118 NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases

walk at 1 year. Thus, of the two modalities, IVIg is now considered the treatment of rst choice due to its efcacy, ease of administration, and low incidence of side effects. Although plasma exchange clearly removes presumed blood-borne factors involved in the pathogenesis of the disease, the mechanisms of action of IVIg administration are less certain, but may include binding of Fc receptors, increased clearance of immunoglobulins, and/or stimulation of remyelination. Unlike CIDP, steroids have not been shown to be helpful in treatment of GBS.

Prognosis

Paparounas K (2004) Anti-GQ1b ganglioside antibody in peripheral nervous system disorders: pathophysiologic role and clinical relevance. Archives of Neurology 61: 10131016. Rabinstein AA and Wijdicks EFM (2003) Warning signs of imminent respiratory failure in neurological patients. Seminars in Neurology 23: 97104. Victor M and Ropper AH (2001) Adams and Victors Principles of Neurology, 7th edn. New York: McGraw-Hill. Willison HJ and Yuki N (2002) Peripheral neuropathies and antiglycolipid antibodies. Brain 125: 25912625. Winer JB (2001) GuillainBarre syndrome. Molecular Pathology 54: 381385. Yuki N, Susuki K, Koga M, et al. (2004) Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes GuillainBarre syndrome. Proceedings of the National Academy of Sciences 101: 1140411409.

Overall, the prognosis for recovery of patients with GBS is favorable with the majority of patients (65%) experiencing little or no disability. Of the remaining patients, less than 5% will die in the acute stages of the illness, usually from cardiac arrhythmias or pulmonary embolism while those who do survive will be left with persistent deficits. The percentage of patients experiencing chronic impairments has not been significantly altered by the introduction of IVIg or plasma exchange, which both shorten time to recovery but not the proportion of patients attaining a good recovery. Factors associated with a poor outcome include advanced age, rapid progression of symptoms, need for ventilatory support, and severely diminished muscle action potential amplitude on electromyography. Also, a more severe course and poorer prognosis are associated with the AMSAN subtype.
See also: Autoantibodies. Myoglobin. Neurophysiology: Neurons and Neuromuscular Transmission.

Upper Motor Neuron Diseases

n, and J Sancho, Valencia E Servera, J Mar University, Valencia, Spain
& 2006 Elsevier Ltd. All rights reserved.

Abstract
Upper motor neuron diseases are a heterogeneous group of disorders in which a degeneration of motor neurons of the cortex and tronchoencephalic motor nucleus occurs. Clinically, these disorders are characterized by weakness, motor clumsiness, spasticity, and hyperreexia. The major cause of morbidity and mortality in these disorders is due to the involvement and dysfunction of respiratory muscles. Amyotrophic lateral sclerosis is the most characteristic example of motor neuron disease in which both the upper and lower motor neuron are involved; when only the upper motor neuron is affected, it is called primary lateral sclerosis. Other diseases with upper motor neuron dysfunction are spinal cord injury, multiple sclerosis, and stroke. In Parkinsons disease, the upper motor neuron is indirectly affected. Respiratory muscle involvement entails alveolar hypoventilation, decreased cough capacity, and the risk of aspiration due to bulbar dysfunction. The use of respiratory muscle aids, noninvasive mechanical ventilation, and manually and mechanically assisted cough can improve survival, quality of life, and avoid hospitalization when respiratory muscles are involved. Moreover, during acute respiratory episodes, the combined use of inspiratory and expiratory muscle aids can avoid endotracheal intubation; this means continuous noninvasive ventilation with adequate respiratory secretions management if different interfaces are correctly used.

