One report investigated the similarities and differences between volumetric analysis and cortical thickness, studying age-related changes, and found that volumetric measures contain a greater amount of variability than cortical thickness measures, suggesting that cortical thickness may be a more sensitive measure (Hutton, Draganski, et al. Importantly, the authors noted that both methods may provide independent information and could therefore be considered complementary. Changes in other measures of cortical morphology have also been reported to accompany advanced age. With regard to any regional differences in the volume of white matter adjacent to cortical regions of interest, Salat, Greve, et al. The authors also report that most of the regions followed a nonlinear path, suggesting that increasing age accelerates the rate of decline. Part of the inconsistencies may be due to the regional susceptibility of this area to agerelated changes (Sullivan, Marsh, et al. There is evidence to suggest regional heterogeneity of age-related changes within the hippocampus with an anterior-posterior age-related gradient whereby the more anterior areas show greater age-related reductions than posterior areas (Chen, Chuah et al. Many of these macroscopic age-related changes have been correlated with performance changes on various cognitive tests (Fjell and Walhovd 2010; Kaup, Mirzakhanian, et al. While morphometric changes in prefrontal areas have typically been linked with performance changes on tasks related to executive functions (Picq, Aujard, et al. In general, the trend in older individuals tends to be that "bigger is better," since most reports find that a decline in performance is correlated with a decline in structural abundance as well. Kennedy and Raz (2009) reported regional variation in the correlation between age-related white matter changes and cognitive performance, with anterior changes accounting for declines in processing speed, posterior changes accounting for declines in performance on task of inhibition and task switching, and central changes accounting for declines in episodic memory. White matter intensity also declined most prominently in the superior/medial frontal, cingulum, and medial/lateral temporal regions. The ratio of gray matter to white matter intensity was also found to be altered by age throughout the cortical mantle with the superior/inferior frontal, lateral parietal, superior temporal, and precuneus regions being most age-sensitive. Interestingly, these observed age effects were significantly stronger than changes in cortical 332 thickness. The authors speculate that the changes in signal intensity are most likely due to changes in myelination, as T1-weighted images are sensitive to macromolecules such as fats. Most notably, the authors found that throughout the life span, anterior regions have a longer gray matter T1 and shorter white matter T1 than posterior regions, possibly suggesting a higher level of myelination in the prefrontal regions. The authors found a posterior to anterior maturation gradient in intracortical T1 signal with T2* signal following a similar trend but later in life. An age-related increase in the correlation between cortical thickness and gray matter signal intensity was also reported, which the authors suggest indicates that measures of cortical thickness become more sensitive with increasing age. It is important that these age-related changes in tissue signal properties be kept in mind when interpreting results that are at least partially dependent on tissue classification based on signal intensity. There is an age-related increase in T1 white matter signal intensity, which could result in it being misclassified as gray matter (Jernigan 2001). Additionally, measures such as cortical thickness rely at least in some part on signal contrast differences to delineate the boundary between white matter and gray matter (Dale, Fischl, et al. Indeed, it has been found that including signal intensity measures as covariates in morphometric analysis can increase the sensitivity of these measures of interest such as cortical thickness (Westlye, Walhovd, et al. Unfortunately the technology is not yet at a point to detect structural changes at the cellular level, and so we must rely on postmortem analysis, as well as animal studies, to gather this information. Nearly all aspects of the dopaminergic system are sensitive to the effects of increasing age, including disruptions in normal dopamine synthesis and breakdown (Burchinsky 1984). Additionally, human postmortem studies have found age-related declines in both D1-like (D1) and D2-like (D2) receptors (Burchinsky 1984; Bäckman, Lindenberger, et al. This evidence indicates that there are clearly widespread significant age-related changes in the dopamine system, which is of great interest given the known relationship between this system and higher order cognitive functions. Widespread age-related changes in the serotonin system have also been reported (Nobler, Mann, et al. While there are reports of a 20%­30% decline in these receptors with age (Shiroma, Geda, et al. Altogether, these results suggest that the serotonergic system is vulnerable to the effects of increasing age. Studying this subpopulation in greater depth with genomics, epigenomics, and multi-modal neuroimaging may enable the identification of mechanisms that confer higher cognitive reserve and facilitate the discovery of strategies to slow cognitive aging. Choline is a cell membrane constituent and may be a marker of membrane turnover, as alterations in choline concentrations have been linked to cellular proliferation as well as membrane breakdown (Gujar, Maheshwari, et al. Creatine and phosphocreatine are markers of brain energy metabolism, and their combined measure is most commonly used as an internal standard (Gujar, Maheshwari, et al. In general, investigators have reported regional increased and/or decreased activation, recruitment of additional cortical areas, as well as different patterns of activity during many different cognitive tasks (Whalley, Deary, et al. These models are in contrast to the notion that alterations in neural function with aging could reflect de-differentiation of neural processing, leading to inefficient processing (Logan et al. To address the relationship between the reported age-related regional alterations in cortical activity during functional imaging studies and cognitive performance, Eyler et al. While this was more often observed in the frontal cortex and parietal and temporal cortices, the findings in the occipital cortex and medial temporal lobe were more mixed. Using advanced analytical tools, alterations in functional connectivity of brain regions within networks have also been documented with advancing age. Functional connectivity of brain regions reflects functional communication and information transfer between regions and is measured based on how synchronized or temporally correlated the activity of different brain regions within a network is. A variety of analysis techniques including graph-theoretical, non-linear, independent component analysis and correlational approaches can be used to measure the functional connectivity of brain regions. Using these approaches, in general both decreased as well as increased functional connectivity across brain regions have been observed with aging (for reviews, see (Ferreira and Busatto 2013; Antonenko and Floel 2014). Decreased connectivity of brain regions with increasing age within specific functional networks underlying different cognitive domains has been associated with worse cognitive performance. Increased connectivity of regions across networks, which could be interpreted as a reduction in specificity of brain networks with more diffuse and less specialized patterns of functional connections with aging, is consistent with the functional de-differentiation