Heterogeneity of Phasic Cholinergic Signaling in Neocortical Neurons

Journal of Neurophysiology. Mar, 2007  |  Pubmed ID: 17122323

Acetylcholine (ACh) is a neurotransmitter critical for normal cognition. Here we demonstrate heterogeneity of cholinergic signaling in neocortical neurons in the rat prefrontal, somatosensory, and visual cortex. Focal ACh application (100 muM) inhibited layer 5 pyramidal neurons in all cortical areas via activation of an apamin-sensitive SK-type calcium-activated potassium conductance. Cholinergic inhibition was most robust in prefrontal layer 5 neurons, where it relies on the same signal transduction mechanism (M1-like receptors, IP(3)-dependent calcium release, and SK-channels) as exists in somatosensory pyramidal neurons. Pyramidal neurons in layer 2/3 were less responsive to ACh, but substantial apamin-sensitive inhibitory responses occurred in deep layer 3 neurons of the visual cortex. ACh was only inhibitory when presented near the somata of layer 5 pyramidal neurons, where repetitive ACh applications generated discrete inhibitory events at frequencies of up to approximately 0.5 Hz. Fast-spiking (FS) nonpyramidal neurons in all cortical areas were unresponsive to ACh. When applied to non-FS interneurons in layers 2/3 and 5, ACh generated mecamylamine-sensitive nicotinic responses (38% of cells), apamin-insensitive hyperpolarizing responses, with or without initial nicotinic depolarization (7% of neurons), or no response at all (55% of cells). Responses in interneurons were similar across cortical layers and regions but were correlated with cellular physiology and the expression of biochemical markers associated with different classes of nonpyramidal neurons. Finally, ACh generated nicotinic responses in all layer 1 neurons tested. These data demonstrate that phasic cholinergic input can directly inhibit projection neurons throughout the cortex while sculpting intracortical processing, especially in superficial layers.

Assessment of Nerve Excitability in Toxic and Metabolic Neuropathies

Journal of the Peripheral Nervous System : JPNS. Mar, 2008  |  Pubmed ID: 18346228

Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.

Acute Abnormalities of Sensory Nerve Function Associated with Oxaliplatin-induced Neurotoxicity

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2009  |  Pubmed ID: 19164207

Neurotoxicity is becoming increasingly recognized as the major dose-limiting toxicity of oxaliplatin. Because the mechanism of oxaliplatin-induced neurotoxicity remains unclear, the present study investigated the potential of axonal excitability techniques in identifying pathophysiologic mechanisms and early markers of nerve dysfunction.

Axonal Ion Channels from Bench to Bedside: a Translational Neuroscience Perspective

Progress in Neurobiology. Nov, 2009  |  Pubmed ID: 19699774

Over recent decades, the development of specialised techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states.

Oxaliplatin-induced Neurotoxicity: Changes in Axonal Excitability Precede Development of Neuropathy

Brain : a Journal of Neurology. Oct, 2009  |  Pubmed ID: 19745023

Administration of oxaliplatin, a platinum-based chemotherapy used extensively in the treatment of colorectal cancer, is complicated by prominent dose-limiting neurotoxicity. Acute neurotoxicity develops following oxaliplatin infusion and resolves within days, while chronic neuropathy develops progressively with higher cumulative doses. To investigate the pathophysiology of oxaliplatin-induced neurotoxicity and neuropathy, clinical grading scales, nerve conduction studies and a total of 905 axonal excitability studies were undertaken in a cohort of 58 consecutive oxaliplatin-treated patients. Acutely following individual oxaliplatin infusions, significant changes were evident in both sensory and motor axons in recovery cycle parameters (P < 0.05), consistent with the development of a functional channelopathy of axonal sodium channels. Longitudinally across treatment (cumulative oxaliplatin dose 776 +/- 46 mg/m(2)), progressive abnormalities developed in sensory axons (refractoriness P < or = 0.001; superexcitability P < 0.001; hyperpolarizing threshold electrotonus 90-100 ms P < or = 0.001), while motor axonal excitability remained unchanged (P > 0.05), consistent with the purely sensory symptoms of chronic oxaliplatin-induced neuropathy. Sensory abnormalities occurred prior to significant reduction in compound sensory amplitude and the development of neuropathy (P < 0.01). Sensory excitability abnormalities that developed during early treatment cycles (cumulative dose 294 +/- 16 mg/m(2) oxaliplatin; P < 0.05) were able to predict final clinical outcome on an individual patient basis in 80% of patients. As such, sensory axonal excitability techniques may provide a means to identify pre-clinical oxaliplatin-induced nerve dysfunction prior to the onset of chronic neuropathy. Furthermore, patients with severe neurotoxicity at treatment completion demonstrated greater excitability changes (P < 0.05) than those left with mild or moderate neurotoxicity, suggesting that assessment of sensory excitability parameters may provide a sensitive biomarker of severity for oxaliplatin-induced neurotoxicity.

Oxaliplatin-induced Lhermitte's Phenomenon As a Manifestation of Severe Generalized Neurotoxicity

Oncology. 2009  |  Pubmed ID: 20016227

Lhermitte's phenomenon, characterized by 'electric-shock' sensations precipitated by neck flexion, may develop during oxaliplatin treatment. Limited cases have been described previously and the pathophysiology underlying Lhermitte's phenomenon in oxaliplatin-treated patients has not been established.

