endothelial growth factor immunoreactive cells were easily found along the peri-infarct area 12 hours after focal cerebral ischemia. The expression of nestin increased throughout the microvasculature in the ischemic core and the peri-infarct area in all experimental rats after 24 hours of ischemic injury. Nestin immunoreactivity increased in the subventricular zone during 12 hours to 3 days, and prominently increased in the ipsilateral cortex between 3–7 days. Nestin-labeled cells showed dual differentiation with microvessels near the infarct core and reactive astrocytes in the peri-infarct area. BrdU-labeled cells were increased gradually from day 1 in the ipsilateral subventricular zone and cortex, and numerous BrdU-labeled cells were observed in the peri-infarct area and non-lesioned cortex at 3 days. BrdU-labeled cells rather than neurons, were mainly co-labeled with nestin and GFAP. Early expressions of hypoxia-inducible factor-1α and vascular endothelial growth factor after ischemia made up the microenvironment to increase the neuronal plasticity of activated endogenous neural stem cells. Moreover, neural precursor cells after large-scale cortical injury could be recruited from the cortex nearby infarct core and subventricular zone.

Putting some excitement into constraint-induced movement therapy

This commentary is on the original article by Gillick et al. on pages 44–52 of this issue. Following publication of the Cochrane review in 2007,1 constraint-induced movement therapy (CIMT) has moved beyond the realm of experiment to a treatment, supported by some of the strongest evidence for children with cerebral palsy (CP). Paradoxically, studies evaluating CIMT have also led to the establishment of similarly strong evidence for bimanual upper limb therapy.2 With 33 published clinical or randomized controlled trials, results from studies of CIMT provide strong support for upper limb treatment models that provide time-limited, top-down or goal-directed, intensive blocks of training. Gone are the days for using bottom-up approaches where a child has therapy ‘done to them’. CIMT studies support two key components of motor learning: the initiation and active ‘doing’ of activities and the repetition of these at a sufficient intensity and level of challenge. Importantly, many models of CIMT embed the practice and learning of skills in a child's natural environment including home, pre-school, and school. These modifications, along with the knowledge that parents and carers, etc. who have received education can implement CIMT, challenge previous concerns that CIMT may not be feasible in a clinical setting. Models of CIMT, and for that matter, bimanual upper limb therapy, can be simple to implement, family-friendly, low-cost, yet very effective in improving outcomes in children with unilateral CP. In the ongoing pursuit to maximize the effect of treatment, a growing list of adjunct interventions, including functional electrical stimulation botulinum toxin-type A, and virtual reality, have been combined with CIMT. The addition of primed, low-frequency repetitive transcranial magnetic stimulation (rTMS) by Gillick et al.3 is an exciting addition to this list. To varying degrees in children with early unilateral brain lesion, the persistence of contralesional corticomotor projections from the non-lesioned cortex is an environmental response to provide movement to a more affected upper limb. Recent data suggest, however, that these projections may negatively influence the quality of unimanual and bimanual upper limb performance and also influence response to CIMT.4, 5 The science of upper limb treatment has, therefore, focused on encouraging repetitive, self-initiated movement of the more affected limb to stimulate activation of ipsilesional corticomotor projections and promote improved crossed corticospinal tract integrity. In a group of children, aged 8 to 17 years, with congenital hemiparesis and intact crossed corticospinal tract integrity, Gillick et al. primed the contralesional primary motor area (M1) using low frequency rTMS. In a fascinating twist, priming the cortex membrane of the contralesional hemisphere using rTMS results in subsequent inhibition of this hemisphere. Releasing, or disinhibiting the ipsilesional hemisphere from the shackles of contralesional hemisphere dominance, provides an advantage for the recruitment of ipsilesional corticomotor projections. The repetitive use of the more affected upper limb (CIMT) during this period facilitates an increase in the excitability of dormant neurons in the ipsilesional M1 and improves the potential to establish crossed projections from the lesioned hemisphere. Put simply, the addition of rTMS to CIMT is a novel method to ramp up the potential for activity-dependent plasticity in older children. This is an exciting preliminary study and despite the potentially invasive nature, no serious adverse events were reported. Larger studies, ensuring baseline group equivalence for ability level and age, are warranted. The nature of rTMS does limit its use to older children. However, this certainly does not mean younger children will be missing out. In fact, quite the opposite. While rTMS may potentially boost outcomes in older children, preliminary data from animal studies strongly support the notion of ‘the earlier the better’ for CIMT.6 Very early therapy during the critical period of brain development (<12 mo of age) moves away from a restorative paradigm to one of prevention. It is an exciting time for upper limb rehabilitation.

The importance of recognizing paradoxes (Commentary on Madhavan et al.)

