Threshold Tracking Research Articles

Excitability properties of motor axons in adults with cerebral palsy

Cerebral palsy (CP) is a permanent disorder caused by a lesion to the developing brain that significantly impairs motor function. The neurophysiological mechanisms underlying motor impairment are not well understood. Specifically, few have addressed whether motoneuron or peripheral axon properties are altered in CP, even though disruption of descending inputs to the spinal cord may cause them to change. In the present study, we have compared nerve excitability properties in seven adults with CP and fourteen healthy controls using threshold tracking techniques by stimulating the median nerve at the wrist and recording the compound muscle action potential over the abductor pollicis brevis. The excitability properties in the CP subjects were found to be abnormal. Early and late depolarizing and hyperpolarizing threshold electrotonus was significantly larger (i.e., fanning out), and resting current–threshold (I/V) slope was smaller, in CP compared to control. In addition resting threshold and rheobase tended to be larger in CP. According to a modeling analysis of the data, an increase in leakage current under or through the myelin sheath, i.e., the Barrett–Barrett conductance, combined with a slight hyperpolarization of the resting membrane potential, best explained the group differences in excitability properties. There was a trend for those with greater impairment in gross motor function to have more abnormal axon properties. The findings indicate plasticity of motor axon properties far removed from the site of the lesion. We suspect that this plasticity is caused by disruption of descending inputs to the motoneurons at an early age around the time of their injury.

Threshold tracking TMS: A novel diagnostic technique for Amyotrophic Lateral Sclerosis (S24.005)

Threshold tracking TMS: A novel diagnostic technique for Amyotrophic Lateral Sclerosis (S24.005)

Threshold tracking TMS: A novel diagnostic technique for Amyotrophic Lateral Sclerosis (I8-5C)

Threshold tracking TMS: A novel diagnostic technique for Amyotrophic Lateral Sclerosis (I8-5C)

Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study

Diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with substantial diagnostic delays. We assessed the sensitivity and specificity of a threshold tracking transcranial magnetic stimulation (TMS) technique, which might allow early detection of upper motor neuron dysfunction, for the diagnosis of the disorder. We did a prospective study of patients referred to three neuromuscular centres in Sydney, Australia, in accordance with the Standards for Reporting of Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as defined by the Awaji criteria; or pure motor disorder with clinical features of upper and lower motor neuron dysfunction in at least one body region, progressing over a 6 month follow-up period; or muscle wasting and weakness for at least 6 months. All patients underwent threshold tracking TMS at recruitment (index test), with application of the reference standard, the Awaji criteria, to differentiate patients with ALS from those with non-ALS disorders. The investigators who did the index test were masked to the results of the reference test and all other investigations. The primary outcome measures were the sensitivity and specificity of TMS in differentiating ALS from non-ALS disorders; these measures were derived from receiver operator curve analysis. Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 with non-ALS disorders; the diagnosis of four patients was inconclusive. The threshold tracking TMS technique differentiated ALS from non-ALS disorders with a sensitivity of 73·21% (95% CI 66·66-79·08) and specificity of 80·88% (69·53-89·40) at an early stage in the disease. All patients tolerated the study well, and we did not record any adverse events from performance of the index test. The threshold tracking TMS technique reliably distinguishes ALS from non-ALS disorders and, if these findings are replicated in larger studies, could represent a useful diagnostic investigation when combined with the Awaji criteria to prove upper motor neuron dysfunction at early stages of ALS. Motor Neuron Disease Research Institute of Australia, National Health and Medical Research Council of Australia, and Pfizer.

Observation of time-dependent psychophysical functions and accounting for threshold drifts.

Methods to obtain estimates of psychophysical functions are used in numerous fields, such as audiology, vision, and pain. Neurophysiological and psychological processes underlying this function are assumed to remain stationary throughout a psychophysical experiment. However, violation of this assumption (e.g., due to habituation or changing decisional factors) likely affects the estimates of psychophysical parameters. We used computer simulations to study how non-stationary processes, resulting in a time-dependent psychophysical function, affect threshold and slope estimates. Moreover, we propose methods to improve the estimation quality when stationarity is violated. A psychophysical detection experiment was modeled as a stochastic process ruled by a logistic psychophysical function. The threshold was modeled to drift over time and was defined as either a linear or nonlinear function. Threshold and slope estimates were obtained by using three estimation procedures: a static procedure assuming stationarity, a relaxed procedure accounting for linear effects of time, and a threshold tracking paradigm. For illustrative purposes, data acquired from two human subjects were used to estimate their thresholds and slopes using all estimation procedures. Threshold estimates obtained by all estimations procedures were similar to the mean true threshold. However, due to threshold drift, the slope was underestimated by the static procedure. The relaxed procedure only underestimated the slope when the threshold drifted nonlinearly over time. The tracking paradigm performed best and therefore, we recommend using the tracking paradigm in human psychophysical detection experiments to obtain estimates of the threshold and slope and to identify the mode of non-stationarity.