theory of aging proposed by Park et al. Evidence suggests that the trajectories of age-related changes in cognition and the underlying neurobiological changes as determined by neuroimaging techniques significantly vary across individuals (Mattay, Goldberg 2007). These observable inter-individual differences in cognitive aging trajectories may be the result of both genetic and non-genetic factors, and we are only beginning to understand how genetic variation accounts for these differences. It is important to note that most inherited aspects of the human aging process do not follow a simple Mendelian inheritance pattern. Instead, age-related phenotypes, including longevity and cognitive aging, are complex genetic traits that follow a polygenetic inheritance pattern whereby many small gene effects may account for a significant portion of inherited variance (Christensen, Johnson, et al. In the context of aging and changes in cognitive ability, genetic variation may be protective by resisting decline or may be detrimental by amplifying decline (Goldberg and Mattay 2007). At the neuronal level, protective genetic variation may act to maintain the structural/functional integrity of existing circuitry and/or promote compensatory activity through plasticity mechanisms. Alternatively, detrimental genetic variation may act to increase the rate at which normal age-related neuronal damage occurs and/or may impair compensatory mechanisms. In addition to genetics, there are several other factors that add to the inter-individual variance in cognitive aging. Investigation into these and other factors and their interactions with genetics is necessary to have a complete understanding of the variability in cognitive aging (Mattay, Goldberg, et al. What genetic analysis can potentially offer, however, is that through a better understanding of the genetic architecture of cognitive aging, specific genes or gene pathways may be identified as being responsible for a significant proportion of the variance in cognitive decline, which in turn will lead to the novel therapeutic targets as identified by these genes products to slow cognitive aging. Imaging genetics allows for the estimation of these genetic effects at the level of neural systems or brain information processing, which represents a more proximate biological link to genes and serves as an obligatory intermediate to age-related changes in cognition and behavior. As in other areas of neuropsychiatry and neuropsychology, the biological impact of a variation in a gene traverses an increasingly complex path from alterations at the molecular and cellular level to alterations in neural systems, which lead to variability in cognition and behavior with aging. Imaging genetics operates on the theory that the biological impact of a variation in a gene is greatest on the phenotypes that are at a level closer to the gene product itself. Neuroimaging phenotypes related to cognitive aging, such as alterations in brain morphometry and functional neural systems, are a step closer to the effect of genes and molecular/cellular function and are less heterogeneous than clinical, behavioral, and cognitive phenotypes. They are therefore deemed to have greater detection power (effect size), making imaging genetics a useful tool in the study of genetic influences on cognitive aging. It is well documented now that brain imaging methods allow the exploration of gene effects at the level of neuronal circuitry that are closer to the biologic effects of genes. In addition, whole brain imaging methods allow the study of many individual processes, in contrast to traditional behavioral measures, which report a single summary measure that is a product of multiple interactive processes. Further, the quantitative and qualitative changes in brain structure and function measured through neuroimaging often predate or precede observable cognitive and behavioral changes. Although promising, the identification of genes associated with cognitive aging from over 20,000 genes expressed in the human brain, many of which have alternative splicing, is a monumental task (Goldberg and Weinberger 2004; Mattay, Goldberg, et al. This issue is not unique to cognitive aging research, and there has been a great effort to generate and implement various strategies to identify genes that are associated with a particular phenotype. Candidate gene approaches investigate potential genes pre-selected by investigators based on their known biological importance, function, and/or association with disease. In the context of cognitive aging, researchers can choose from a long list of genes known to be associated with neurodegenerative/dementia diseases, longevity, cardiovascular and other systemic diseases, neuronal plasticity and stress response, as well as those known to be associated with cognitive ability (Deary, Wright, et al. These studies highlight the advantages and limitations of using an imaging genetics approach to studying the genetics of cognitive aging. Not surprisingly, the E4 allele has also been shown to decrease the probability of survival into very old age (Schachter, Faure-Delanef, et al. At the amino acid level, the three isoforms differ in containing either cysteine or arginine at positions 112 and 158, which results in different structural and functional properties (Hatters, Peters-Libeu, et al. Also, there is evidence to suggest that the E2 allele has a protective effect when compared to the E3 or E4 allele, although the rare E2 allele has also been associated with premature cardiovascular disease (Hatters, Peters-Libeu, et al. As a candidate gene for cognitive aging studies, this gene has proven to be quite informative in studying one of the many biological mechanisms responsible for cognitive aging, as it has been shown to influence structural, functional, and behavioral measures across the life span, and its underlying biology is relatively well understood. Furthermore, a recent meta-analysis of 77 studies including over 40,000 cognitively healthy adults reported that there was a larger performance gap between non-E4 carriers and E4 allele carriers in tests of episodic memory and global cognition in favor of the non-carriers (Wisdom, Callahan, et al. A decline in general cognitive ability from age 11 to age 79 was found only in the E4 carriers (Deary, Whiteman, et al. Along with these behavioral measures, there have been reports of this polymorphism influencing measures of brain structure and function. Additionally, the authors note that the E4 allele was also associated with decreased cerebral blood flow and glucose metabolism globally. Another study found that reductions in frontal lobe white matter and cortical volumes were related to slower processing and increase in systolic blood pressure in E4 carriers compared to E3 homozygotes. The authors suggest that even in healthy E4 carriers, clinically unremarkable increase in vascular risk may be associated with reduced frontal volumes and impaired cognitive functions (Bender and Raz 2012). Longitudinal analyses have also shown that the E4 allele is associated with greater rates of medial temporal lobe cortical thinning (Donix, Burggren, et al. Studies have also found thinner frontal cortical thickness and decreased gray matter volume in middle-aged E4 carriers, suggesting that the polymorphism could be associated with morphologic change several years before the potential onset of cognitive symptoms (Fennema-Notestine, Panizzon, et al. There is evidence to suggest that white matter also is regionally influenced by this polymorphism, with the E4 allele conferring reduced integrity across the life span in areas such as the corpus callosum, superior longitudinal fasciculus, and parahippocampal gyrus (Honea, Vidoni, et al. Since there was no memory impairment in the older group, the authors suggest that the decreased activity in the E4 carriers may be