Spinal Lamina Research Articles

Properties of spinal lamina III GABAergic neurons in naïve and in neuropathic mice

Nerve injury leads to Aβ-fibre-mediated mechanical allodynia that is in part due to an impaired GABAergic inhibition in the spinal cord dorsal horn. The properties and function of GABAergic neurons in spinal cord lamina III, an area where low-threshold mechanosensitive Aβ-fibres terminate are, however, largely unknown. We used transgenic mice, which express enhanced green fluorescent protein (EGFP) under control of the promoter GAD67. The morphology and neurochemical characteristics of GABAergic, EGFP-expressing neurons were characterized. We assessed active and passive membrane properties of spinal lamina III GABAergic neurons in naïve animals and animals with a chronic constriction injury (CCI) of the sciatic nerve. EGFP-expressing neurons in lamina III were predominantly islet cells (47%), whereas non-EGFP-expressing neurons were largely inverted stalked cells (40%). EGFP-expressing neurons accounted for about 25% of GABAergic neurons in lamina III. Forty-four percent co-expressed glycine, 10% neuronal nitric oxide synthase and 3% co-expressed parvalbumin. We found costaining with protein kinase CβII in 42% of EGFP-expressing neurons but no expression of protein kinase Cγ. Membrane properties and excitability of EGFP-and non-EGFP-expressing neurons from naïve and neuropathic animals were indistinguishable. The most frequent firing pattern was tonic firing (naïve: 35%, neuropathic: 37%) followed by gap firing (naïve: 33%, neuropathic: 25%). Delayed, initial burst and single-spike firing patterns made up the remainder in both groups. A change in membrane excitability or discharge pattern of this group of lamina III GABAergic neurons is unlikely the cause for mechanical allodynia in animals with CCI.

Microglia take control in chronic pain

Microglia activation, BDNF release and the subsequent effect on Cl− homeostasis in spinal lamina I neurons have been shown to play key parts in the hyperalgesia side effect of chronic morphine.

Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis

A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We show here that hyperalgesia-inducing treatment with morphine causes downregulation of the K+-Cl− cotransporter KCC2, impairing Cl− homeostasis in spinal lamina l neurons. Restoring Eanion reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signalling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which BDNF was deleted from microglia did not develop hyperalgesia to morphine. Yet, neither morphine antinociception nor tolerance was affected in these animals. Our findings dissociate morphine-induced hyperalgesia from tolerance and unveil the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target to prevent hyperalgesia without affecting morphine analgesia.

Nuclear Calcium Signaling in Spinal Neurons Drives a Genomic Program Required for Persistent Inflammatory Pain

Persistent pain induced by noxious stimuli is characterized by the transition from normosensitivity to hypersensitivity. Underlying mechanisms are not well understood, although gene expression is considered important. Here, we show that persistent nociceptive-like activity triggers calcium transients in neuronal nuclei within the superficial spinal dorsal horn, and that nuclear calcium is necessary for the development of long-term inflammatory hypersensitivity. Using a nucleus-specific calcium signal perturbation strategy in vivo complemented by gene profiling, bioinformatics, and functional analyses, we discovered a pain-associated, nuclear calcium-regulated gene program in spinal excitatory neurons. This includes C1q, a modulator of synaptic spine morphogenesis, which we found to contribute to activity-dependent spine remodelling on spinal neurons in a manner functionally associated with inflammatory hypersensitivity. Thus, nuclear calcium integrates synapse-to-nucleus communication following noxious stimulation and controls a spinal genomic response that mediates the transition between acute and long-term nociceptive sensitization by modulating functional and structural plasticity.