Simplified flexible-PON upstream transmission using pulse position modulation at ONU and DSP-enabled soft-combining at OLT for adaptive link budgets

We demonstrate a flexible modulation and detection scheme for upstream transmission in passive optical networks using pulse position modulation at optical network unit, facilitating burst-mode detection with automatic decision threshold tracking, and DSP-enabled soft-combining at optical line terminal. Adaptive receiver sensitivities of -33.1 dBm, -36.6 dBm and -38.3 dBm at a bit error ratio of 10(-4) are respectively achieved for 2.5 Gb/s, 1.25 Gb/s and 625 Mb/s after transmission over a 20-km standard single-mode fiber without any optical amplification.

Axonal excitability in primary amyloidotic neuropathy.

Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in vivo assessment of the properties of the axonal membrane and may shed light on pathogenetic mechanisms underlying neuropathic disorders. We studied 10 subjects with primary amyloidosis using conventional nerve conduction studies and quantitative sensory, autonomic, and axonal excitability testing of median motor and sensory fibers. As expected, subjects with amyloidosis had evidence of small- and large-fiber neuropathy on conventional testing. There was no significant difference in axonal excitability between subjects and controls apart from the stimulus required to activate sensory fibers. Amyloid-related neuropathy does not produce a change in membrane potential as either a primary or secondary event. This suggests that ischemia and axonal compression are unlikely mechanisms for the neuropathy.

Estimation of a single motor unit's threshold and activation range, a study on patients with muscular disorders.

Background:In clinical neurophysiology, threshold tracking studies are used to evaluate the functionality of a muscle through studying the functionality of its motor units (MUs) that govern the muscle. The functionality of an MU can be quantified by estimation of its excitability properties via MU's stimulus-response curve. In this study, we aim to develop a model-based approach to estimate MU's threshold mean and its activation range as indications of MU's excitability. This is a different approach from routine strategies in neurophysiology, which are mostly subjective.Methods:To assess the excitability of a single MU, needle electromyography examination was used to obtain the axonal activity of that MU. To improve estimation, the examination was repeated several times on individuals. Replication of experiment introduces serial correlation between observations. We account for this correlation by using a mixed-effects model. We investigate the appropriateness of classical logistic mixed-effects model and its Bayesian formulation for estimation purpose.Results:Both classical and Bayesian models can obtain a reliable estimation of MU's threshold. However, we found Bayesian approach to provide a better estimate of MU's activation range. Moreover, if data contain outliers both classical and Bayesian methods are vulnerable to some extent.Conclusions:Compared to the classical approach, Bayesian method is more flexible in dealing with overdispersion and provides more robust estimation of MU's parameters.

Motor cortical function and the precision grip.

While task‐dependent changes in motor cortical outputs have been previously reported, the issue of whether such changes are specific for complex hand tasks remains unresolved. The aim of the present study was to determine whether cortical inhibitory tone and cortical output were greater during precision grip and power grip. Motor cortex excitability was undertaken by using the transcranial magnetic stimulation threshold tracking technique in 15 healthy subjects. The motor‐evoked potential (MEP) responses were recorded over the abductor pollicis brevis (APB), with the hand in the following positions: (1) rest, (2) precision grip and (3) power grip. The MEP amplitude (MEP amplitude REST 23.6 ± 3.3%; MEP amplitude PRECISION GRIP 35.2 ± 5.6%; MEP amplitude POWER GRIP 19.6 ± 3.4%, F = 2.4, P < 0.001) and stimulus‐response gradient (SLOPEREST 0.06 ± 0.01; SLOPEPRCISION GRIP 0.15 ± 0.04; SLOPE POWER GRIP 0.07 ± 0.01, P < 0.05) were significantly increased during precision grip. Short interval intracortical inhibition (SICI) was significantly reduced during the precision grip (SICI REST 15.0 ± 2.3%; SICI PRECISION GRIP 9.7 ± 1.5%, SICI POWER GRIP 15.9 ± 2.7%, F = 2.6, P < 0.05). The present study suggests that changes in motor cortex excitability are specific for precision grip, with functional coupling of descending corticospinal pathways controlling thumb and finger movements potentially forming the basis of these cortical changes.