representative of the early stages of neuronal dysfunction, which may later manifest as memory impairment. Interestingly, overactivity is a common phenomenon reported in cognitive aging literature when comparing older adults to younger adults at the same level of performance (considered compensatory activity), suggesting the possibility that the overactivity observed in this study may indicate the early onset of a cognitive aging phenotype reflected as cortical inefficiency in the E4 carriers. Regional variation included loss of interconnectivity within the precuneus, orbitofrontal cortex, and lateral parietal cortex, as well as mean global loss of interconnectivity (Brown, Terashima, et al. Overall these studies, which include a wide range of imaging measures, provide evidence on how risk-associated gene variants can be used to explore their impact on brain structure and function across the life span, thereby leading to greater insight into the biological mechanisms that eventually lead to cognitive dysfunction later on in life. Neurotrophins are a class of molecules that are important for neuronal survival, growth, maintenance, and plasticity (McAllister, Katz, et al. The exact mechanism driving these age-related changes in expression is still unresolved, although the notion that it may be in part due to epigenetic mechanisms, some of which could be the result of early life experiences, has some support (Martinowich, Hattori, et al. In healthy adult individuals, the Met allele has been associated with lower performance on multiple cognitive tests, including those of episodic (Egan, Kojima, et al. Contrary to what may be assumed from these previous studies, it has been reported that the Met allele confers an advantage on tasks of response inhibition (Beste, Baune, et al. We should note, however, that there have been studies reporting no effect of this polymorphism on cognitive abilities (Gong, Zheng, et al. The reported genetic effect is present at the older end of the aging spectrum as well. In older adults, the Met allele is associated with lower ability in cognitive processes such as episodic memory, processing speed, working memory, and executive function (Erickson, Kim, et al. It has also been shown that the allele variants can impact cognitive performance in an age-dependent manner with performance differences only being manifested at older ages (Li, Chicherio, et al. Another study reported that the Met allele is associated with better performance in old age on a memory-based task-switching cognitive paradigm (Gajewski, Hengstler, et al. Younger Met allele carriers exhibit decreased hippocampal activity during tasks of episodic memory (Egan 2003; Hariri, Goldberg, et al. The Val66Met polymorphism has also been shown to influence neuronal activity in other cortical areas during behavioral adaptation (Beste, Kolev, et al. Individual differences in regional brain structure, including the prefrontal cortex and hippocampus, are also associated with genetic variation in this gene (Pezawas, Verchinski et al. The effect of the Val66Met polymorphism on neuroimaging measures extends into old age (and in some cases may be exaggerated). A decline in white matter integrity with increasing age for only Met carriers has been observed (Kennedy, Rodrigue, et al. Similar to the cortical morphology results, the age-related decline in hippocampal activity during both the encoding and retrieval sessions was significantly steeper in Met carriers when compared to performance-matched Val homozygotes. Importantly, for many of these neurotransmitter systems there is evidence of age-related changes (see previous section discussing age-related changes in molecular imaging), which may be in part due to temporal patterns of gene expression (Colantuoni, Lipska, et al. Dopaminergic activity, with its known importance for many cognitive abilities that decline with age and well-established neural circuits known to be impacted by normal aging, has been identified as a possible culprit for cognitive decline, and there is compelling evidence to suggest that this is indeed the case (Li, Lindenberger, et al. This polymorphism has proven to be especially fruitful in the context of understanding how dopaminergic activity can modulate neuronal activity related to cognitive performance through optimal dopamine levels following an inverted U function (Mattay, Goldberg, et al. Additionally, allelic differences have been associated with differences in brain structure (Ehrlich, Morrow, et al.

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Unlike motor conductions, the recording electrodes are placed over nerve not muscle. Nerve rather than muscle action potentials are measured, with maximal amplitudes measured in micro- rather than millivolts: making them more technically difficult to obtain. The same disc recording electrodes, or in the case of the median and ulnar nerves, ring electrodes on digits are utilized. The tested nerve is then stimulated at either a more proximal or a distal location than the recording site. The former technique is described as antidromic, as the impulse travels in the direction opposite to that of normal centripetal physiologic conduction in sensory nerve fibers. With stimuli delivered distal to the recording site in sensory or mixed nerves, conduction is considered orthodromic. Nerves routinely studied include the median, ulnar, dorsal cutaneous ulnar, radial, medial antebrachial cutaneous, lateral antebrachial cutaneous, sural, and superficial peroneal. Median motor nerve conduction at four different points of stimulation demonstrating differential slowing (temporal dispersion) in patient with multifocal motor neuropathy. Date: 9 Aug 06 A 1 238 V 500 uV Recording Site: Abductor pollicis brevis Stimulus site Lat1 ms 2. Many of these latter studies are fairly easy to obtain in the young, healthy, slender, and nonedematous but can be technically difficult in those with the opposite characteristics. As there are no neuromuscular junctions to contend with in sensory nerves, both the distal latency and the conduction velocity are measures of nerve conduction speed, differing only in the segment of nerve tested and the units with which it is reported. With motor conductions, there are some disorders in which distal latencies are prolonged disproportionate to forearm or leg conduction velocities. As there are few, if any, recognized conditions in which conduction speed is consistently more affected in one segment of sensory nerves than another, it can be argued that the reporting of distal latency as the sole measurement of sensory conduction speed is adequate. With motor distal latencies, the onset of the waveform is used for measurement, thereby identifying the fastest conducting axons. This phenomenon is more pronounced than its motor counterpart due to the far wider range of conduction velocities in sensory nerves. F Waves and H Reflexes Motor and sensory conduction studies are typically performed in the below elbow and knee segments where nerves are more anatomically accessible. F waves and H reflexes have potential value as a result of their ability to assess conduction in more proximally located nerve segments. F waves can be obtained by delivering supramaximal stimulation to any motor or mixed nerve in a normal individual, in most instances. F waves can be difficult to obtain in certain nerves, for example, common peroneal, even in the apparent absence of pathology. For that reason, it can be perilous to suggest the existence of nerve injury based solely on the absence of an F response from a single nerve. In normal adults, H reflexes can be elicited from the soleus muscle while stimulating the tibial nerve and, on occasion, from the flexor carpi radialis. Identification of H reflexes in other nerve/muscle pairs implies the existence of upper motor neuron disease due to decreased central nervous system