Transhemispheric Diaschisis Research Articles

Adaptive Mechanisms of Somatostatin-Positive Interneurons after Traumatic Brain Injury through a Switch of α Subunits in L-Type Voltage-Gated Calcium Channels.

Unilateral traumatic brain injury (TBI) causes cortical dysfunctions spreading to the primarily undamaged hemisphere. This phenomenon, called transhemispheric diaschisis, is mediated by an imbalance of glutamatergic versus GABAergic neurotransmission. This study investigated the role of GABAergic, somatostatin-positive (SST) interneurons in the contralateral hemisphere 72h after unilateral TBI. The brain injury was induced to the primary motor/somatosensory cortex of glutamate decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mice at postnatal days 19-21 under anesthesia in vivo. Single GFP+ interneurons of the undamaged, contralateral cortex were isolated by fluorescence-activated cell sorting and analyzed by mass spectrometry. TBI caused a switch of 2 α subunits of pore-forming L-type voltage-gated calcium channels (VGCC) in GABAergic interneurons, an increased expression of CaV1.3, and simultaneous ablation of CaV1.2. This switch was associated with 1) increased excitability of single SST interneurons in patch-clamp recordings and (2) a recovery from early network hyperactivity in the contralateral hemisphere in microelectrode array recordings of acute slices. The electrophysiological changes were sensitive to pharmacological blockade of CaV1.3 (isradipine, 100nM). These data identify a switch of 2 α subunits of VGCCs in SST interneurons early after TBI as a mechanism to counterbalance post-traumatic hyperexcitability.

Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia.

Carbon monoxide-generating heme oxygenase-2 is expressed in neurons and plays a crucial role for regulating hypoxic vasodilation through mechanisms unlocking carbon monoxide-dependent inhibition of H2S-generating cystathionine β-synthase expressed in astrocytes. This study aims to examine whether heme oxygenase-2 plays a protective role in mice against stroke. Focal ischemia was induced by middle cerebral artery occlusion. Regional differences in metabolites among ipsilateral and contralateral hemispheres were analysed by quantitative imaging mass spectrometry equipped with an image-processing platform to optimize comparison of local metabolite contents among different animals. Under normoxia, blood flow velocity in precapillary arterioles were significantly elevated in heme oxygenase-2-null mice vs controls, while metabolic intermediates of central carbon metabolism and glutamate synthesis were elevated in the brain of heme oxygenase-2-null mice, suggesting greater metabolic demands to induce hyperemia in these mice. In response to focal ischemia, heme oxygenase-2-null mice exhibited greater regions of ischemic core that coincide with notable decreases in energy metabolism in the contralateral hemisphere as well as in penumbra. In conclusion, these findings suggest that heme oxygenase-2 is involved in mechanisms by which not only protects against compromised energy metabolism of the ipsilateral hemisphere but also ameliorates transhemispheric diaschisis of the contralateral hemisphere in ischemic brain.

Acute Cortical Transhemispheric Diaschisis after Unilateral Traumatic Brain Injury.

Focal neocortical brain injuries lead to functional alterations, which can spread beyond lesion-neighboring brain areas. The undamaged hemisphere and its associated disturbances after a unilateral lesion, so-called transhemispheric diaschisis, have been progressively disclosed over the last decades; they are strongly involved in the pathophysiology and, potentially, recovery of brain injuries. Understanding the temporal dynamics of these transhemispheric functional changes is crucial to decipher the role of the undamaged cortex in the processes of functional reorganization at different stages post-lesion. In this regard, little is known about the acute-subacute processes after 24-48 h in the brain hemisphere contralateral to injury. In the present study, we performed a controlled cortical impact to produce a unilateral traumatic brain injury (TBI) in the motor and somatosensory cortex of mice. In vitro extracellular multi-unit recordings from large neuronal populations, together with single-cell patch-clamp recordings in the cortical network contralateral to the lesion, revealed a strong, but transient, neuronal hyperactivity as early as 24-48 h post-TBI. This abnormal excitable state in the intact hemisphere was not accompanied by alterations in neuronal intrinsic properties, but it was associated with an impairment of the phasic gamma aminobutyric acid (GABA)ergic transmission and an increased expression of GABAA receptor subunits related to tonic inhibition exclusively in the contralateral hemisphere. These data unravel a series of early transhemispheric functional alterations after diffuse unilateral cortical injury, which may compensate and stabilize the disrupted brain functions. Therefore, our findings support the hypothesis that the undamaged hemisphere could play a significant role in early functional reorganization processes after a TBI.