Acute, Reversible Axonal Energy Failure During Stroke-like Episodes in MELAS

Pediatrics. Sep, 2010  |  Pubmed ID: 20679297

The pathophysiology of stroke-like episodes in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) remains unresolved. Possible mechanisms include mitochondrial angiopathy, cytopathy, or both, collectively resulting in cellular energy depletion. To clarify disease mechanisms, axonal excitability properties were investigated in a 10-year-old child with MELAS. Serial assessments during a stroke-like episode revealed reversible depolarization of the axonal membrane consistent with disruption of energy-dependent processes. Axonal parameters correlated with the clinical assessment of central dysfunction and biochemical measures of acidosis. Novel axonal excitability techniques have established acute, reversible ischemic-like depolarization that may serve as a surrogate marker of central events that develop during stroke-like episodes in MELAS.

Utilizing Natural Activity to Dissect the Pathophysiology of Acute Oxaliplatin-induced Neuropathy

Experimental Neurology. Jan, 2011  |  Pubmed ID: 20965170

Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose-limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na(+)/K(+) pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na(+) channel-associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na(+)/K(+) pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na(+) channel inactivation.

Early, Progressive, and Sustained Dysfunction of Sensory Axons Underlies Paclitaxel-induced Neuropathy

Muscle & Nerve. Mar, 2011  |  Pubmed ID: 21321953

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.

The Contribution of SK3 Polymorphisms to Acute Oxaliplatin-induced Neurotoxicity: Direct or Indirect Effects?

Cancer Chemotherapy and Pharmacology. May, 2011  |  Pubmed ID: 21327679

Long-term Neuropathy After Oxaliplatin Treatment: Challenging the Dictum of Reversibility

The Oncologist. 2011  |  Pubmed ID: 21478275

Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments.

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

PloS One. 2011  |  Pubmed ID: 21494615

Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction.

Neuroprotection for Oxaliplatin-induced Neurotoxicity: What Happened to Objective Assessment?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2011  |  Pubmed ID: 21606425

Modulatory Effects on Axonal Function After Intravenous Immunoglobulin Therapy in Chronic Inflammatory Demyelinating Polyneuropathy

Archives of Neurology. Jul, 2011  |  Pubmed ID: 21747028

To investigate the immediate and longitudinal mechanisms of action of intravenous immunoglobulin (IVIg) on axonal function in chronic inflammatory demyelinating polyneuropathy (CIDP).

Purple Pigments: the Pathophysiology of Acute Porphyric Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Dec, 2011  |  Pubmed ID: 21855406

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.

Dysfunction of Axonal Membrane Conductances in Adolescents and Young Adults with Spinal Muscular Atrophy

Brain : a Journal of Neurology. Nov, 2011  |  Pubmed ID: 21926101

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K(+) and Na(+) conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

Activity-dependent Conduction Failure: Molecular Insights

Journal of the Peripheral Nervous System : JPNS. Sep, 2011  |  Pubmed ID: 22003929

Weakness and fatigue are commonly encountered symptoms in neurological disorders and significantly impair quality of life. In the case of motor axons, conduction block contributes to weakness and fatigue and may be associated with aberrant nerve activity including fasciculations and cramp. These symptoms result from dysfunction of the constituent channels and pumps of the axonal membrane. In critically conducting axons, impulse conduction can be impaired by the effects of activity or by other mechanisms that produce a significant shift in membrane potential. Conduction failure may be accentuated or relieved by maneuvers that manipulate the time course of the driving current, including the administration of agents that interfere with Na(+) channel function. In patients with inflammatory neuropathies, normal activity may be sufficient to precipitate conduction failure at sites of impaired function in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). From a clinical perspective, these features are not assessed adequately by conventional neurophysiological techniques. As weakness and fatigue may only develop following activity or exertion, it is useful to assess the effects of impulse trains to determine the extent of conduction failure and the resulting symptoms in neurological patients. These techniques and the physiological mechanisms underlying the development of activity-dependent hyperpolarization will be critically appraised in this review, with a focus on demyelinating neuropathies, MMN and the neurodegenerative disease, and amyotrophic lateral sclerosis (ALS).

Regional Differences in Ulnar Nerve Excitability May Predispose to the Development of Entrapment Neuropathy

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jan, 2011  |  Pubmed ID: 20591727

To assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow.

Longitudinal Assessment of Oxaliplatin-induced Neuropathy

Neurology. Jan, 2012  |  Pubmed ID: 22232054

Impact of Oxaliplatin-induced Neuropathy: a Patient Perspective

Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. Mar, 2012  |  Pubmed ID: 22426503

INTRODUCTION: Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. OBJECTIVES: The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. METHODS: Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. RESULTS: Twenty patients were assessed, 12.6 ± 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). CONCLUSION: Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin-induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients.

Progressive Axonal Dysfunction Precedes Development of Neuropathy in Type 2 Diabetes

Diabetes. Apr, 2012  |  Pubmed ID: 22522615

To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA(1c) levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0-1 [n = 35]), grade 1 (TNS 2-8 [n = 42]), and grade 2/3 (TNS 9-24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA(1c) level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.