THEME 2 IMAGING, ELECTROPHYSIOLOGY AND MARKERS OF DISEASE PROGRESSION

R1 and R2 components, in all FOSMN patients tested. Pathological studies disclosed the presence of axonal degeneration with absence of infl ammation or amyloid deposition. Cortical excitability studies revealed that the resting motor threshold was increased in FOSMN patients (71.8 � 4.3%) when compared to ALS (57.2 � 0.9%, P � 0.001) and controls (61.8 � 1.6%, F � 8.7, P � 0.05). In addition, averaged short interval intracortical inhibition was increased in FOSMN patients (6.8 � 1.3%) when compared to ALS (2.6 � 0.9%, F � 11.2, P � 0.05) but comparable to healthy controls (10.5 � 1.1%, P � 0.09). Of relevance, there was a signifi cant difference between groups in the cortical silent period duration (FOSMN 204 � 12.7 ms; ALS 181.3 � 4.3 ms; controls 215.3 � 3.8 ms, F � 8.5, P � 0.001), and MEP amplitude (FOSMN 26.6 � 7.0%; ALS 38.1 � 2.2%; controls 25.2 � 2.8%, F � 4.7, P � 0.05). Discussion and conclusions: The fi ndings in the present study suggest that although FOSMN syndrome is a slowly progressive neurodegenerative disorder of sensory and motor neurons, cortical hyperexcitability does not appear to underlie the development of FOSMN syndrome. In addition, the threshold tracking TMS technique clearly differentiated FOSMN syndrome from ALS, thereby arguing against a potential link between these two disorders.

15.: Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper (UMN) and lower motor neuron (LMN) signs. The current ALS diagnostic criteria formulated at Awaji attempts to improve the diagnostic sensitivity by incorporating neurophysiological measures of LMN dysfunction, though assessment of UMN dysfunction remains clinically based. Given that cortical hyperexcitability appears to be an early feature in ALS, the present study assessed the diagnostic utility of threshold tracking transcranial magnetic stimulation (TMS) technique as an aid to the Awaji criteria in establishing of an earlier diagnosis of ALS. Studies were undertaken prospectively on a cohort of 82 patients (52 men and 30 women, mean age 60 years) with suspected ALS. Paired pulse threshold tracking TMS studies were undertaken along with clinical and conventional neurophysiological examination and results were compared to 34 healthy controls (17 men, 17 women, mean age 56 years). At time of TMS testing, 61% of patients were classified as “possible” and 39% as ”probable/definite” ALS by the Awaji diagnostic criteria. Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients ( p AWAJI POSSIBLE 1.3 ± 1.3%; SICI AWAJI PROBABLE/DEFINITE 1.4 ± 1.7%). Central motor conduction time was significantly prolonged ( p p p

63.: Cortical dysfunction in hereditary spastic paraparesis patients with the spastin mutation

In autosomal dominant hereditary spastic paraplegia (HSP), mutations in the spastin (SPG4) gene account for 45% of all cases. The key diagnostic clinical findings are lower limb spasticity, hyperreflexia and extensor plantar responses. The main neuropathological finding in HSP is axonal degeneration in the terminal portions of the long descending and ascending tracts in the spinal cord. Current hypothesis suggest impairment of axonal transport or disturbance of mitochondrial function. We utilised the threshold tracking transcranial magnetic stimulation (TTTMS) technique to evaluate if cortical abnormalities may coexist in these patients. Cortical excitability studies were undertaken on 12 HSP patients with the SPG4 mutation (five males and seven females, mean age 56 years). Patients were compared with age-matched controls. The mean spastic paraplegia rating scale was 17.3 ± 3.0 and the mean upper motor neuron score was 13.5 ± 0.5. Short-interval intracortical inhibition was significantly reduced in HSP patients when compared to controls (HSP 5.0 ± 1.6%; controls 11.8 ± 1.0%, p p p p

16.: Cortical excitability in hereditary spastic paraparesis patients with SPAST mutations