Further Reading
Asbury AK (2005) Approach to the patient with peripheral neuropathy. In: Kasper DL, Braunwald E, Fauci AS, et al. (eds.) Harrisons Principles of Internal Medicine, 16th edn., pp. 2500 2510. New York: McGraw-Hill. Asbury AK and Thomas PK (eds.) (1995) Peripheral Nerve Disorders II. Oxford: ButterworthHeinemann. Bennett CL and Chance PF (2001) Molecular pathogenesis of hereditary motor, sensory and autonomic neuropathies. Current Opinion in Neurology 14: 621627. Chalela JA (2001) Pearls and pitfalls in the intensive care management of GuillainBarre syndrome. Seminars in Neurology 21: 399405. Donofrio PD (2003) Immunotherapy of idiopathic inammatory neuropathies. Muscle and Nerve 28: 273292. Kieseier BC and Hartung HP (2003) Therapeutic strategies in the GuillainBarre syndrome. Seminars in Neurology 23: 159168. Kieseier BC, Kiefer R, Gold R, Hemmer B, Willison HJ, and Hartung HP (2004) Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle & Nerve 30: 131156.

Introduction
Upper motor neuron diseases are a heterogeneous group of disorders in which a degeneration of motor neurons of the cortex and tronchoencephalic motor nucleus occurs. Clinically, these disorders are characterized by muscular weakness, particularly of the extensor musculature of the upper limb and of the exor musculature of the lower limb, motor clumsiness,

NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases 119

spasticity, and hyperreexia; they may be associated with clonus and pathological reexes (e.g., Babinski sign). When these disorders affect the corticobulbar way bilaterally, the most characteristic symptom is emotional lability. In these disorders, dysfunction of the respiratory muscles (the inspiratory and expiratory muscles) and the upper airway muscles accounts for the major cause of morbidity and mortality.

Etiology
Amyotrophic lateral sclerosis (ALS) is the most characteristic example of motor neuron disease. In ALS, both upper and lower motor neuron diseases are involved. When the dysfunction is selective of the upper motor neuron, it is called primary lateral sclerosis (PLS); this is a sporadic disease with a lower incidence than ALS. Spinal cord injury (SCI) is another important cause of upper motor neuron affection and is the main cause of chronic hypoventilation failure in young people. Other disorders that can affect upper motor neurons are multiple sclerosis (MS) and strokes in which corticospinal and bulbospinal tracts are involved. Another serious disorder in which the upper motor neuron is indirectly affected is Parkinsons disease (PD). In PD, the excessive inhibition of the talamocortical pathway produces a diminution of the stimulus of motor and premotor cortical areas.

gradually increases, which is related to the inability to achieve a full inhalation and contributes to increase the effort required for breathing. This loss of the capacity to perform maximum inations produces structural changes of the lung and the thoracic cage. Deformities associated with the disease, such as kyphoscoliosis, also contribute to chest wall stiffness and increase the effort required for breathing. Cough capacity decreases due to inspiratory muscle weakness that inhibits a deep inspiration at the beginning of the cough effort, expiratory muscle weakness that inhibits an energetic contraction, unstable upper airway dysfunction, and inability to close the glottis (Figure 1). Involvement of the bulbar muscles produces inadequate respiratory protection and a risk of aspiration.
Spinal Cord Injury

Pathology and Physiopathology

Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis

In PLS, there is a selective degeneration of the Betz motor neuron in lamina V of the cortex and a degeneration of corticospinal tracts. In ALS, the abnormality spreads to the anterior horn of the medulla and bulbar motor centers. In both diseases, the respiratory problems are related to weakness of respiratory muscles; respiratory complications are more severe in ALS than in PLS because in the former both upper and lower motor neurons are affected. Inspiratory muscle weakness produces hypoventilation. In the early stages of the disease, hypoventilation is present only in the rapid eye movement phase of sleep, but worsening gas exchange abnormalities contribute to frequent arousals, reducing sleeping time and sleeping efciency, and result in daytime symptoms of sleep deprivation. As the disease worsens, hypoventilation extends to total sleeping time and then to the period during which the patient is awake. Moreover, due to inspiratory muscle weakness, the elastic load of the chest wall