The word paradox is derived from the Greek prefix para-, meaning ‘contrary or opposed’, and the word doxos, meaning ‘opinion’. As defined by the Oxford English Dictionary, paradox is ‘a statement or tenet contrary to received opinion or belief, especially one that is difficult to believe’. Paradoxes represent instances where the present knowledge is lacking and expectations are inconsistent with actual events or findings. Paradoxes surprise us and should evoke a desire to gain deeper understanding. Therefore, realizing and highlighting paradoxes is important as unique opportunities to acquire new knowledge and question assumed truths. A recent book, The Paradoxical Brain (Kapur et al., 2010), provides a comprehensive overview and discussion of the importance of paradoxes in brain sciences. In this issue of EJN, Madhavan et al. (2010) provide evidence that following a stroke, activity in the non-lesioned motor cortex may be maladaptive for some aspects of lower limb motor control. The notion that activity in the non-lesioned motor cortex may limit functional recovery after a stroke is supported by findings in human and animal studies (Ward & Cohen, 2004; Fregni & Pascual-Leone, 2006; Allred et al., 2010), and fits with the longstanding realization that functional consequences of a brain lesion are not simply the manifestation of the injury (Allred & Jones, 2008). Initially following an injury, rapid changes may occur to minimize the damage and prevent excitotoxic and neurotoxic cascades. These may be followed by complex processes to cope with behavioral consequences of the insult that may in the long run prove adaptive (beneficial) or maladaptive (deleterious) for the affected individual. Ultimately, behavior after a lesion reflects the capacity of the brain to adapt to the injury, and is thus a manifestation of the plastic adaptation of dynamic neural networks, constrained by pre-existing connections and influences (Pascual-Leone et al., 2005; Pascual-Leone, 2009). The final behavioral consequence of a brain injury may be degraded (worse-than-normal) performance, but also paradoxically superior (better-than-normal) performance, or there might be improvement of function or recovery of the deleterious consequences of a pre-existing insult or disease (Kapur, 1996). Madhavan et al. (2010) find that strong ipsilateral conductivity from the non-lesioned cortex results in greater degradation of lower limb motor performance, specifically in patients with relatively preserved cortico-spinal projections from the lesioned hemisphere. It might have been sensible to assume that more damage would have worse functional consequences and that some preserved connections would be better than none. However, paradoxically, for a task where patients had to simultaneously dorsiflex their ankle in one limb and plantarflex the ankle in the other limb, strong ipsilateral drive from the non-lesioned cortex to paretic ankle motoneurons appears to worsen the functional outcome in patients with some persevered contralateral projections. The results are consistent with ideas of ‘motor conflict’ generated by partly degraded signals and fit well with approaches that call for differential interventions for treatment of the lesioned and non-lesioned hemispheres to optimize functional outcomes following a stroke (Schallert et al., 2003). Integrating diffusion tensor imaging and transcranial magnetic stimulation results, Madhavan et al. (2010) present an algorithm to divide patients into two groups depending on measures of cortico-spinal integrity and excitability. The algorithm predicts that some patients will benefit from a reduction in ipsilateral drive from the non-lesioned hemisphere, for example by non-invasive brain stimulation, while others will benefit from having their non-lesioned cortex facilitated. Such approaches offer the promise of individualized optimization of neurorehabilitation approaches. It will be important to investigate the mechanisms governing shifting cortico-spinal and interhemispheric connectivity and function, neural network dynamics, and the mapping relations between brain activity and behavior following injury or stroke. Such information could be employed to foster the recovery of desirable functions and to suppress changes that may lead to undesirable behaviors. Attention to paradoxical phenomena, such as described in Madhavan et al. (2010), holds the promise of enabling a paradigmatic shift in our understanding of brain function and dysfunction, and of generating valuable insights that may lead to novel treatment strategies designed to alleviate impairment and disability resulting from disease and injury.

Altered Receptor Subunit Expression in Rat Neocortical Malformations

Identification of changes in neurotransmitter function in animal models of epilepsy provides a basis for rational drug development and an understanding of the mechanisms underlying epileptogenesis. We investigated changes in the efficacy of the benzodiazepine type I agonist zolpidem and the polyamine site N-methyl-D-aspartate receptor antagonist ifenprodil in a rat model of microgyria. Neonatal freeze lesions were used to produce a microsulcus in the normally lissencephalic rat neocortex with anatomical similarities to human polymicrogyria. Whole-cell voltage-clamp recordings were made from visually identified layer 2/3 pyramidal cells in acutely prepared brain slices from nonlesioned and lesioned rats. The effect of 20 nmol/L zolpidem on the decay time constant of inhibitory postsynaptic currents was significantly less in neurons from brain slices containing the freeze lesion. A higher concentration (100 nmol/L) of zolpidem was equally efficacious in lesioned and nonlesioned cortex. In lesioned cortex, the threshold for evoking epileptiform discharges was significantly increased in the presence of 10 micromol/L ifenprodil. This effect was significant in both intrinsic hyperexcitability and partial disinhibition with 2 micromol/L bicuculline in lesioned cortex. Ifenprodil had significantly less effect on the threshold of discharges evoked in control cortex in the partial disinhibition model. The decreased sensitivity of gamma-aminobutyric acid A receptors to 20 nmol/L zolpidem in the freeze-lesion model is consistent with a delayed or arrested maturation in this animal model. These data support a delay in the developmental switch from alpha2 to alpha1 subunits in gamma-aminobutyric acid A receptors of neocortical pyramidal cells in lesioned cortex. The increased ifenprodil sensitivity of the threshold for evoking epileptiform discharges in both control and disinhibited slices containing the microsulcus is explained by a delay in the expression of the 2A (NR2A) N-methyl-D-aspartate receptor subunit. Delayed development may be a hallmark of this type of cortical dysplasia.