Neuronal mechanisms underlying transhemispheric diaschisis following focal cortical injuries

Unilateral cortical lesions cause disturbances often spreading into the hemisphere contralateral to the injury. The functional alteration affecting the contralesional cortex is called transhemispheric diaschisis and is believed to contribute to neurological deficits and to processes of functional reorganization post-lesion. Despite the profound implications for recovery, little is known about the cellular mechanisms that underlie this phenomenon. In the present study, transhemispheric diaschisis was investigated with an in vivo-ex vivo model of unilateral lesions, induced by an infrared laser in rat visual cortex. Visually evoked cortical activity was evaluated by the expression level of the cellular activity marker zif268, which showed an elevation in the cortex contralateral to the lesion. In vitro patch-clamp recordings from layer 2/3 pyramidal neurons revealed a shift in the excitatory–inhibitory balance in favor of excitability, particularly expressed in the undamaged hemisphere. Layer 5 principal neurons displayed an increased spontaneous firing rate contralateral to the lesion, while cells of the injured cortex displayed a reduced firing upon somatic current injection. These data suggest that a cortical lesion triggers an enhanced neuronal activity in the hemisphere contralateral to the damage. Our findings constitute an important step toward the understanding of transhemispheric diaschisis on the cellular level.

Effect of intracortical vascular endothelial growth factor infusion and blockade during the critical period in the rat visual cortex

VEGF is the major angiogenic and vascular permeability factor in health and disease. Vascular development depends on function, and in sensory areas is experience-dependent. Our aim was to investigate, qualitatively and quantitatively, the effects of intracortical infusion and neutralisation of VEGF during the first days of the critical visual period, when peak levels of endogenous VEGF secretion are reached.VEGF was intracortically delivered into middle cortical layers of P18 Long–Evans rats. Another cohort received anti-VEGF. Vehicle (PBS)-infused and non-operated animals were used as controls. Various immunopathological analyses were performed: Endothelial Barrier Antigen (EBA) for the BBB integrity and GFAP for astroglial response. Vascular density was measured by Butyryl Cholinesterase Histochemistry, neuronal density by NeuN immunohistochemistry and apoptosis by TUNEL staining. VEGF levels were measured by Western Blot.Decreased vascular permeability was evoked in VEGF-infused rats whilst EBA expression remained constant, suggesting a preserved BBB function. When VEGF was blocked, tissue showed a higher degree of extravasation and a decreased number of EBA-positive vessels surrounding the injury. Lesion induced by cannula implantation annulled the normal increase in vascular density and the decrease in neuronal density during this time. VEGF rescued in part the vascular increase, and also prevented physiological and pathological neuronal death. VEGF blockade induced a higher amount of neural loss and lower astrocytic reaction.Our results support the role of VEGF as extending beyond vascularization, preventing physiological and pathological neuronal death, not only in the injured hemisphere but also in the intact one suggesting a process of transhemispheric diaschisis.

Mitochondrial involvement in transhemispheric diaschisis following hypoxia–ischemia: Clomethiazole-mediated amelioration

Mitochondria play a central role in both the physiological and pathophysiological regulation of cell survival/death. Increasing evidence places mitochondrial dysfunction at the center of many neuropathological conditions. The present study investigates the extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues in a rat model of hypoxia–ischemia (HI). We hypothesized that; mitochondrial dysfunction in situ may be prevented by treatment with clomethiazole (CMZ), a GABAA receptor agonist. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-day post-HI revealed a marked decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, small changes were seen in contralateral cortical and hippocampal tissues as well as in the cerebellum at 3-days (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I–V), and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed mitochondrial impairment in ipsilateral regions following HI. Complexes I, II–III, V and citrate synthase were also impaired in contralateral regions and cerebellum 3-days post-HI. Treatment with CMZ (414 mg/kg/day via minipumps) provided marked protection to all aspects of neuronal tissue assessed. Circulating cytokine (interleukin [IL]-1α, IL-1β, tumor necrosis factor [TNF]-α, granulocyte macrophage colony-stimulating factor [GM-CSF], IL-4 and IL-10) levels were also assessed in these animals 3-days post-HI. Plasma IL-1α, IL-1β, TNF-α and GM-CSF levels were significantly increased post-HI. Treatment with CMZ ameliorated the increases in IL-1α, IL-1β, TNF-α and GM-CSF levels while increasing plasma IL-4 and IL-10 levels. This study provides evidence of the extent of mitochondrial damage following an HI-insult. In addition, we have shown that protection afforded by CMZ extends to preservation of mitochondrial function and integrity via anti-inflammatory mediated pathways.