inhibition on the reflex arc, analogous to a hyperactive deep tendon reflex. The relevant anatomy and physiology of an F response can be described in the following manner. In addition, the initial nerve depolarization also produces an antidromic action potential traveling centripetally toward the spinal cord. At the level of the corresponding anterior cell(s), this antidromic action potential establishes a persistent or second action potential at the level of either the perikaryon or its axon hillock. This supplemental action potential is carried in a centrifugal or orthodromic direction along the entire length of one or more of the same motor axon(s) back to the original target muscle. As a result, the muscle is depolarized twice in response to a single stimulus, the second muscle action potential (F wave) having understandably a much longer latency and smaller amplitude. As a result, sequential F wave responses have varying latencies and morphologies in comparison to those occurring with the previous or subsequent stimuli. Amplitude measurements are of no particular value, as these represent the action potentials of only a small and varying proportion of single muscle fibers. There is heterogeneity of F wave latencies as sequential responses rarely arise from motor axons with identical conduction velocities. A number of latency measurements can be made, the response with the shortest latency typically being the parameter reported. The potential value of F waves is their ability to detect conduction slowing over the segments of nerve not tested by routine conduction velocity measurements, that is, the proximal to elbow and knee segments. This value is most apparent early in the course of acquired demyelinating neuropathies, where prolonged F wave latencies may occur because of disease predilection for nerve roots, prior to slowing of conduction velocity or prolongation of distal latency in more distal nerve segments. In most cases however, F waves are either absent, or prolonged in the setting of slowed conduction velocities. Simultaneous slowing of conduction velocities and F waves has no localizing value, as the slowing of the F latency in this circumstance may represent slowing in the same distal aspect of the nerve where the conduction velocity is measured. The H reflex represents the electrophysiologic analog of the Achilles deep tendon reflex. As in the F response, the stimulus applied to the tibial nerve in the popliteal fossa will travel in two directions. With delivery of stimuli of low intensity and long duration (1 ms), the lower-threshold 1 A sensory fibers within the tibial nerve are preferentially activated. As a result, the initial action potentials are propagated solely within thickly myelinated sensory nerve fibers. These impulses travel both centrifugally, where they have no known clinical or diagnostic consequence, and centripetally (orthodromically) along tibial and sciatic sensory fibers. Impulse transmission through the dorsal root of the S1 segment allows completion of a monosynaptic reflex to S1 anterior horn cells. Typically, the H reflex has a latency in the high 20 to mid-30 s range, depending on patient height. As the intensity of the stimulus delivered to the tibial nerve increases, characteristic H reflex behavior is demonstrable. Action potentials will develop within the higherthreshold tibial motor fibers in addition to the 1 A sensory fibers already activated. This has a far shorter latency than the H reflex and does not typically make its appearance until the H reflex is well established. The antidromic action potentials created in tibial motor fibers have a different effect. These will collide in a proximal location with the action potentials responsible for the H reflex. The tibial motor fibers distal to the stimulus site are depolarized twice, whereas both the tibial sensory fibers and the tibial motor fibers proximal to the stimulation site are depolarized once in response to a single stimulus. The former estimates the number of viable motor units and muscle fibers within the S1 segment/ soleus muscle complex and is typically greater than 1 mV in size. The latter provides at least an estimate of conduction speed within the motor and sensory fibers of the S1 segment. H reflex-five consecutive and increasing stimuli to the tibial nerve in the popliteal fossa in a normal individual, recording from the soleus demonstrating a typical H reflex pattern, that is, H reflex amplitude initially > M response amplitude, subsequent peaking than decline, and eventual absence of H reflex, associated with gradual increase to supramaximal M response. This applies most frequently early in the course of acquired demyelinating polyneuropathies. In addition, H reflex amplitudes have value in the assessment of S1 radiculopathies. If an H reflex is absent more than a week after symptom onset in the setting of normal routine conduction parameters and reduced recruitment in S1 innervated muscles, proximal conduction block in the tibial nerve, sciatic nerve, sacral plexus, or S1 nerve root can be inferred. Focal slowing of nerve conduction in a proximal location is theoretically detectable by H reflex assessment. In reality, this slowing is usually obscured by normal conduction speed in the other normal and more extensive parts of the S1 reflex arc. Attempts to provide an anatomic diagnosis of a focal neuropathy or radiculopathy on the basis of by F and H responses alone should be discouraged. Their amplitudes are proportionate to the number of successful interactions between acetylcholine (Ach) molecules and muscle end-plate receptor sites. To avoid false-positive results based on technical factors, a decrement of at least 10% is required to be considered abnormal although a smaller decrement in a technically pristine study is suspicious. This decremental response has both clinical and single fiber analogues, that is, fatigable weakness and blocking of single fiber action potentials, respectively. Unfortunately the muscles with the highest diagnostic yield are also those most prone to movement and technical artifact. In order for a decremental response to be considered pathologic, it must be reproducible and conform to the typical pattern. If a train of 8­10 stimuli are delivered, the resulting configuration will have an asymmetric saucer-like appearance, with the left edge being higher. In a seemingly paradoxical manner, this can be accomplished by the delivery of ChAptEr 2 TesTing in neuromuscular Disease 33 Rec:Trapezius 2 mV Rep stim Right Accessory (spinal) Review Right Trapezius Recalling number 6 #4 16:53:46 2 s 2 mV 5 ms Stim. Stated in a different way, this is accomplished with stimuli delivered at intervals shorter than 200 s. This is the most notable difference between pre- and postsynaptic disorders and sets the stage for the ability to demonstrate an incremental response. With the brief exercise technique, a supramaximal stimulus is followed by 10 seconds of isometric exercise to the muscle being studied, and then immediately by a second post-exercise supramaximal stimulus. Trains of fast repetitive stimulation are typically reserved for those who cannot perform or cooperate with the post-exercise technique. To overly simplify the concept, if it is small, try to make it bigger, and if it is big, try to make it smaller. This can be accomplished by brief exercise, fast repetitive stimulation (10­50 Hz) or by administration of an anticholinesterase medication. If a decrement is not demonstrable at baseline, repeating the train once a minute for 5 minutes following 1 minute of exercise applied to that muscle may improve diagnostic yield. Early in the course, this may be the only abnormality found with nerve conductions. In this case, the initial response from the electrodiagnostician should be to attempt to elicit an incremental response. This is easily done in a cooperative