Electroacupuncture Improves Thermal and Mechanical Sensitivities in a Rat Model of Postherpetic Neuralgia

BackgroundElectroacupuncture (EA) is effective in relieving pain in patients with postherpetic neuralgia (PHN). However, the mechanism underlying the therapeutic effect of EA in PHN is still unclear. Systemic injection of resiniferatoxin (RTX), an ultrapotent analog of TRPV1 agonist, in adult rats can reproduce the clinical symptoms of PHN by ablating TRPV1-expressing sensory neurons. In this study, we determined the beneficial effect of EA and the potential mechanisms in this rat model of PHN.MethodsPHN was induced in rats by a single injection of RTX. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified with von Frey filaments. TRPV1 receptors were shown by using immunofluorescence labeling. The ultrastructural changes of the sciatic nerve were assessed by electron microscopic examination. The sprouting of myelinated primary afferent terminals into the spinal dorsal horn was mapped by using the transganglionic tracer cholera toxin B-subunit (CTB).ResultsRTX injection diminished thermal sensitivity and gradually induced tactile allodynia within 3 weeks. EA applied to GB30 and GB34 at 2 and 15 Hz, but not 100 Hz, significantly increased the thermal sensitivity 4 weeks after treatment and decreased the tactile allodynia 2 weeks after treatment in RTX-treated rats. EA treatment at 2 and 15 Hz recovered the loss of TRPV1-positive dorsal root ganglion neurons and their central terminals of afferent fibers in the spinal superficial dorsal horn of RTX-treated rats. Moreover, EA significantly reduced the loss of unmyelinated fibers and the damage of the myelinated nerve fibers of RTX-treated rats. Furthermore, EA at 2 and 15 Hz inhibited the sprouting of myelinated primary afferent terminals into the spinal lamina II of RTX-treated rats.ConclusionsEA treatment improves thermal perception by recovering TRPV1-positive sensory neurons and nerve terminals damaged by RTX. EA Also reduces RTX-induced tactile allodynia by attenuating the damage of myelinated afferent nerves and their abnormal sprouting into the spinal lamina II. Our study provides new information about the mechanisms of the therapeutic actions of EA in the treatment of PHN.

Intraosseous ganglion cyst within the L4 lamina causing spinal stenosis

There are rare reports of intraosseous ganglion cysts in the cervical spine. However, to our knowledge, there are no previous reports of these cysts occurring in the lumbar spine. To report a case of symptomatic lumbar spinal stenosis caused by an intraosseous ganglion cyst of the L4 lamina that communicated with the spinal canal. Case report. An 86-year-old woman was referred to our spine service for a 2-year history of anterior thigh and leg pain. Magnetic resonance imaging revealed a benign-appearing intraosseous cyst in the left L4 lamina communicating with a posterior epidural cyst at L4-L5 causing marked spinal stenosis. The patient was treated successfully with a laminectomy and resection. The patient underwent partial laminectomies of L4 and L5 preserving the interspinous ligaments between L5-S1 and L3-L4. The cyst was removed en bloc without violation of the cyst wall. Histopathologic examination revealed focal myxoid changes without a cellular lining of the cyst wall, confirming the diagnosis of intraosseous ganglion cyst. This is the first report to describe an intraosseous ganglion cyst occurring in the lumbar spine. Although spinal stenosis is commonly a result of degenerative joint or disc disease, it occasionally may result from more obscure causes. This case illustrates a patient with an intraosseous ganglion cyst within the spinal lamina resulting in spinal stenosis, treated successfully with a laminectomy and resection.

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons

The cannabinoid 1 (CB1) receptor is expressed by a sub-population of primary sensory neurons. However, data on the neurochemical identity of the CB1 receptor-expressing cells, and CB1 receptor expression by the peripheral and central terminals of these neurons are inconsistent and limited. We characterised CB1 receptor expression in dorsal root ganglia (DRG) and spinal cord at the lumbar 4-5 level, as well as in the urinary bladder and glabrous skin of the hindpaw. About 1/3 of DRG neurons exhibited immunopositivity for the CB1 receptor, the majority of which showed positivity for the nociceptive markers calcitonin gene-related peptide (CGRP) or/and Griffonia (bandeiraea) simplicifolia IB4 isolectin-binding. Virtually all CB1 receptor-immunostained fibres showed immunopositivity for CGRP in the skin, while very few did in the urinary bladder. No CB1 receptor-immunopositive nerve fibres were IB4 positive in either peripheral tissue. Spinal laminae I and II-outer showed the highest density of CB1 receptor-immunopositive punctae, the majority of which showed positivity for CGRP or/and IB4 binding. These data indicate that a major sub-population of nociceptive primary sensory neurons expresses CB1 receptors that are transported to both peripheral and central terminals of these cells. Therefore, the present data suggest that manipulation of endogenous CB1 receptor agonist levels in these areas may significantly reduce nociceptive input into the spinal cord.