Impaired neurovascular coupling by transhemispheric diaschisis in rat cerebral cortex.

In acute brain disorders, elimination of the excitatory output from an injured brain region reduces activity in connecting brain regions remote from the lesion site (i.e., diaschisis). The authors examined the effect of functional ablation of the left cerebral cortex by cortical spreading depression (CSD) or topical application of tetrodotoxin on single cell spiking activity, baseline CBF, and neurovascular coupling in the right rat sensory cortex. CSD or tetrodotoxin in left cortex reduced the right cortical spontaneous spike rate by 36% and 45%, respectively. Baseline CBF in the right cortex was unaffected by a left-sided CSD, but decreased by 12% for left cortical application of tetrodotoxin. This suggested dissociation between spontaneous spiking activity and basal CBF. Left in-fraorbital nerve stimulation evoked local field potentials in right cerebral cortex that were reduced in amplitude by 19% for left CSD and by 23% for left tetrodotoxin application. The corresponding declines in the evoked CBF responses were 42% for CSD and 23% for tetrodotoxin. Vascular reactivity to adenosine remained unchanged in right cortex. Thus, transhemispheric diaschisis produced a pronounced decrease in the spontaneous spike rate accompanied by no reduction or a small reduction in basal CBF, and an attenuation in amplitudes of evoked synaptic responses and corresponding rises in CBF. The findings suggest that disturbed neurovascular coupling may contribute to the disturbance in brain function in acute transhemispheric diaschisis.

Remote Effects of Acute Ischemic Stroke: A Xenon CT Cerebral Blood Flow Study

Objective: The purpose of this study was to verify transhemispheric diaschisis in the early hours after an ischemic event. Methods: XeCT cerebral blood flow (CBF) studies within 8 h of stroke were studied in 23 patients. Mean CBF was evaluated in the ischemic area, contralateral hemisphere and ipsilateral cerebellum. Results: A severe CBF reduction was found in the ischemic area (mean 9 ± 3 ml/100 g/min). The mean CBF in the unaffected hemisphere (33 ± 10 ml/100 g/min) was 35% less compared to the normal mean value. CBF was decreased in the cerebellum ipsilateral to the stroke (mean 31 ± 12 ml/100 g/min) suggesting a blood flow depression of the whole brain. Conclusions: During the initial hours of cerebral ischemia, the asymptomatic hemisphere demonstrated CBF depression that was part of the global flow reduction.

Temporal changes of the apparent diffusion coefficients of water and metabolites in rats with hemispheric infarction: experimental study of transhemispheric diaschisis in the contralateral hemisphere at 7 tesla.

The purpose of the present study was to clarify the temporal changes of the apparent diffusion coefficients (ADCs) of cerebral metabolites during early focal ischemia using stimulated echo acquisition mode with short echo time at a 7 T magnet to assess the pathophysiology of the reduction in diffusion properties observed both in the ischemic cerebral hemisphere and in the contralateral hemisphere. The ADCs of metabolites in the infarcted hemisphere 1 hour and 3 hours after the onset of ischemia decreased with 25% and 29% for choline containing compounds (Cho), 16% and 26% for creatine and phosphocreatine (Cre), and 19% and 19% for N-acetylaspartate (NAA), respectively, compared with the ADC values 2 hours later in the contralateral hemisphere. There were decreases in the ADC of Cho, Cre, and NAA with 21%, 7%, and 18% 8 hours later, respectively, in the noninfarcted hemisphere, which suggested transhemispheric diaschisis in rats with focal cerebral ischemia. The present study proposed that the diffusion characteristics of the brain metabolites might offer new insights into circulatory and metabolic alteration in the cerebral intracellular circumstance.

Diaschisis and neurobehavior.

We review forms of diaschisis and their relationship with neurobehavioral and neuropsychological findings. The following forms of diaschisis are discussed: (1) cortico-cerebellar diaschisis; (2) cerebello-cortical diaschisis; (3) transhemispheric diaschisis; (4) cortico-thalamic diaschisis; (5) thalamo-cortical diaschisis; and (6) basal ganglia-cortical diaschisis. For each form, the neurobehavioral and neuropsychological findings are discussed. Diaschisis can be classified from the behavioral point of view as follows: (1) forms in which the metabolic effect at distance is not followed by neurobehavioral impairment; (2) forms in which the remote metabolic impairment could induce neurobehavioral and neuropsychological disorders; and (3) forms in which the role of the lesion itself and its remote metabolic effects on the production of neurobehavioral and neuropsychological abnormalities cannot be disentangled.