Alterations in NMDA receptors in a rat model of cortical dysplasia.

Recent studies have demonstrated an important role for the N-methyl-D-aspartate receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role in hyperexcitability associated with several animal models of human epilepsy. Using whole-cell voltage clamp recordings in brain slices, we studied evoked paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The voltage dependence of epileptiform discharges indicated that these paroxysmal events were produced by a complex pattern of excitatory and inhibitory inputs. We examined the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals. Both compounds consistently raised the threshold for evoking the discharge but had modest effects on the discharge peak and amplitude. For comparison with nonlesioned cortex, we examined the effects of ifenprodil on the epileptiform discharge evoked in the presence of 2 microM bicuculline (partial disinhibition). In slices from nonlesioned cortex, 10 microM ifenprodil had little effect on the threshold whereas 71% of the recordings in bicuculline-treated lesioned cortex showed a >25% increase in threshold. These results suggest that NR2B-containing receptors are functionally enhanced in freeze-lesioned cortex and may contribute to the abnormal hyperexcitability observed in this model of neocortical microgyria.

Intravenous fluid tonicity: effect on intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury

An investigation into the role of intravenous fluid tonicity in determining intracranial pressure (ICP) after brain injury is described. The authors compare the results of infusion of a hypotonic fluid (Ringer's lactate, 270 mOsm/liter) to those of a hypertonic fluid (hypertonic sodium lactate, 500 mOsm/liter) in a porcine model of focal cryogenic brain injury. Hemodynamic parameters (ICP, regional cerebral blood flow (CBF), and oxygen delivery) and serum osmolarity were measured every 3 hours for 24 hours after injury. At sacrifice, the water content of the lesioned and nonlesioned cortex was determined by specific gravity. The cryogenic injury produced a significant increase in ICP and a significant decrease in CBF in all experimental groups. Maintenance infusion of hypertonic sodium lactate for 24 hours resulted in significantly lower ICP, higher CBF and oxygen delivery, and higher serum osmolarity than Ringer's lactate infusion. Cortical water content in the area of the lesion was similar in both groups, but in the uninjured hemisphere it was significantly lower in the hypertonic group. These data suggest that hypertonic maintenance fluid improves intracranial compliance by dehydrating uninjured cortex. Improved CBF in the hypertonic group may be due to dehydration of cerebrovascular endothelium and erythrocytes. By reducing ICP and improving CBF, hypertonic fluid administration may thus reduce secondary brain injury after head trauma.

The Effects of Aortic Crossclamping and Resuscitation on Intracranial Pressure, Cerebral Blood Flow, and Cerebral Water Content in a Model of Focal Brain Injury and Hemorrhagic Shock

Aortic crossclamping (AOXC) is performed frequently in hypotensive trauma patients who may have had a head injury. The effect of AOXC on the injured brain is unknown. We studied the effect of AOXC on mean arterial pressure (MAP), intracranial pressure (ICP), cerebral blood flow (CBF), cerebral perfusion pressure (CPP), and cerebral water content in a porcine model of focal cryogenic brain injury. Four groups of animals were studied: Group I--brain injury only; Group II--brain injury and AOXC; Group III--brain injury with hemorrhage and AOXC; and Group IV--AOXC only. Focal cryogenic grain injury increased the ICP in Groups I-III. Aortic crossclamping increased MAP, CBF, ICP, and CPP after hemorrhage in Group III. Following declamping and resuscitation there were no differences between the groups in any studied variable. Cerebral water content at the site of the focal brain injury was greater than in nonlesioned cortex but there was no significant difference between groups despite a greater positive fluid balance in hemorrhaged animals. AOXC improved perfusion to the injured brain without a significant increase in ICP. Increased MAP induced by AOXC and large fluid resuscitation appeared to have no detrimental effect on ICP, CBF, cerebral water content, or CPP in this model of brain injury.