The Mu Opioid Receptor Modulates Neurotransmission in the Rat Spinal Ventral Horn

Opioids inhibit excitatory neurotransmission and produce antinociception through μ opioid receptors (MORs). Although MORs are expressed in the spinal ventral horn, their functions and effects are largely unknown. Therefore, we examined the neuromodulatory effects of μ opioids in spinal lamina IX neurons at the cellular level. The effects of the selective μ agonist [D-Ala(2),-N-Me-Phe(4), Gly(5)-ol]enkephalin (DAMGO) on synaptic transmission were examined in spinal lamina IX neurons of neonatal rats using the whole-cell patch-clamp technique. DAMGO produced outward currents in 56% of the lamina IX neurons recorded, with a 50% effective concentration of 0.1 μM. Analysis of the current-voltage relationship revealed a reversal potential of approximately -86 mV. These currents were not blocked by tetrodotoxin but were inhibited by Ba(2+) or a selective μ antagonist. Moreover, the currents were suppressed by the addition of Cs(+) and tetraethylammonium or guanosine 5'-[β-thio]diphosphate trilithium salt to the pipette solution. In addition, DAMGO decreased the frequency of spontaneous excitatory and inhibitory postsynaptic currents, and these effects were unaltered by treatment with tetrodotoxin. Our results suggest that DAMGO hyperpolarizes spinal lamina IX neurons by G protein-mediated activation of K(+) channels after activation of MORs. Furthermore, activation of MORs on presynaptic terminals reduces both excitatory and inhibitory transmitter release. Although traditionally opioids are not thought to affect motor function, the present study documents neuromodulatory effects of μ opioids in spinal lamina IX neurons, suggesting that MORs can influence motor activity.

The spinal precerebellar nuclei: Calcium binding proteins and gene expression profile in the mouse

We have localized the spinocerebellar neuron groups in C57BL/6J mice by injecting the retrograde neuronal tracer Fluoro-Gold into the cerebellum and examined the distribution of SMI 32 and the calcium-binding proteins (CBPs), calbindin-D-28K (Cb), calretinin (Cr), and parvalbumin (Pv) in the spinal precerebellar nuclei. The spinal precerebellar neuron clusters identified were the dorsal nucleus, central cervical nucleus, lumbar border precerebellar nucleus, lumbar precerebellar nucleus, and sacral precerebellar nucleus. Some dispersed neurons in the deep dorsal horn and spinal laminae 6–8 also projected to the cerebellum. Cb, Cr, Pv, and SMI 32 were present in all major spinal precerebellar nuclei and Pv was the most commonly observed CBP. A number of genes expressed in hindbrain precerebellar nuclei are also expressed in spinal precerebellar groups, but there were some differences in gene expression profile between the different spinal precerebellar nuclei, pointing to functional diversity amongst them.

TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord

Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1(-/-) mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.

Effect of Xenon on Excitatory and Inhibitory Transmission in Rat Spinal Ventral Horn Neurons

The minimum alveolar concentration is determined in the spinal cord rather than in the brain. Xenon inhibits glutamatergic excitatory synaptic transmission in the dorsal horn neurons. However, its actions in the ventral horn neurons have not been investigated. The effects of 50 or 75% xenon on excitatory and inhibitory synaptic transmission were examined in the spinal lamina IX neurons of neonatal rats by using a whole cell patch clamp technique. Fifty percent xenon inhibited the α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents (amplitudes = 72 ± 9% and integrated area = 73 ± 13% of the control values), and α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated electrically evoked excitatory postsynaptic currents (amplitudes = 69 ± 13% of the control values). Seventy-five percent xenon similarly inhibited α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents. However, xenon had no effect on the N-methyl-D-aspartate-induced currents or N-methyl-D-aspartate receptor-mediated electrically evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There were no discernible effects on the currents induced by γ-aminobutyric acid or glycine or on miniature inhibitory postsynaptic currents. Xenon inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated glutamatergic excitatory transmission in the spinal lamina IX neurons via a postsynaptic mechanism. In contrast, there are no substantial effects on N-methyl-D-aspartate receptor-mediated or inhibitory synaptic transmission. The suppressive effects on excitatory synaptic transmission in the ventral horn neurons partly account for the mechanism behind xenon's ability to produce immobility in response to noxious stimuli and to determine the minimum alveolar concentration.