Is the Cortical Blindness Due to Diaschisis?

Cortical blindness is defined as a loss of vision that is caused by bilateral occipital lobe lesions. Many reports of patients with cortical blindness describe bilateral occipital lesions visualized on morphologic and functional imaging studies. The authors present the case of a patient who became cortically blind after a hemorrhagic lesion of the right occipital lobe. CT failed to reveal bilateral occipital involvement, but the brain SPECT showed decreased perfusion of both parleto-occipital areas. The brain SPECT findings correlated better with the clinical status. SPECT may be more useful than CT for detecting functional brain abnormalities, and the clinical and imaging findings of the present patient could be attributed to the transhemispheric diaschisis.

Copper-zinc superoxide dismutase and isolectin B 4 binding are markers for associative and transhemispheric diaschisis induced by focal ischemia in rat cortex

Copper/zinc-superoxide dismutase (Cu/Zn-SOD) belongs to a class of enzymes, identified as essential and highly effective endogenous scavengers of cytotoxic oxygen radicals. These radicals contribute to postlesional neurotoxicity. In order to determine the superoxide-scavenging potential of regions affected by unilateral cortical photothrombosis, we studied the changes in the distribution of Cu/Zn-SOD and the appearance of activated microglia by immunohistochemistry and isolectin B 4 binding. Four hours postlesion, Cu/Zn-SOD increased significantly within a homotopic area of the contralateral hemisphere and in ipsilateral thalamic nuclei, whereas isolectin B 4-positive microglia were upregulated at days 5 and 7 postlesion within the same regions. The contralateral increase in the amount of the superoxide-scavenging Cu/Zn-SOD indicates that this enzyme is induced by a retrograde reaction carried through callosal connections.

Decreased cerebral glucose metabolism in patients with brain tumors: an effect of corticosteroids

The authors measured cerebral glucose metabolism (CMRglu) using [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in patients with brain tumors to evaluate the effect of exogenous corticosteroids (in this instance, dexamethasone) on glucose metabolism. Fifty-six FDG-PET studies obtained in 45 patients with unilateral supratentorial brain tumors were analyzed. Patients with brain tumors were divided into three groups: 1) patients with cushingoid symptoms, who had been treated with combinations of radiotherapy and chemotherapy taking oral dexamethasone; 2) patients not taking dexamethasone but treated with radiotherapy; and 3) patients not taking dexamethasone who had not been treated with radiotherapy. Serial FDG-PET scans were obtained in eight of the cushingoid patients. Glucose metabolism was measured in the contralateral cerebral and ipsilateral cerebellar hemispheres in patients and compared to measurements taken from 19 normal volunteers. The authors found that in the cushingoid brain tumor patients there was a marked reduction in CMRglu compared to normal volunteers and other brain tumor patients (Kruskal-Wallis test; p 0.001). In the majority of patients who had serial FDG-PET scans, there was a decline in glucose metabolism over time and in one patient, in whom dexamethasone was reduced in dosage, there was a subsequent increase in CMRglu. The authors conclude that there is a generalized reduction in CMRglu in brain tumor patients taking dexamethasone compared to other brain tumor patients and normal volunteers, and that this effect is independent of radiotherapy, concurrent anticonvulsant medication, and transhemispheric functional disconnection (transhemispheric diaschisis).

Transhemispheric diaschisis. A review and comment.

We review here the literature in both animal models and humans concerning electrical activity, blood flow, and metabolism in the hemisphere contralateral to unilateral cerebral ischemia. We analyze the data by periods based on the time from initial injury to emphasize the time course of transhemispheric diaschisis. Contralateral electrical activity, such as evoked potential amplitude, is increased in the late stages after unilateral infarction, with the data from the more acute periods being inconclusive. Contralateral blood flow changes probably depend on the magnitude of the ischemic injury, with a larger insult resulting in a decrease not seen with smaller insults. Some studies have shown a decrease in contralateral blood flow over the first week followed by a gradual return toward baseline. Most measures of contralateral metabolism show a time course similar to blood flow, that is, a decrease followed by gradual recovery. The effects of corpus callosum section on transhemispheric diaschisis are not yet established. We provide examples to show that under certain conditions, diaschisis may represent a loss of remote inhibition rather than a loss of remote facilitation, as von Monakow originally suggested. By following the contralateral changes over time, particularly during the first minutes and hours of ischemia, insight will be gained into the brain's responses remote from the focus of ischemic injury. These responses should bear a relation to the brain's defense mechanisms ipsilaterally to the region of ischemia.

