Threshold Tracking Transcranial Magnetic Stimulation Research Articles

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.

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.

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

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

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

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.

Apraxia and Motor Dysfunction in Corticobasal Syndrome

BackgroundCorticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.MethodsImitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination – Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.ResultsIn total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/− 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.ConclusionsCortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy.

3. Diagnostic utility of threshold tracking TMS in ALS: Comparative study to Awaji criteria

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on identification of a combination of upper (UMN) and lower motor neuron (LMN) clinical features. Such clinical criteria have resulted in significant diagnostic delays, perhaps beyond the therapeutic window period. In order to improve the sensitivity of diagnostic criteria, recently the Awaji criteria have been developed whereby neurophysiological evidence of LMN dysfunction was equated with clinical features of LMN dysfunction. While these criteria appeared to increase the diagnostic sensitivity for ALS, the involvement of UMNs was not objectively assessed by the Awaji criteria. Given that cortical hyperexcitability, as reflected by the threshold tracking transcranial magnetic stimulation (TTTMS) technique, was an early feature in ALS, the present study assessed the diagnostic utility of TTTMS, when compared to Awaji criteria, in establishing of an earlier diagnosis of ALS. Prospective cortical excitability studies were undertaken on a cohort of 65 patients classified as either “possible” or “probable/definite” ALS based on the Awaji criteria. Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (1.57 ± 1.1%) when compared controls (10.6 ± 0.8%, P < 0.0001). Importantly, there was a comparable reduction of SICI in the ALS cohorts compared to controls (SICI POSSIBLE ; −1.88 ± 1.75, P < 0.0001, SICI PROBABLE/DEFINITE 2.77 ± 1.58, P < 0.0001). In addition, the cortical silent period duration was significantly reduced in the ALS patients compared to controls (CSP POSSIBLE 160.1 ± 12, P = 0.001, CSP PROBABLE/DEFINITE 177.8 ± 7, P = 0.0001) in ALS. Of further relevance, the diagnostic accuracy of the TTMS technique was 80% compared to 60% for the Awaji criteria in the present ALS cohort. Cortical hyperexcitability appears to be an early diagnostic biomarker for ALS. The TTTMS techniques may prove useful as a diagnostic aid for establishing an earlier diagnosis of ALS.

Cortical hyperexcitability and the split-hand plus phenomenon: Pathophysiological insights in ALS

Preferential involvement of thenar muscles compared to flexor pollicis longus (FPL), termed ‘the split-hand plus sign’, appears to be a clinical feature of amyotrophic lateral sclerosis (ALS). In an attempt to understand the pathophysiological mechanisms underlying this clinical phenomenon, threshold tracking transcranial magnetic stimulation techniques were utilized to assess whether cortical mechanisms may be a significant contributing influence. Cortical excitability studies were undertaken on 17 ALS patients, with motor evoked potentials (MEP) recorded from thenar muscles and FPL. Split-hand plus index (SHPI) was derived by dividing motor amplitudes recorded over APB with those recorded over FPL. Results showed the SHPI was significantly reduced in ALS (SHPIALS 0.87 ± 0.12; SHPICONTROLS 1.7 ± 0.2, p < 0.001). Cortical studies disclosed significant increases in MEP amplitudes recorded over thenar muscles (p < 0.05) but not FPL (p = 0.11), and were significantly correlated with the SHPI (R = –0.83, p < 0.01). The cortical silent period duration was reduced from thenar muscles (p < 0.01). Although there was a ubiquitous reduction in short-interval intracortical inhibition (APB, p < 0.01; FPL < 0.05), this reduction was more prominent over the thenar muscles. In conclusion, findings from the present study suggest that cortical dysfunction in the form of hyperexcitability contributes to the pathophysiological basis of the split-hand plus sign in ALS.

Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0.45) or motor evoked potential amplitude (P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90-100 ms) 49.1 ± 1.8%; controlsTEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+ conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system.

Cortical excitability differences between flexor pollicis longus and APB

Although abductor pollicis brevis (APB) and flexor pollicis longus (FPL) share a common peripheral nerve supply, these muscles subserve different functions and may be differently affected in neurodegenerative disease such as amyotrophic lateral sclerosis (ALS). As a consequence, differences in cortical excitability may potentially develop in relation to these functional differences. Cortical excitability was assessed using the threshold tracking transcranial magnetic stimulation (TMS) technique in 15 healthy controls with motor responses recorded over the APB and FPL using surface electrode recordings. Short-interval intracortical inhibition (SICI) was significantly reduced from the FPL compared to APB (SICIFPL 6.9±1.8%; SICIAPB 10.7±1.4%, P<0.01). In addition, the FPL motor evoked potential amplitude (MEPFPL 14.7±2.3%; MEPAPB 21.7±3.9%; P<0.01) and cortical silent period duration (CSPFPL 174.7±6.7ms; CSPAPB 205.4±3.9ms, P<0.01) were significantly smaller. The findings in the present study indicate that cortical inhibition and corticomotoneuronal output is reduced when recording over the FPL. The differences in cortical excitability may develop as a consequence of varied function and could potentially explain the dissociated muscle atrophy evident in ALS.