Cervical interneuron bursting during hypoxia in anesthetized rats

Cervical spinal laminae VII‐X contain interneurons that are synaptically coupled to phrenic motoneurons (PMNs). Neurophysiological studies suggest these cells are not necessary for transmission of inspiratory drive, but their role in modulating PMN output during respiratory stimulation or plasticity is unknown. In ongoing studies, we are exploring the role of cervical interneurons in hypoxia‐induced phrenic plasticity. Since spinal serotonin (5‐HT) can induce phrenic plasticity, we first examined whether pre‐phrenic cervical interneurons are innervated by 5‐HT. 5‐HT immunoreactivity was robust throughout cervical laminae VII‐X and in the immediate vicinity of pre‐phrenic interneurons identified with a transynaptic retrograde tracer (pseudorabies virus, delivered to the diaphragm). Cervical interneuron activity was recorded in anesthetized, paralyzed, vagotomized and ventilated adult rats. Initial results indicate that tonic and phasic bursting interneurons are distributed throughout the C3‐C5 intermediate gray matter. During respiratory stimulation with hypoxia a subset of the cervical interneurons showed an increase in burst frequency, and in some cases switched from tonic to phasic bursting. Cervical interneurons are anatomically positioned to modulate phrenic motor output, but their potential role in initiating and/or maintaining phrenic plasticity remains to be determined.

Cholinergic neurons in the mouse rostral ventrolateral medulla target sensory afferent areas

The rostral ventrolateral medulla (RVLM) primarily regulates respiration and the autonomic nervous system. Its medial portion (mRVLM) contains many choline acetyltransferase (ChAT)-immunoreactive (ir) neurons of unknown function. We sought to clarify the role of these cholinergic cells by tracing their axonal projections. We first established that these neurons are neither parasympathetic preganglionic neurons nor motor neurons because they did not accumulate intraperitoneally administered Fluorogold. We traced their axonal projections by injecting a Cre-dependent vector (floxed-AAV2) expressing either GFP or mCherrry into the mRVLM of ChAT-Cre mice. Transduced neurons expressing GFP or mCherry were confined to the injection site and were exclusively ChAT-ir. Their axonal projections included the dorsal column nuclei, medullary trigeminal complex, cochlear nuclei, superior olivary complex and spinal cord lamina III. For control experiments, the floxed-AAV2 (mCherry) was injected into the RVLM of dopamine beta-hydroxylase-Cre mice. In these mice, mCherry was exclusively expressed by RVLM catecholaminergic neurons. Consistent with data from rats, these catecholaminergic neurons targeted brain regions involved in autonomic and endocrine regulation. These regions were almost totally different from those innervated by the intermingled mRVLM-ChAT neurons. This study emphasizes the advantages of using Cre-driver mouse strains in combination with floxed-AAV2 to trace the axonal projections of chemically defined neuronal groups. Using this technique, we revealed previously unknown projections of mRVLM-ChAT neurons and showed that despite their close proximity to the cardiorespiratory region of the RVLM, these cholinergic neurons regulate sensory afferent information selectively and presumably have little to do with respiration or circulatory control.

Developmental regulation of membrane excitability in rat spinal lamina I projection neurons

It is now universally recognized that neonates can experience considerable pain. While spinal lamina I neurons projecting to the brain contribute to the generation of hyperalgesia, nothing is known about their electrophysiological properties during early life. Here we have used in vitro whole cell patch-clamp recordings in rat spinal cord slices to determine whether the intrinsic membrane properties of lamina I projection neurons, as well as their synaptic inputs, are developmentally regulated during the early postnatal period. Projection neurons were identified via retrograde transport of DiI injected into the parabrachial nucleus (PB) or periaqueductal gray (PAG) and characterized at postnatal days (P)2-5, P10-12, P19-23, and P30-32. Both spino-PB and spino-PAG neurons demonstrated an age-dependent reduction in spike threshold and duration at room temperature, which was accompanied by a developmental increase in the frequency of miniature excitatory and inhibitory postsynaptic currents. Notably, in both groups, age-dependent changes in the passive membrane properties or rheobase only occurred after the third postnatal week. However, spontaneous activity was significantly more prevalent within the developing spino-PB population and was dominated by an irregular pattern of discharge. In addition, while the instantaneous firing frequency remained unaltered in spino-PB neurons during the first weeks of life, spino-PAG cells fired at a higher rate at P19-23 compared with younger groups, suggesting that the gain of parallel ascending nociceptive pathways may be independently regulated during development. Overall, these results demonstrate that intrinsic membrane excitability is modulated in a cell type-specific manner within developing spinal nociceptive circuits.