Evidence for transhemispheric diaschisis in unilateral stroke.

Nineteen patients with strictly unilateral ischemic stroke as determined by clinical examination, computed tomography, magnetic resonance imaging, and standard angiography underwent cerebral blood flow (CBF) analysis using fluorine 18 fluoromethane and positron emission tomography. Mean flow values for averaged hemispheric, infarct, and homologous contralateral regions of interest (ROIs) were determined. All patient CBF values were significantly below comparable CBF ROIs in neurologically normal controls using Wilcoxon's two-sample rank testing. Multiple regression analysis disclosed a significant correlation between contralateral CBF are both localized CBF in the infarct ROI and patient age. Correlations between contralateral CBF and dependency score or severity of neurologic deficit at time of positron emission tomography, expired PCO2, mean arterial blood pressure, serum glucose or hematocrit, risk factor score, and number of days studied after stroke were not statistically significant. Although we did not identify the biologic mechanisms involved, we conclude that CBF reduction contralateral to a strictly unilateral ischemic infarction is due to a combination of aging and transhemispheric diaschisis.

破裂脳動脈瘤症例の病態と予後

Changes of cerebral blood flow (CBF), low perfusion areas (LPA) and redistribution phenomenon (RD), in which operations were performed within 24 hours after the onset of SAH, were examined using N-isopropyl-p-[123I] iodoamphetamine (IMP) SPECT in 16 cases.CBF patterns changed remarkably during the acute, subacute and chronic stages. In the acute stage, CBF of the affected side decreased due to vasospasm and operative procedures, and large LPAs were seen in many cases. However, good RD was recognized in most cases. In the subacute stage, CBF of the affected side increased and LPA decreased in size and number. In the chronic stage, CBF of the affected side decreased again, and in some cases transhemispheric diaschisis was seen.In eight cases the absolute values of CBF were also measured. These values showed almost the same changes described above in each stage. Cases with remarkably low CBF and large LPA without RD in the acute stage showed poor prognosis.

Contralateral flow reduction in unilateral stroke: evidence for transhemispheric diaschisis.

Using clinical presentation, angiography, computed tomography, and nuclear magnetic resonance imaging, 7 patients were identified who had strictly unilateral hemispheric infarction and unilateral cerebrovascular disease. In 6, cerebral blood flow measured by fluorine-18-fluoromethane inhalation and positron emission tomography was reduced in the contralateral hemisphere (p less than 0.05). Multiple regression analysis demonstrated a high correlation between contralateral flow reduction and the degree of flow impairment in the infarcted area (r = 0.941, p = 0.0014) but not with age, risk factor profile, blood pressure, PCO2, hematocrit, or duration of stroke. We conclude that transhemispheric diaschisis best explains the contralateral flow reduction seen in supratentorial ischemic stroke.

No evidence for transhemispheric diaschisis after human cerebral infarction.

Forty-four studies of regional cerebral blood flow (rCBF), fractional oxygen extraction (rOER) and oxygen consumption (rCMRO2) were made on twenty-five patients with recent internal carotid artery territory infarcts. The purpose was to study flow-metabolism relationships in the contralateral hemispheres, and to investigate whether contralateral rCMRO2 was depressed as a result of the recent infarcts. Two groups of controls were included for comparison--seventeen normal volunteers, and ten patients with proven extracranial cerebrovascular disease but without evidence of cerebral infarction. The results demonstrated that: contralateral hemispheric rCMRO2 was less variable than regional oxygen availability (the product of rCBF and arterial oxygen content). This was due, in part, to the effect of individual variations in PaCO2 on rCBF, but other uncontrolled factors, such as intracranial pressure, may have had influences. As a result, rCMRO2 did not correlate with rCBF; mean rCMRO2 in the contralateral hemispheres was 12% lower than normal (a significant difference), but was not different from the value found in patients with extracranial vascular disease in whom there was no evidence of infarction or ischemia; contralateral rCMRO2 did not correlate with the size of the infarct in the opposite hemisphere. It is concluded that rCMRO2 cannot be inferred from rCBF measurements in uncontrolled human studies (as frequently done in the past), and that depression of contralateral rCMRO2 may have preceded infarction in the opposite hemisphere, a consequence of the previous influences of diseases that predispose to stroke.