patient by exercising the appropriate muscle for 10 seconds and then immediately delivering a second supramaximal stimulus as described above. If the patient is not cooperative, a train of fast repetitive stimuli (10­50 Hz) may be used as a surrogate. If an increment is demonstrated, a subsequent train of stimuli delivered at 2­3 Hz will produce a characteristic decrement and further solidify the diagnosis of a neuromuscular transmission defect. Short- and Long-Exercise Tests the nondystrophic muscle channelopathies constitute a complex, overlapping group of disorders related to gene mutations of chloride, calcium, sodium, and potassium (Andersen­Tawil syndrome) channels in muscle. As a result of their pathophysiologies, the phenotypes are typically dominated at least initially by episodic symptoms, either stiffness related to myotonia, weakness related to periodic paralysis, or a combination of both. Stiffness is felt to result from persistent muscle fiber depolarization and contraction whereas periodic weakness is felt to represent a more severe degree of depolarization rendering the muscle inexcitable. In chronic stages, particularly in the periodic paralyses, persistent weakness may develop. Shortand long-exercise tests offer diagnostic support for both the existence and type of muscle channelopathy. Both forms of exercise testing require careful attention to uniform patient positioning, limb temperature, muscle relaxation, and stimulus intensity. The first step is to try and demonstrate a decremental response to slow repetitive stimulation. After a 10-second rest period between trials, two subsequent, identical trials are performed, each preceded by 10 seconds of isometric exercise. Five patterns of abnormality have been described, the first three of which utilize the short-exercise test alone. The other two patterns are defined by a combination of the long- and short-exercise tests. In normal individuals, cooling with or without rewarming the limb does not alter the normal pattern. During the period of exercise, single supramaximal stimuli are delivered at 1-minute intervals. Subsequent to the exercise, single supramaximal stimuli are then delivered immediately, every minute for 5­6 minutes, and then every 2­5 minutes for 40­50 minutes. The long-exercise test is of the greatest utility in the identification of the periodic paralyses. Authorities recommend that an abnormal decrement on long-exercise testing for amplitude and area exceeds 40%. In general, because of discomfort, repetitive stimulation is performed in suspected nondystrophic myotonia cases only when the remainder of the electrodiagnostic assessment is inconclusive. The reader is referred to Table 2-1 and Chapter 30 for summary and complete description of these disorders. If it exceeds 40% of baseline, it is considered pathognomonic of a chloride channel disorder. With the subsequent two trials, the magnitude of the decrement lessens but the trajectory of the curves remains the same. With cooling, the magnitude the decrement increases slightly, particularly in dominantly inherited disease. The magnitude of this response becomes more dramatic in the second and third trials. In this type 1 pattern, the most dramatic effect occurs following limb cooling, or rewarming following cooling. They dissipate both within an individual trial and between subsequent short-exercise trials. The clinical weakness associated with the long-exercise test may preclude its completion.

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Genetic main effects: Higher genetic risk profile scores predicted elevated cortisol response to acute experimental stress. Interactive effects: Higher profile scores in interaction with stressful life events during early childhood and predicted differences in left amygdala and hippocampal volume in adolescence. Cortisol response in early childhood mediated the interaction of profile scores and early-life events on amygdala volume. Genetic main effects: G allele carriers of rs4142324 had greater dorsolateral prefrontal cortex activation during the working memory task. Haplotypes (rs7728378, rs1875999, rs10474485, rs7704995, and rs1500) for Plains Indians and (rs7728378, rs1875999, rs7704995, and rs1500) for Caucasian group were also associated with decreased alpha. Genetic main effects: T allele carriers had significant differences in hippocampal morphology. Interaction effect: C allele carriers exposed to high solar activity while in the womb (first trimester) had relatively larger left hippocampal volumes and lower neuroticism scores. Specifically, there was a positive association between emotional neglect and threat-related amygdala reactivity in Iso allele homozygotes. In contrast, Val-allele carriers had increased amygdala reactivity relative to Iso allele homozygotes, but only in the context of relatively low childhood adversity. Thus, even in the context of low prior adversity, Val allele carriers display neural patterns similar to those of maltreated individuals. Additionally, it suggests that Iso allele homozygotes may be more sensitive to environmental circumstances, including both social adversity and support. However, Val allele carriers may be more vulnerable to the development of stress-related illness, even in the absence of significant environmental stress. Unlike the ventral amygdala which primarily receives sensory, hippocampal, and prefrontal input, the dorsal amygdala projects to the brain stem, hypothalamus, and prefrontal cortex. These dorsal afferents drive autonomic and neuroendocrine systems, as well as attention and vigilance, to respond to environmental challenges (Davis and Whalen 2001; LeDoux 2007). Furthermore, preliminary research has replicated this interaction in an independent sample of ethnically-heterogeneous young adults (n = 334; Di Iorio et al. The vast majority of imaging genetics research has examined the association between single polymorphic loci and individual differences in neural phenotypes. Very broadly, this approach can be qualified into two primary scoring schemes: (1) summation of risk alleles or weighted effects, providing a "risk" score, or (2) a biologically-informed score based upon previously reported associations with gene function or downstream consequences representing the function of a biological system. Consistent with the literature, the profile predicted elevated cortisol response to acute stress. Interestingly, the profile interacted with stressful life events during early childhood to predict later differences in amygdala (as well as hippocampal) 404 volume measured during ages 7­12, which is consistent with a cortisol-mediated mechanism predicting later structural differences (Burghy et al. This profile predicted individual differences in threat-related amygdala reactivity, as well as risk for mood and anxiety disorders. It will be important for future studies to examine gene expression changes in response to acute stress manipulations concurrent with the collection of neuroimaging data to more directly investigate potential mediating mechanisms. In the following sections, we highlight these challenges and discuss ways in which the field is presently confronting them. In human research, the assessment of environmental exposure is fraught with difficulties, ranging from memory and information-processing biases. For example, there is only a modest correlation between self-reported versus clinician-assessed stressful life events (McQuaid et al. Moreover, in self reports, individuals may endorse events that objective raters would not report as stressful. Numerous studies emphasize the importance of both an objective evaluation of stress. Ideally, measures of the environment would be carefully selected to assess various aspects of stress exposure, including the subjective perception of stress and its objective contextual characterization, and, when possible, used