In autosomal dominant hereditary spastic paraplegia (HSP), mutations in the SPAST (SPG4) gene account for 45% of all patients. The key diagnostic clinical findings are that of lower limb spasticity, hyperreflexia and extensor plantar responses. The main neuropathological finding in HSP is of axonal degeneration in the terminal portions of the long descending and ascending tracts in the spinal cord. The current hypothesis suggests impairment of axonal transport or disturbance of mitochondrial function. We utilised the threshold tracking transcranial magnetic stimulation technique to evaluate if cortical abnormalities may coexist in these patients. Cortical excitability studies were undertaken on 12 HSP patients with the SPG4 mutation (five males and seven females, mean age 56 years). Patients were compared with age-matched controls. The mean spastic paraplegia rating scale was 17.3 ± 3.0 and the mean upper motor neuron score was 13.5 ± 0.5. Short-interval intracortical inhibition (SICI) was not significantly reduced in HSP patients when compared to controls (HSP 9.1 ± 1.5%; controls 11.8 ± 1.0%, p = 0.09). The cortical silent period duration was significantly reduced (HSP 192.9 ± 11.5 ms; controls 214.2 ± 3.9, p = 0.05). Resting motor threshold was significantly reduced amongst HSP patients (HSP 51.8 ± 2.2%; controls 60.3 ± 1.4%, p

Inter-individual variation in the after-effect of paired associative stimulation can be predicted from short-interval intracortical inhibition with the threshold tracking method.

Paired associative stimulation (PAS), which is used to test a long term potentiation (LTP)-like effect, involves repeated pairing of peripheral somatosensory input with transcranial magnetic stimulation (TMS) given 25ms later over M1 (PAS25). The effect is usually quantified as an increase in amplitude of motor evoked potentials evoked by single pulse TMS. However, the effect varies greatly between individuals. We hypothesized that variability depends on either the individual level of GABAAergic activity in cortex, or on the proportion of late I-wave inputs that are evoked by TMS pulses during PAS25. Low levels of GABA facilitate LTP, whereas late I-waves are the site of facilitation after PAS25. GABAAergic inhibition was quantified using SICI measured with a threshold tracking method (SICI-TT) before and after PAS25 in 18 healthy volunteers. The PAS25 effect correlated with the level of SICI-TT (r=0.6) before PAS25. Contrary to the GABA hypothesis, people who had good facilitation after PAS25 had good inhibition measured by SICI-TT. On completion of the PAS25 protocol, SICI-TT was reduced by an amount correlated with the size of the PAS25 effect (r=0.5-0.6 at an interstimulus interval of 2.5-3.0ms). SICI is known to target late I-waves, thus SICI-TT will depend on the proportion of late I-waves evoked by the TMS test pulse. If the pulse recruits a large fraction of late I-waves, individuals will show good SICI-TT; they will also respond well to PAS25 since this relies on facilitation of late I-waves.

P544: Cortical hyperexcitability of the thenar group of intrinsic hand muscles may contribute to the split-hand sign in ALS

Objective Preferential wasting of the thenar group of intrinsic hand muscles including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) termed the split-hand sign, has been described as a specific feature of Amyotrophic Lateral Sclerosis (ALS). Greater corticomotorneuronal input to the thenar intrinsic hand muscles has been proposed as one of the pathophysiological mechanisms underlying the split hand sign and consequently difference in cortical excitability between the thenar and hypothenar intrinsic hand muscles was assessed in the present study, in a group of ALS patients and age matched healthy controls. Methods Cortical excitability was recorded using the threshold tracking transcranial magnetic stimulation (TMS) technique from the APB, FDI and abductor digiti minimi (ADM) muscles in 26 Awaji Criteria possible/probable ALS patients (17 male; 9 female; mean age 58.6 ± 1.9 years. Results were compared with 21 age matched healthy controls. Results Short interval intracortical inhibition (SICI) was globally reduced ( P P Conclusion There is a global increase in cortical excitability in ALS, further characterised by a preferential increase in cortical excitability of the APB and FDI muscles, which may underlie the clinical development of the ALS split-hand sign.

S76: The diagnostic utility of threshold tracking TMS in amyotrophic lateral sclerosis

S76: The diagnostic utility of threshold tracking TMS in amyotrophic lateral sclerosis

Cortical excitability differences in hand muscles follow a split‐hand pattern in healthy controls

Differences in cortical and axonal excitability may underlie preferential atrophy of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) in amyotrophic lateral sclerosis, termed the split-hand. Consequently, this study aimed to determine whether differences in excitability follow a split-hand pattern across the intrinsic hand muscles. Excitability studies were undertaken using threshold tracking techniques in 26 healthy controls with responses recorded over APB, FDI, and abductor digiti minimi. Short interval intracortical inhibition was significantly greater from the APB and FDI. In addition, motor evoked potential amplitude was greater, while cortical silent period was longer from APB and FDI. At a peripheral level, the strength-duration time constant was greater when recorded over APB. This study establishes that differences in cortical excitability follow the split-hand pattern in healthy controls, a finding potentially explained by evolution of specialized activity of APB/FDI in complex hand tasks. Muscle Nerve 49: 836-844, 2014.

Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper and lower motor neuron signs. In order to improve the diagnostic sensitivity for ALS, Awaji criteria were developed, in part to better incorporate neurophysiological measures, although assessment of upper motor neuron dysfunction remained clinically based. Given that cortical hyperexcitability appears to be an early feature in ALS, the present study assessed the diagnostic utility of a threshold tracking transcranial magnetic stimulation technique as an aid to the research-based Awaji criteria in establishing an earlier diagnosis of ALS. Prospective studies were undertaken on a cohort of 82 patients with suspected ALS and results were compared with 34 healthy controls. Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (P<0.0001), with a comparable reduction evident in the Awaji groups (SICIAWAJI POSSIBLE 1.3%±1.3%; SICIAWAJI PROBABLE/DEFINITE 1.4%±1.7%). Central motor conduction time was significantly prolonged (P<0.001), whereas the motor evoked potential amplitude (P<0.05) and intracortical facilitation (P<0.05) were increased. The frequency of transcranial magnetic stimulation abnormalities was similar across Awaji subgroups, and addition of transcranial magnetic stimulation abnormalities as a diagnostic category enabled reclassification of 88% of Awaji possible patients to Awaji probable/definite. Cortical excitability studies potentially facilitate an earlier diagnosis of ALS when combined with clinical and conventional neurophysiological findings, albeit in a research setting.

Motor excitability measurements: The influence of gender, body mass index, age and temperature in healthy controls

The technique of threshold tracking to test axonal excitability gives information about nodal and internodal ion channel function. We aimed to investigate variability of the motor excitability measurements in healthy controls, taking into account age, gender, body mass index (BMI) and small changes in skin temperature. We examined the left median nerve of 47 healthy controls using the automated threshold-tacking program, QTRAC. Statistical multiple regression analysis was applied to test relationship between nerve excitability measurements and subject variables. Comparisons between genders did not find any significant difference (P>0.2 for all comparisons). Multiple regression analysis showed that motor amplitude decreases with age and temperature, stimulus-response slope decreases with age and BMI, and that accommodation half-time decrease with age and temperature. The changes related to demographic features on TRONDE protocol parameters are small and less important than in conventional nerve conduction studies. Nonetheless, our results underscore the relevance of careful temperature control, and indicate that interpretation of stimulus-response slope and accommodation half-time should take into account age and BMI. In contrast, gender is not of major relevance to axonal threshold findings in motor nerves.

Sustained Maximal Voluntary Contraction Produces Independent Changes in Human Motor Axons and the Muscle They Innervate

The repetitive discharges required to produce a sustained muscle contraction results in activity-dependent hyperpolarization of the motor axons and a reduction in the force-generating capacity of the muscle. We investigated the relationship between these changes in the adductor pollicis muscle and the motor axons of its ulnar nerve supply, and the reproducibility of these changes. Ten subjects performed a 1-min maximal voluntary contraction. Activity-dependent changes in axonal excitability were measured using threshold tracking with electrical stimulation at the wrist; changes in the muscle were assessed as evoked and voluntary electromyography (EMG) and isometric force. Separate components of axonal excitability and muscle properties were tested at 5 min intervals after the sustained contraction in 5 separate sessions. The current threshold required to produce the target muscle action potential increased immediately after the contraction by 14.8% (p<0.05), reflecting decreased axonal excitability secondary to hyperpolarization. This was not correlated with the decline in amplitude of muscle force or evoked EMG. A late reversal in threshold current after the initial recovery from hyperpolarization peaked at −5.9% at ∼35 min (p<0.05). This pattern was mirrored by other indices of axonal excitability revealing a previously unreported depolarization of motor axons in the late recovery period. Measures of axonal excitability were relatively stable at rest but less so after sustained activity. The coefficient of variation (CoV) for threshold current increase was higher after activity (CoV 0.54, p<0.05) whereas changes in voluntary (CoV 0.12) and evoked twitch (CoV 0.15) force were relatively stable. These results demonstrate that activity-dependent changes in motor axon excitability are unlikely to contribute to concomitant changes in the muscle after sustained activity in healthy people. The variability in axonal excitability after sustained activity suggests that care is needed when using these measures if the integrity of either the muscle or nerve may be compromised.