Neural cell adhesion molecule and its polysialic acid moiety exhibit opposing and linked effects on neuropathic hyperalgesia

Spinal lamina II, where nociceptive C-fibers terminate, expresses high amounts of the polysialylated form of neural cell adhesion molecule (PSA-NCAM). While enzymatic removal of the PSA moiety from NCAM did not affect normal sensitivity to thermal stimuli, it exacerbated nerve injury-induced neuropathic hyperalgesia. The genetic removal of the NCAM core protein also did not alter thermal sensitivity. However in the presence of a peripheral nerve injury, NCAM-null mutants exhibited a complete suppression of thermal hyperalgesia. This strong NCAM mutant phenotype appears to involve the long form of NCAM's cytoplasmic domain, in that it is duplicated by selective genetic deletion of the NCAM-180 isoform. PSA appears therefore to provide a mechanism for modulation of chronic sensory overload, by means of attenuation of the activity of the NCAM-180 isoform, which reduces nociceptive transmission.

Heterosynaptic Long-Term Potentiation at GABAergic Synapses of Spinal Lamina I Neurons

Neurons in spinal dorsal horn lamina I play a pivotal role for nociception that critically depends on a proper balance between excitatory and inhibitory inputs. Any modification in synaptic strength may challenge this delicate balance. Long-term potentiation (LTP) at glutamatergic synapses between nociceptive C-fibers and lamina I neurons is an intensively studied cellular model of pain amplification. In contrast, nothing is presently known about long-term changes of synaptic strength at inhibitory synapses in the spinal dorsal horn. Using a spinal cord-dorsal root slice preparation from rats, we show that conditioning stimulation of primary afferent fibers with a stimulating protocol that induces LTP at C-fiber synapses also triggered LTP at GABAergic synapses (LTP(GABA)). This LTP(GABA) was heterosynaptic in nature and was mediated by activation of group I metabotropic glutamate receptors. Opening of ionotropic glutamate receptor channels of the AMPA/KA or NMDA subtype was not required for LTP(GABA). Paired-pulse ratio, coefficient of variation, and miniature IPSCs analysis revealed that LTP(GABA) was expressed presynaptically. Nitric oxide as a retrograde messenger signal mediated this increase of GABA release at spinal inhibitory synapses. This novel form of synaptic plasticity in spinal nociceptive circuits may be an essential mechanism to maintain the relative balance between excitation and inhibition and to improve the signal-to-noise ratio in nociceptive pathways.

Resolving TRPV1- and TNF-α-Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1

Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 (transient receptor potential subtype V1) and TNF-α, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lacking Trpv1 the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP) in vivo is abolished in Trpv1 knock-out mice. TNF-α also increases sEPSC frequency but not amplitude in spinal outer lamina II (lamina IIo) neurons, and this increase is abolished in Trpv1 knock-out mice. Single-cell PCR analysis revealed that TNF-α-responding neurons in lamina IIo are exclusively excitatory (vGluT2(+)) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from ω-3 polyunsaturated fatty acid (docosahexaenoic acid), blocks TNF-α- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC(50) = 0.4 nm) in dissociated dorsal root ganglion neurons, and this IC(50) is ≈ 500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had no effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1-10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-α-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-α-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain.

Functional recovery following motor cortex lesions in non-human primates: experimental implications for human stroke patients.