within the context of prospective designs that can assess changes over time (Pagliaccio et al. Recent developments in naturalistic experience sampling methods among self-report measures (Wichers et al. Finally, it is critical to consider theoretical work postulating that polymorphisms typically characterized as risk alleles by the diathesis-stress model may be more accurately envisioned as plasticity variants (Belsky et al. Thus, research incorporating environmental measures integrating both adversity and enrichment. This is underscored by the recently-described stress-buffering effects of positive enrivonmental circumstances (Cohen and Hoberman 1983; Chi 2001; Hyde et al. However, our understanding of the ways in which genetic variation and the environment influence neural phenotypes will remain limited until we begin to examine putative mediational mechanisms (Hyde et al. Despite the potential utility of such mediating constructs, important factors may also limit their explanatory potential. Similarly, measuring gene expression differences is limited to measures from peripheral tissues. In light of evidence for regionally specific differences in gene expression and methylation which we are presently unable to examine in live humans, it will be important for convergent non-human animal work and postmortem human studies to examine regionally-specific gene expression. However, excitement from initial imaging genetics research has been tempered by sober realizations that common genetic variation confers, at best, only a small effect on brain and behavior. For example, a recent imaging genetics study found that the combined effect of 122,072 variants nominally associated with depression (p <. Small effects of single common variants present a major challenge to the field, as such weak pentrance is difficult to detect and likely to result in non-replication, especially in the small samples that compose most current imaging genetics studies. Due to increasing concerns of inadequate statistical power (McClelland and Judd 1993), research incorporating the environment enhances the challenge of small effects, particularly when interactions are driven by the extreme ends of a distribution. Recent reports suggest that GxE studies of psychiatric disorders have a high false-discovery rate and are tainted by both publication bias. These concerns have led to increasing demands for large sample sizes to ensure appropriate statistical power, as well as direct replication studies that increase our confidence in novel findings. While inconclusive, some research suggests that effect sizes for intermediate phenotypes. Notably, independent and collaborative imaging genetics studies are beginning to approach sample sizes that will allow for adequate testing within larger samples, and ideally, replication efforts across samples (Duke Neurogenetics Study, Moreover, for the true strength of this research to be realized, it will need to integrate environmental measures and manipulations, as well as test mediational pathways that might underlie the effect of gene x environment interaction on brain circuitry. Finally, and like other forms of imaging genetics research, it will be important for this research to use longitudinal assessment to examine whether these individual differences predict the development of psychopathology. Do early-life events permanently alter behavioral and hormonal responses to stressors Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders. Behavioral inhibition system activity is associated with increased amygdala and hippocampal gray matter volume: a voxel-based morphometry study. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology. Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity. Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence. Stressful life events and depressive symptoms: social support and sense of control as mediators or moderators Therapy insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression The brain and the stress axis: the neural correlates of cortisol regulation in response to stress. A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. Insights into causal pathways for ischemic heart disease: adverse childhood experiences study. A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis. Genetic modulation of neural response during working memory in healthy individuals: interaction of glucocorticoid receptor and dopaminergic genes. AutoSense: unobtrusively wearable sensor suite for inferring the onset, causality, and consequences of stress in the field. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. The heritability of hypothalamus pituitary adrenal axis responses to psychosocial stress is context dependent. Frodl T, Meisenzahl E, Zetzsche T, Bottlender R, Born C, Groll C, Jäger M, Leinsinger G, Hahn K, Möller H-J. Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation. Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo­pituitary­adrenocortical responsiveness. Neurogenetics of individual differences in brain, behavior and risk for psychopathology. Perceived social support moderates the link between threat-related amygdala reactivity and trait anxiety. Association of childhood socioeconomic status with subsequent coronary heart disease in physicians. Human models in acute and chronic stress: Assessing determinants of individual hypothalamus­pituitary­adrenal axis activity and reactivity. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Long-term behavioural alterations in female rats after a single intense footshock followed by situational reminders. Increased amygdala: hippocampal volume ratios associated with severity of anxiety in pediatric major depression. Altered amygdala and hippocampus function in adolescents with hypercortisolemia: a functional magnetic resonance imaging study of Cushing syndrome. Glucocorticoid dysregulations and their clinical correlates: from receptors to therapeutics. Responsiveness of the hypothalamic-pituitary-adrenal axis to different novel environments is a consistent individual trait in adult male outbred rats. The impact of childhood maltreatment: a review of neurobiological and genetic factors. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. A comparison of two life stress assessment approaches: prospective prediction of treatment outcome in recurrent depression. Toward the standardization of life stress assessment: Definitional discrepancies and inconsistencies in methods. Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Mineralocorticoid receptor overexpression in basolateral amygdala reduces corticosterone secretion and anxiety. Gene-environment interactions in depression research: genetic polymorphisms and life-stress polyprocedures. Severe life events predict specific patterns of change in cognitive biases in major depression. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. Stress-System Genes and Life Stress Predict Cortisol Levels and Amygdala and Hippocampal Volumes in Children. Corticosteroid-induced adverse psychiatric effects: incidence, diagnosis and management. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Cognition and life stress in depression: cognitive factors and the definition, rating, and generation of negative life events. Variability factors in the expression of stress-induced behavioural sensitisation. Depression and hypothalamicpituitary-adrenal activation: a quantitative summary of four decades of research. Elevated amygdala response to faces following early deprivation: neurodevelopment and adversity. A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. The neurobiological correlates of childhood adversity and implications for treatment. Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. Early neglect and abuse predict diurnal cortisol patterns in adults A study of international adoptees. Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study.