The Puzzling Case of Hyperexcitability in Amyotrophic Lateral Sclerosis

The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na+ conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research.

FOSMN syndrome

To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms.

Cortical dysfunction underlies disability in multiple sclerosis

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing–remitting MS patients (RRMS) and 66 controls. Results: Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.

Maladaptation of cortical circuits underlies fatigue and weakness in ALS

Although fatigue is frequently reported in amyotrophic lateral sclerosis (ALS), the underlying mechanisms remain to be elucidated. Cortical excitability studies were utilized to determine the contribution of central mechanisms to development of fatigue and weakness in ALS. Threshold-tracking transcranial magnetic stimulation (TMS) studies were undertaken in 16 ALS patients and 22 normal controls using a 90-mm circular coil. TMS studies were performed at baseline, immediately after a voluntary contraction (VC) period of 120 s duration (three VC periods), and at 5, 10 and 20 min after last VC. At baseline, there was a significant reduction of short-interval intracortical inhibition (SICI) at interstimulus interval of 1 ms (ALS 2.3 ± 2.3%; controls 9.5 ± 2.5%, p < 0.01) and 3 ms (ALS5.1 ± 3.4%; controls 16.8 ± 1.7%, p < 0.01) in ALS patients. Although there was a significant reduction of SICI post-VC in controls at ISI 1 ms (p < 0.05) and ISI 3 ms (p < 0.05), there was no significant change in ALS patients at ISI 1 ms (p = 0.15) or 3 ms (p = 0.31). The changes in cortical excitability correlated with fatigue (R = 0.59, p < 0.05). In conclusion, maladaptation of cortical processes related to degeneration of inhibitory GABAergic intracortical circuits, is a feature of ALS that significantly correlates with development of fatigue and weakness.

Clarifying variability of corticomotoneuronal function in kennedy disease

Although Kennedy disease (KD) is regarded as a pure lower motor neuron disorder, recent transcranial magnetic stimulation (TMS) studies have reported subclinical corticomotoneuronal dysfunction in KD. To clarify these findings, this study applied novel triple stimulation (TST) and threshold tracking TMS techniques to gain further insights into corticomotoneuronal function in KD. TMS studies were undertaken in 12 KD patients and 38 age-matched controls. Motor evoked potentials were recorded over the abductor pollicis brevis (threshold tracking TMS) and abductor digiti minimi (TST). The mean TSTtest:TSTcontrol amplitude (99 ± 0.7%, normal >93%) and area (98.4 ± 1.6%, normal >92%) ratios were normal in Kennedy disease. In addition, short-interval intracortical inhibition (SICI) was similar in KD and controls (KD: 8.1 ± 1.3%; controls: 10.1 ± 0.7%; P = 0.11), as were the motor evoked potential amplitude, resting motor threshold, intracortical facilitation, and cortical silent period duration. Triple stimulation and threshold tracking TMS techniques have reiterated normal corticomotoneuronal function in KD.

Cortical excitability distinguishes ALS from mimic disorders

Objective The diagnosis of amyotrophic lateral sclerosis (ALS) relies on stringent clinical criteria, resulting in diagnostic delay and inevitably the institution of appropriate therapy. Cortical hyperexcitability, as assessed by the novel threshold tracking transcranial magnetic stimulation (TTTMS) technique, appears as an early feature of ALS. Consequently, the present study assessed the diagnostic utility of threshold tracking TMS and developed algorithms to aid the diagnosis of ALS. Methods Prospective studies were undertaken on a cohort of 156 consecutive patients with neuromuscular symptoms (104 ALS and 52 lower motor neuron syndrome, non-ALS syndrome, NALS) and 62 healthy controls. Results Short-interval intracortical inhibition (SICI) was significantly reduced in ALS patients (2.4 ± 0.9%) compared to NALS (8.7 ± 0.8%, P < 0.0001) and controls (10.6 ± 0.8%, P < 0.0001). The MEP amplitude and intracortical facilitation were increased, while the cortical silent period duration was reduced in ALS, all indicative of cortical hyperexcitability. Analysis of receiver operating characteristic curves suggested that threshold tracking TMS distinguished ALS from NALS, with averaged (area under curve 0.76, P < 0.0001) and peak SICI 3 ms (area under curve 0.73, P < 0.0001) being the most robust diagnostic markers. Conclusions The presence of cortical hyperexcitability distinguishes ALS from mimic disorders. Significance The threshold tracking TMS techniques may prove useful as a diagnostic investigation for ALS.