In SCI, respiratory muscle impairment depends on the level of the medullary lesion. High cervical cord lesions (C1C2) and middle cervical cord lesions (C3 C5) cause paralysis of the diaphragm, intercostal, scalene, and abdominal muscles. These lesions result in severe hypoventilation, reduced ability to clear secretions (due to the loss of the ability to hyperinate the lungs and an ineffective cough), and atelectasis. Low cervical lesions (C6C8) and upper thoracic cord lesions denervate the intercostal and abdominal muscles but leave the diaphragm and neck muscles intact. Although phrenic nerves remain completely, or at least partially, intact at these levels, the intercostal activity necessary to stabilize the ribcage is lost, resulting in a compromised ventilation. Moreover, cough capacity is decreased due to weakness of expiratory muscles. Prognosis improves as lesions move downwards. When the lesion is lower in the spinal cord, the expiratory muscles, and thus cough capacity, are often more affected than the inspiratory muscles.
Multiple Sclerosis

The pathological hallmark of MS is the presence of multiple areas of nerve demyelination, which may vary in size and localization. When MS affects the motor pathway, it causes muscle weakness and spasticity. Respiratory failure is a late manifestation of advanced disease, although acute respiratory failure can occur due to demyelination lesions of the cervical spinal cord or the respiratory centers of the medulla. Patients usually develop the insidious onset of chronic respiratory failure due to weakness of the respiratory muscles, especially the expiratory muscles. This weakness is produced due to demyelination, inactivity, and the effects of treatment with steroids. The respiratory dysfunction in MS may be

120 NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases

Malnutrition Fatigue Bulbar dysfunction

Weakness

Thoracic cage deformities Decreased parenchima

Decreased cough capacity Alveolar hy hypoventilation

Loss of compliance Bronchial obstruction

Sleep disturbances

a 2003; Figure 1 Factors determining respiratory failure in motor neuron disease. Figure reprinted from Archivos de Bronconeumolog 39(9): 418427. Permission granted by Ediciones Doyma S.L. Table 1 Patterns of respiratory involvement in multiple sclerosis depending on demyelinating plaque localization Abnormality Paralysis of voluntary breathing Paralysis of automatic breathing Diaphragmatic paralysis Apneustic breathing preserved Paroxysmal hyperventilation Obstructive sleep apnea Neurogenic pulmonary edema Anatomic localization Bilateral corticospinal tracts, brainstem, or cervical cord Dorsomedial medulla, nucleus ambiguus, and medial lemnisc Upper cervical cord Lower brainstem Lower brainstem Tegmentum of medulla Medulla in region of nucleus tractus solitarius and oor of fourth ventricle Table 2 Indications for noninvasive mechanical ventilation in neuromuscular diseases Symptoms: e.g., fatigue, dyspnea, and morning headache Physiologic criteria (one of the following): PaCO2445 mmHg Nocturnal oximetry demonstrating oxygen saturation o88% for 5 consecutive min For progressive neuromuscular disease, maximal inspiratory pressures o60 cmH2O or FVC o50% predicted Source: American College of Chest Physicians; Goldberg AC, Legger P, Hill NS, et al. (1999). Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD and nocturnal hypoventilation. A consensus conference report. Chest 116: 521534.

caused by respiratory muscle weakness (hypoventilation and ineffective cough), bulbar dysfunction, obstructive sleep apnea, abnormalities in respiratory control, and paradoxical hyperventilation (Table 1).
Stroke

The two most important motor pathways for respiratory control are the corticospinal tracts and the bulbospinal tracts. The former is responsible for voluntary breathing and the latter for automatic breathing. Hemispheric ischemic strokes inuence respiratory function to only a modest degree; reduced chest wall movement and diaphragmatic excursion contralateral to the stroke have been reported. Therefore, vascular accidents of the cortex do not cause significant diaphragmatic impairment; however, in capsular stroke with extensive damage of the pyramidal respiratory bers, the voluntary control of breathing

can be impaired with inability to change breathing voluntarily in the presence of preserved autonomic respiratory function. Damage to the bulbospinal tract eliminates autonomic control of breathing but leaves voluntary control intact (Ondines syndrome). In this situation, severe hypoventilation is produced during resting. Lateral medullary strokes can cause hypoventilation, apneustic breathing, ataxic breathing, and hyperventilation.
Parkinsons Disease

In PD, there is a degeneration of the compact part of the nigra substance resulting in a degradation of the dopaminergic nigrostriatal pathway that produces a dopaminergic denervation of the striatum nucleus. This results in an increase in acid g-aminobutiric inhibitory activity due to an increase in the activity of inner palidus nucleus neurons. The dysfunction of

NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases 121

Figure 2 (a) Noninvasive mechanical ventilation via mouthpiece and (b) mechanical aids to coughing with the Emerson In mez-Merino E, ExsufatorTM for a hospitalized patient with ALS and a pulmonary infection. Reproduced from Servera E, Sancho J, Go et al. (2003) Noninvasive management of an acute chest infection for a patient with ALS. Journal of Neurological Science 209: 1113, with permission from Elsevier.

respiratory muscles results in alveolar hypoventilation, a decrease in cough effectiveness, and upper airway dysfunction. Inspiratory muscle strength decreases with the progression of the disease due to impaired neural drive of the muscles. Inspiratory muscle endurance decreases in early PD due to impaired activation of the motor cortex for the respiratory muscles, a shift in the bers fatigue-resistant type I and IIa to the more fatigable type IIb, mitochondrial abnormalities, and lack of coordination between inspiratory and

expiratory muscles. Expiratory muscle weakness produces a decrease in cough capacity. Upper airway dysfunction can produce occasional sudden and intermittent airway closure.

Clinical Features
Respiratory symptoms in disorders that damage upper motor neurons are related to alveolar hypoventilation, impaired cough capacity, and upper airway dysfunction. Dyspnea, orthopnea, restless sleep,

122 NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases

nightmares, early morning headaches, and daytime hypersomnolence are related to alveolar hypoventilation. When respiratory impairment progresses, pulmonary hypertension with cardiac failure (cor pulmonale) can be present with increased orthopnea and dyspnea and lower extremity edema. Impaired cough capacity produces retained respiratory secretions that increase airway resistance and alter the respiratory mechanics. Moreover, these retained secretions can produce atelectasis and there is a high risk of superinfection and pneumonia. With the involvement of the upper airway, speaking and swallowing are affected and the risk of aspiration is greater, contributing to the impairment of cough effectiveness. This results in inadequate nutrition, weight loss, drooling, choking episodes and recurrent pulmonary infections due to aspiration episodes. In PD, the upper airway muscle dysfunction with closure can produce stridor, sudden death by apnea, and obstructive sleep apnea. During an acute respiratory episode such as a banal chest cold, respiratory muscle weakness is increased, impairing hypoventilation and cough capacity. In this way, these episodes can lead to acute respiratory failure.
Lung Function Tests

In order to view the drop in pulseoxihemoglobin saturation during sleep, a nocturnal pulse oximetry must be performed. A polysomnographic record is appropriate when obstructive sleep apnea is suspected. To study swallowing disorders related to bulbar dysfunction, videouoroscopy is performed.

Management of Respiratory Problems

Management of respiratory problems in motor neuron disorders must be centered on three key points: alveolar hypoventilation, respiratory secretions, and swallowing disorders.
Alveolar Hypoventilation

Noninvasive mechanical ventilation (NIV) has been used successfully to treat hypoventilation in neuromuscular patients (Table 2). NIV provides mechanical ventilation without access to the trachea and relieves dyspnea, and it also improves survival, cognitive function, and quality of life. The most common method of NIV is positive pressure ventilation with a pressure or volume ventilator. Initially, NIV is administered nocturnally and as needed during the daytime. A combination of different interfaces can be used to maintain NIV continuously throughout the

Arterial blood gases show hypoxemia and, with the progression of the disease and impairment of hypoventilation, hypoxemia and hypercapnia. Spirometry and lung volumes show a restrictive pattern with decreased vital capacity and forced expiratory volume in 1 s and total lung capacity. Vital capacity has been shown to be a good prognostic factor; however, maximum insufation capacity (MIC) is proposed to be a more useful prognostic measurement. MIC is the maximum volume of air that can be stacked in lungs with the glottis closed. MIC lower than 1500 ml indicates great difculty in attaining an effective cough. Respiratory muscle force tests, such as static maximum pressures at the mouth (PImax and PEmax) and transdiaphragmatic pressure (Tdi), are infrequently used. Measurement of ows generated during a coughing effort has been proposed as an effective and useful parameter of cough capacity because peak ows generated during the expulsive phase of cough (PCF) are responsible for airway secretion removal. PCF lower than 2.7 l s 1 probably results in an ineffective cough, and PCF lower than 4.5 l s 1 in a stable patient indicates a high risk that the cough will become ineffective during an acute chest episode. Another test for measuring cough capacity is gastric pressure during a cough effort (PgaCo); however, this causes discomfort to the patient.