Usage: q.3h.

Benzodiazepines have less well-developed antispasticity properties and are frequently used as an adjunct rather than as a primary antispasticity treatment. Intrathecal baclofen delivered by a programmable pump is an option if oral drugs do not provide the desired effect. The theoretical benefit is to deliver the drug directly to the afflicted end organ in small titratable doses in order to avoid the side effects commonly associated with the larger oral doses required. Intrathecal baclofen may allow certain patients who are spastic to remain ambulatory longer than their natural history would otherwise allow. A more realistic goal is to diminish refractory painful spasms or to diminish lower extremity tone to facilitate hygiene. Injection of botulinum toxin into spastic muscles provides an alternative means to diminish muscle tone. Many payers limit reimbursement to 400 units per session, which may be inadequate to achieve the desired goals. The effect of botulinum toxin is greatest when the toxin is delivered in proximity to the motor point. Identification of the most severely affected muscles and delivery of the lowest effective doses are the two major principles used. There are a number of pharmacological agents that may ameliorate but rarely resolve this problem. Tizanidine is an alpha adrenergic agent thought to produce presynaptic inhibition of motor neurons, potentially by reducing glutamate release, again at the spinal cord level. Typically however, the first-line treatments are muscarinic anticholinergic agents which counteract detrusor hyperreflexia mediated through parasympathetic nerve fibers traveling via the S2­4 roots and the pelvic nerve. Tricyclic antidepressants may also be utilized for their anticholinergic properties. Other, less frequently used therapies with uncertain benefit include botulinum toxin injections into the detrusor, intravesicular delivery of certain drugs including capsaicin, and S2­4 ventral root stimulation coupled with analogous dorsal rhizotomies. Durable medical equipment and home modification can provide substantial benefit to individual patients. Ankle­foot orthoses are of great benefit to individual patients to prevent falls due to tripping. Ideally, they should be custom fitted to improve comfort, particularly in consideration of associated cavus foot deformities. A skilled physical therapist is an invaluable tool to decide whether a cane, Lofstran or Canadian crutches, a walker, or a wheelchair is the best solution for an individual patient. The Dashaway walker is particularly helpful in these patients in that it diminishes the risk of falling backward more so than traditional walker designs. Reimbursement may be problematic as payers typically require documentation that a patient is unable to propel themselves in a manual chair prior to authorization. Patients who require forms of power mobility who also have trunk, upper extremity, or bulbar weakness are better served by a power chair because of the trunk support, ability to operate with a joystick control, and the ability to mount other equipment that may be beneficial to the patient. Many patients resent the symbolism of durable medical equipment, viewing it as a "setback" and a constant reminder of their impaired condition. It may be effective to promote durable medical equipment to them as an opportunity. Specifically, it may allow them to maintain their independent mobility while minimizing the risk of falls and the potential of severe injury, the quickest and most likely threat to their independence. In patients who live in multiple-story dwellings who require access to more than one floor, stair lifts provide a safe and energysparing option. Patients motivated to perform daily stretching exercises claim to enjoy considerable benefit from doing so. Examples include: · National Institute of Neurological Disorders and Stroke · Hereditary Spastic Paraplegia Foundation, Inc. Meta-analysis of age at onset in spastin-associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class. Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: Discrete entities or spectrum Differentiation of hereditary spastic paraparesis from primary lateral sclerosis in sporadic adult-onset upper motor neuron syndromes. Paraplegin mutations in apparently sporadic adult-onset upper motor neuron syndromes. Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegia. For these reasons, we find it difficult to recommend prenatal testing in view of the risk to the fetus associated with amniocentesis or chorionic villous sampling. It is a disorder that offers the opportunity to understand how semi-selective vulnerability of a single component of the nervous system can occur as a result of seemingly disparate pathophysiologies. The prevalence of "pure" autosomal dominant hereditary spastic paraplegia in the island of Ireland. Hereditary "pure" spastic paraplegia: A clinical and genetic study of 22 families. Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. We have become very aware that the historical boundaries of hereditary neuromuscular disease are inaccurate. Even more damaging to the historical nosology of hereditary neuromuscular disease is the discovery that mutations of a single gene may produce variable phenotypes that have been historically represented as two or more diseases (Table 8-1). Its incidence is estimated to occur in a range of four to ten × 105 live births, depending on the geographic cohort studied. Affected infants are hypotonic with a symmetric, generalized, or proximally predominant pattern of weakness. Fasciculations are seen in the tongue but rarely in limb muscles, presumably due to the ample subcutaneous tissue of neonates. Abdominal breathing, and bulbar symptoms such as a weak cry, poor suck and feeding, and impaired secretion clearance are commonplace. The characteristic appearance includes pectus excavatum with a diminished anterior­posterior diameter of the chest, a bell-shaped chest, and a protuberant abdomen. These features are due to the relative diaphragmatic sparing in comparison to external intercostals early in the disease course. Mild contractures may occur, but arthrogryposis is not part of the classic phenotype. Without mechanical ventilation, the large majority die in the first two years of life usually as a direct or indirect consequence of bulbar and/or ventilatory muscle weakness. Postural hand tremor is the only significant phenotypic variance from Werdnig­Hoffman disease. Approximately 98% of these individuals survive to the age of 5 years and two-thirds to the age of 25 years. Afflicted individuals develop the ability to stand and walk which are subsequently lost in childhood, adolescence, or adulthood. Initial symptoms are referable to weakness of proximal leg muscles in the vast majority of cases. Hip flexors and extensors and knee extensors are usually the most severely affected muscles. Tongue and limb fasciculations, hand tremor, and, in some