This review discusses selected classical works and contemporary research on recovery of contralesional fine hand motor function following lesions to motor areas of the cerebral cortex in non-human primates. Findings from both the classical literature and contemporary studies show that lesions of cortical motor areas induce paresis initially, but are followed by remarkable recovery of fine hand/digit motor function that depends on lesion size and post-lesion training. Indeed, in recent work where considerable quantification of fine digit function associated with grasping and manipulating small objects has been observed, very favorable recovery is possible with minimal forced use of the contralesional limb. Studies of the mechanisms underlying recovery have shown that following small lesions of the digit areas of primary motor cortex (M1), there is expansion of the digit motor representations into areas of M1 that did not produce digit movements prior to the lesion. However, after larger lesions involving the elbow, wrist and digit areas of M1, no such expansion of the motor representation was observed, suggesting that recovery was due to other cortical or subcortical areas taking over control of hand/digit movements. Recently, we showed that one possible mechanism of recovery after lesion to the arm areas of M1 and lateral premotor cortex is enhancement of corticospinal projections from the medially located supplementary motor area (M2) to spinal cord laminae containing neurons which have lost substantial input from the lateral motor areas and play a critical role in reaching and digit movements. Because human stroke and brain injury patients show variable, and usually poorer, recovery of hand motor function than that of nonhuman primates after motor cortex damage, we conclude with a discussion of implications of this work for further experimentation to improve recovery of hand function in human stroke patients.

Editorial: Brain sag

Alaraj and colleagues1 report on 5 patients who, following the surgical repair of ruptured anterior communicating artery (ACoA) aneurysms aided by spinal drainage with or without fenestration of the lamina terminalis, demonstrated clinical “brain sag” with classic CT features: elongation of the midbrain and effacement of the basal cisterns. In all cases the angiogram obtained during the “sag episode” showed inferior displacement of the basilar artery when compared with the “pre-sag” angiogram, and in 3 cases, this displacement was so severe that the basilar artery kinked. Vertebral artery kinking was seen in some cases as well. In 4 of the 5 cases, brain sag was recognized in a timely fashion, and patients responded favorably to conventional maneuvers, most notably placement in the Trendelenburg position. In 3 of the 4 patients who improved with positional changes together with a blood patch or clamping of the spinal drain, a “post-sag” angiogram showed marked improvement in the displacement of the basilar artery. The fourth patient whose condition improved did not undergo post-sag angiography, as it was not deemed clinically necessary. The authors are careful to note that this angiographic picture was not seen in a similar population of patients lacking clinical brain sag who were being studied for vasospasm. While the authors’ series is small, it is carefully documented and provides dramatic evidence that the clinical symptoms of brain sag may not be solely due to mechanical displacement of the brainstem. Instead, regional posterior circulation cerebral ischemia may be a contributing factor. The fact that a surprisingly high percentage of their patients also exhibited early signs of vasospasm leads one to wonder whether brain sag is more common but becomes symptomatic only when there is concomitant vascular compromise. My initial impression, based on routine examination of early postsurgical CT scans, is that it is decidedly rare to see dramatic CT evidence of sag in an otherwise stable patient, although a more systematic review is needed. Such a review should clearly focus on ACoA aneurysms treated with spinal drainage. At my institution, our initial impression was that the combination of lamina terminalis fenestration and spinal drainage predisposes to brain sag,2 but maybe it is more a function of the subarachnoid dissection in this region given that ACoA aneurysm rupture often may have already rendered the ventricles in communication with the suprasellar cistern. In any case, since we recognized this phenomenon some years ago, we have kept all patients with spinal drainage and lamina terminalis fenestration flat in the immediate postoperative period, and we are quick to place a patient in the Trendelenburg position in the rare instance that it is needed. Using this approach we rarely need to resort to blood patch, and no patient has exhibited obvious irreversible deficits from the sag episode.3 That said, we have not looked to see whether patients with brain sag were more likely to develop delayed cerebral infarction from vasospasm or neurocognitive symptoms with delayed follow-up. While assuming the Trendelenburg position, many patients may have experienced increased systemic blood pressure, as vasospasm may have been in the differential diagnosis. Whether induced hypertension led to a more rapid reversal of symptoms was not examined. In conclusion, the proceeding paper is important because it documents for the first time the angiographic features of brain sag and leads us to reexamine what we think we know about its underlying pathophysiology, as well as how best to prevent it, treat it, and determine its true sequelae.