Figure 3 Complete atelectasis due to aspiration solved after 6 h with intensive use of mechanical in-exsufation.

NEUROMUSCULAR DISEASE / Upper Motor Neuron Diseases 123

day (mouthpiece during day and nasal, oronasal, or lipseal during sleep) (Figure 2). In patients with severe bulbar involvement, NIV is often ineffective and poorly tolerated. When NIV is ineffective or poorly tolerated or refused by the patient, a tracheostomy is mandatory to initiate invasive mechanical ventilation. During acute episodes, continuous NIV can avoid endotracheal intubation with adequate respiratory secretions management and if different interfaces are correctly used. In patients with severe bulbar dysfunction, NIV tends to fail in acute episodes.
Respiratory Secretions

When the patient is unable to perform an effective cough effort (PCFo2:70 l s1 ), there is a high risk of major complications, such as atelectasis, superinfection of retained secretion, pneumonia, increased difculty in breathing with acute respiratory failure, and failure of NIV. Several approaches are available to increase cough capacity in neuromuscular patients; however,
12 8 4 4 2

manually and mechanically assisted techniques have proved effective in removing respiratory secretions. In manually assisted cough, a thoracic and/or abdominal thrust is applied in synchrony with the patients cough effort, leading to enhanced expiratory ow rates. The effectiveness of manually assisted cough is greater if the patients lungs are insufflated before the highest volume that can be retained with a closed glottis with a manual resuscitator or a portable volume-limited ventilator. This technique requires patient cooperation and good bulbar function to close the glottis. When manually assisted cough cannot generate an effective cough effort, mechanically assisted cough TM with Cough Assist is the best alternative (Figures 3 TM and 4). Cough Assist delivers a deep insufation using positive pressure followed immediately by an equal negative pressure that produces a forced exsufation (MI-E). If a thoracic and/or abdominal thrust is applied during the exsufation cycle, the PCF generated will be greater. MI-E does not require

4 8 12 1 (a) 12 8 4 2 3 4 5 6 7

2 4 6 (b)

PCFMI-E PCFMIC PCF

4 2

4 8 12 (c)

2 4 6 1 2 3 4 5 6 7 (d) 1 2 3 4

Figure 4 Flowvolume loops during coughing show unassisted and assisted peak cough ow (PCF). (a) No respiratory muscle involvement with effective unassisted PCF. (b) Ineffective unassisted PCF. It is effective, however, when manual and mechanical aids are applied: Both have the same values. (c) Ineffective unassisted PCF. Mechanically assisted PCF are clearly greater than manually assisted ones, but both are effective. (d) Severe bulbar dysfunction with ineffective assisted PCF.

124 NEUROMUSCULAR DISEASE / Myasthenia Gravis and Other Diseases

the patients collaboration; in severe bulbar dysfunction, however, MI-E can be ineffective due to a dynamic upper airway collapse during the exsufation cycle (Figure 4(d)). When assisted coughing techniques cannot remove airway secretions, a tracheostomy must be performed in order to gain direct access to them. MI-E can be applied through a tracheostomy to avoid complications related to aspiration with a catheter. Moreover, aspiration with a conventional catheter through a tracheostomy tube fails to enter the main left stem bronchus in 90% of cases, but MI-E, when it is applied through the tracheostomy tubes, is able to clear the central, medium, and small bronchi of both left and right airways.
Swallowing Disorders

When bulbar dysfunction produces aspiration, a percutaneous endoscopic gastrostomy must be performed in order to provide adequate nutrition and avoid the risk of respiratory problems related to an incompetent glottis.
See also: Arterial Blood Gases. Carbon Dioxide. Neuromuscular Disease: Inherited Myopathies; Lower Motor Neuron Diseases; Acquired Myopathies; Peripheral Nerves; Upper Motor Neuron Diseases; Myasthenia Gravis and Other Diseases of the Neuromuscular Junction. Neurophysiology: Neurons and Neuromuscular Transmission. Respiratory Muscles, Chest Wall, Diaphragm, and Other. Signs of Respiratory Disease: Breathing Patterns. Sleep Disorders: Central Apnea (Ondines Curse); Hypoventilation. Ventilation, Mechanical: Negative Pressure Ventilation; Noninvasive Ventilation; Positive Pressure Ventilation.