cases, calf hypertrophy occur. Clinical clues implicating a potential but less common neuromuscular cause of a floppy infant include preservation of alertness, depressed or absent deep tendon reflexes, the pattern of weakness, and fasciculations if present. Fasciculation potentials may or may not be identified in part because of the necessary brevity of the needle examination in many children. The density and geographic distribution of fibrillation potentials in comparison to changes of chronic partial denervation and reinnervation is related to the rapidity with which these disorders progress. Although pragmatically difficult to apply to the pediatric patient, motor unit instability and the rate of decline of motor unit number estimation may also provide prognostic insight. A mutation detected in only one parent is reassuring but does not guarantee healthy children. In addition, as with many chronic neurogenic disorders, "pseudomyopathic" features such as fiber splitting, increased endomysial connective tissue, and an increased number of internal nuclei may be seen. Although 95% of affected individuals have homozygous mutations, 5% have more complex compound heterozygotic mutations with a typical deletion in one allele with a subtle intragenic defect on the other. Autosomal-dominant inheritance, referred to as the Finkel type, is estimated to occur in approximately 30% of these patients. Aminoglycosides, quinazoline derivatives and drugs that can inhibit the enzyme histone deacetylase have been used in animal models and in some cases in humans. Mouse models utilizing gene therapy as well as intrathecal embryonic stem cell transplants have shown considerable promise. In summary, physicians are urged to provide parents, and when applicable the patient, information related to the natural history of the disease, genetic implications, and the role and availability of clinical trials. The development of kyphoscoliosis is a common problem in children who become wheelchair bound. Spine stabilization is commonly recommended in individuals whose curves exceed 50 degrees and whose vital capacities exceed 40% of the predicted normal value. The goals of this intervention are patient comfort, ease of patient management, and potential stabilization of restrictive pulmonary deficits. Noninvasive positive pressure ventilation may provide an improved quality and duration of life in child with symptoms of ventilatory insufficiency until a decision regarding tracheostomy is required. Understandably, without mechanical ventilation, life expectancy is limited to months in most cases. There appear to be clusters of increased prevalence in Japan and the Vasa region of Western Finland. As the name implies, the clinical manifestations are largely referable to the lower cranial nerve motor nuclei and the anterior horn cells of the spinal cord. There are notable exceptions including distal weakness and asymmetric limb weakness that may occur in more than a half of patients. Approximately 10% of the time, the initial symptoms pertain to involvement of brainstem motor nuclei with difficulty in swallowing, chewing, or speaking. Postural tremor of the limbs or perioral tremor are commonplace and on occasion, may be the presenting manifestation. Only a third of affected individuals will be wheel chair dependent 20 years following symptom onset. A singular case has been reported in which treatment with a low fat diet, riboflavin, carnitine, 3-hydroxybutyrate, and glycine seemed to have provided temporary clinical stabilization. Oligo- or azospermia, elevated levels of testosterone, progesterone, estradiol, follicle stimulating hormone, or luteinizing hormone may occur. The pattern is however nonspecific, and does not allow distinction from many other neuromuscular diseases. Approximately half of the women who are heterozygous for the Kennedy disease mutation will be minimally symptomatic. Hyperlipidemia and abnormal liver function are thought to occur in this population as well. There is a proximal form of hereditary sensory motor neuropathy with locus at 3q13. Upper extremity sensory conductions seem just as likely as lower extremity sensory conductions to be abnormal in a manner consistent with a dorsal root ganglionopathy. Animal modeling would suggest that these findings may be related to a separate myopathic disease component that may precede motor neuron degeneration. Inclusions are also found through numerous regions of the central nervous system including the basal ganglia. This concept is supported by observations of the rare female homozygotes, or in mouse models in which homozygous females and mutant castrated males where little if any disease develops. Cramps may respond to nightly stretching and medications such as valproate, mexiletine gabapentin, tizanidine, baclofen, magnesium, or carbamazepine although in our experience, none of these are particularly effective. Tremor is rarely severe enough to warrant treatment but may respond to propranolol or primidone. Gynecomastia, if problematic, may be treated with hormonal therapy, castration, or surgical reduction. Durable medical equipment to facilitate safe mobility is a mainstay of treatment in the latter stages of the disease. A normal repeat number will remain stable in subsequent generations whereas progeny of individuals with 38 or 39 repeats may develop disease from gene expansion. The majority of cases appear to be genetically transmitted; spontaneous mutations are thought to occur rarely. Approximately 30% of diagnosed individuals in one series had no other identifiable family members. Although there have been occasional reports of more than one firstdegree family member involved, the majority of cases appear to be sporadic. With Hirayama disease and other related phenotypes, bilateral involvement is not rare. Preserved brachioradialis bulk in contrast to the atrophied medial flexor compartment muscles is a notable observation in many cases. Over the course of months to years, the weakness may spread gradually to more proximal arm muscles. In 30­40% of cases, there is clinical weakness of the opposite limb, with an even higher percentage having electrodiagnostic evidence of bilateral involvement. A bilateral symmetric form of the disease has been described and in one large series represented 10% of cases although even in these cases the disease evolved asymmetrically. The first of these was described in an Indian population in 1981 where most affected individuals had weakness distributed throughout the affected lower limb although preferential quadriceps involvement did occur. Like Hirayama, it may be either unilateral or bilateral in approximately half of affected individuals and appears to have a similar male predominance. If the patient has coincident evidence of cervical spondylosis on imaging or electrodiagnostic evidence of ulnar nerve slowing at the elbow or prolonged median distal latencies, unnecessary surgical intervention may take place.