Hadjikoutis S and Wiles CM (2001) Respiratory complications related to bulbar dysfunction in motor neuron disease. Acta Neurologica Scandinavia 103: 207213. Laghi F and Tobin MJ (2003) Disorders of the respiratory muscles. American Journal of Respiratory and Critical Care Medicine 168: 1048. Make BJ, Hill NS, Goldberg AL, et al. (1998) Mechanical ventilation beyond the intensive care unit. Report of a consensus conference of the American College of Chest Physicians. Chest 113(5 supplement): 289S344S. Mausel JK and Norman JR (1990) Respiratory complications and management of spinal cord injuries. Chest 97: 14461452. Miller RG, Rosenberg JA, Gelinas DF, et al. (1999) Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence based review): report of the quality standards subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology 52: 13111323. Perrin C, Uterborn J, Da mbrosio C, et al. (2004) Pulmonary complications of chronic neuromuscular diseases and their management. Muscle & Nerve 29: 527. Servera E, Sancho J, and Zafra MJ (2003) Cough and neuromuscular diseases. Noninvasive airway secretions management. Archivos de Bronconeumolog a 39: 418427. Servera E, Sancho J, Go mez-Merino E, et al. (2003) Noninvansive management of an acute chest infection for a patient with ALS. Journal of Neurological Science 209: 1113. Vingerhoest F and Bogousslavsk J (1994) Respiratory dysfunction in stroke. Clinical Chest Medicine 15: 729737. Winslow C and Rozovsky J (2003) Effect of spinal cord injury on the respiratory system. American Journal of Physical Medicine and Rehabilitation 82: 803814.

Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

H M DeLisser, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
& 2006 Elsevier Ltd. All rights reserved.

Further Reading
Bach JR (1994) Update and perspectives on noninvasive respiratory muscle aids. Part 1: The inspiratory aids. Chest 105(4): 12301240. Bach JR (1994) Update and perspective on noninvasive respiratory muscle aids. Part 2: The expiratory aids. Chest 105(5): 15381544. Bach JR (2004) Noninvasive respiratory muscle aids: intervention goals and mechanisms of action. In: Bach JR (ed.) Management of Patients with Neuromuscular Disease, pp. 211270. Philadelphia: Hanley & Belfus. Brown LK (1994) Respiratory dysfunction in Parkinsons disease. Clinical Chest Medicine 15: 715722. Goldberg AC, Legger P, Hill NS, et al. (1999) Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD and nocturnal hypoventilation. A consensus conference report. Chest 116: 521534. Gosselink R, Kovacs L, and Decramer M (1999) Respiratory muscle involvement in multiple sclerosis. European Respiratory Journal 13: 449454.

Abstract
Processes that target the neuromuscular junction may result in clinical syndromes characterized by muscle weakness. Among these disorders, the most common is myasthenia gravis (MG), an acquired, autoimmune disease in which the acetylcholine receptor is targeted in the majority of affected patients. The underlying cause of MG, however, remains unknown. Fluctuating muscle weakness is the hallmark feature of MG. Ocular, facial, oropharyngeal, axial and limb muscles may be differentially involved, leading to a variety of clinical presentations. Ventialtory support may be required for up to 20% of patients who develop respiratory insufciency due to inspiratory muscle weakness and/or inability to maintain a patent upper airway. MG must be distinguished from a number of other disorders including, the LambertEaton myasthenic syndrome, botulism, and non-immune genetic congenital myasthenic syndromes. In addition to several general measures, a number of treatments are available for MG with differing onsets, peaks and durations of effects.