Safety and effects of a therapeutic 15 Hz rTMS protocol administered at different suprathreshold intensities in able-bodied individuals.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) remains a promising strategy for neurorehabilitation. The stimulation intensity (SI) influences the aftereffects observed. Here, we examined whether single sessions of a 15 Hz rTMS protocol, administered at suprathreshold SI, can be safely administered to able-bodied (AB) individuals. Six right-handed men were included in this pilot study. HF-rTMS was delivered over the right M1, in 10 trains of 75 biphasic stimuli at 15 Hz, at 105-120% of the individual resting motor threshold (RMT). To assess safety, electromyography (EMG) was monitored to control for signs of spread of excitation and brief EMG burst (BEB) after stimulation. Additionally, TMS side effects questionnaires and the numeric rating scale (NRS) were administered during each session. We assessed corticospinal excitability (CSE) and motor performance changes with measures of resting (rMEP) and active (aMEP) motor evoked potential and grip strength and box and blocks test (BBT) scores, respectively. Overall, the sessions were tolerated and feasible without any pain development. However, EMG analysis during 15 Hz rTMS administration revealed increased BEB frequency with SI. Statistical models revealed an increase of CSE at rest (rMEP) but not during active muscle contraction (aMEP). No linear relationship was observed between 15 Hz rTMS SI and rMEP increase. No significant changes were highlighted for motor performance measures. Although feasible and tolerable by the AB individuals tested, the results demonstrate that when administered at suprathreshold intensities (≥ 105% RMT) the 15 Hz rTMS protocol reveals signs of persistent excitation, suggesting that safety precautions and close monitoring of participants should be performed when testing such combinations of high-intensity and high-frequency stimulation protocols. The results also give insight into the nonlinear existent relationship between the SI and HF-rTMS effects on CSE.NEW & NOTEWORTHY The results of this pilot study show the effects of a therapeutically promising 15 Hz repetitive transcranial magnetic stimulation (rTMS) protocol, administered at different suprathreshold intensities in able-bodied individuals. Although tolerable and feasible with a neuromodulatory potential, 15 Hz rTMS might result in persistent excitability that needs to be closely monitored if administered at suprathreshold stimulation intensity. These results reaffirm the importance of feasibility studies, especially in translational animal-to-human research.

Corrigendum: EEG-based spectral analysis showing brainwave changes related to modulating progressive fatigue during a prolonged intermittent motor task.

[This corrects the article DOI: 10.3389/fnhum.2022.770053.].

High-Frequency rTMS Combined with Task-Specific Hand Motor Training Modulates Corticospinal Plasticity in Motor Complete Spinal Cord Injury: A case report.

Since its first use in spinal cord injury (SCI) in the early 2000s [1], high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) demonstrated a capacity to modulate corticospinal excitability (CSE) and motor performance. Studies focused on individuals with incomplete SCI. Here, we examined the feasibility of a 15-day therapeutic stimulation protocol combining HF-rTMS with task-specific motor training targeting the weaker hand in an individual with early chronic complete SCI. In this case report, we present evidence of progressive increase of CSE at rest and during muscle activation, and decreased cortical inhibition, associated with a trend toward improvement in pinch function of the weaker hand. These promising findings need to be confirmed in a larger population. Clinical Relevance- These preliminary results are promising and demonstrate the importance of a large number of training session repetitions to induce consistent changes relevant to the recovery after a complete SCI.

EEG-Based Spectral Analysis Showing Brainwave Changes Related to Modulating Progressive Fatigue During a Prolonged Intermittent Motor Task.

Repeatedly performing a submaximal motor task for a prolonged period of time leads to muscle fatigue comprising a central and peripheral component, which demands a gradually increasing effort. However, the brain contribution to the enhancement of effort to cope with progressing fatigue lacks a complete understanding. The intermittent motor tasks (IMTs) closely resemble many activities of daily living (ADL), thus remaining physiologically relevant to study fatigue. The scope of this study is therefore to investigate the EEG-based brain activation patterns in healthy subjects performing IMT until self-perceived exhaustion. Fourteen participants (median age 51.5 years; age range 26-72 years; 6 males) repeated elbow flexion contractions at 40% maximum voluntary contraction by following visual cues displayed on an oscilloscope screen until subjective exhaustion. Each contraction lasted ≈5 s with a 2-s rest between trials. The force, EEG, and surface EMG (from elbow joint muscles) data were simultaneously collected. After preprocessing, we selected a subset of trials at the beginning, middle, and end of the study session representing brain activities germane to mild, moderate, and severe fatigue conditions, respectively, to compare and contrast the changes in the EEG time-frequency (TF) characteristics across the conditions. The outcome of channel- and source-level TF analyses reveals that the theta, alpha, and beta power spectral densities vary in proportion to fatigue levels in cortical motor areas. We observed a statistically significant change in the band-specific spectral power in relation to the graded fatigue from both the steady- and post-contraction EEG data. The findings would enhance our understanding on the etiology and physiology of voluntary motor-action-related fatigue and provide pointers to counteract the perception of muscle weakness and lack of motor endurance associated with ADL. The study outcome would help rationalize why certain patients experience exacerbated fatigue while carrying out mundane tasks, evaluate how clinical conditions such as neurological disorders and cancer treatment alter neural mechanisms underlying fatigue in future studies, and develop therapeutic strategies for restoring the patients' ability to participate in ADL by mitigating the central and muscle fatigue.

Stimulation Parameters Used During Repetitive Transcranial Magnetic Stimulation for Motor Recovery and Corticospinal Excitability Modulation in SCI: A Scoping Review.

There is a growing interest in non-invasive stimulation interventions as treatment strategies to improve functional outcomes and recovery after spinal cord injury (SCI). Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulatory intervention which has the potential to reinforce the residual spinal and supraspinal pathways and induce plasticity. Recent reviews have highlighted the therapeutic potential and the beneficial effects of rTMS on motor function, spasticity, and corticospinal excitability modulation in SCI individuals. For this scoping review, we focus on the stimulation parameters used in 20 rTMS protocols. We extracted the rTMS parameters from 16 published rTMS studies involving SCI individuals and were able to infer preliminary associations between specific parameters and the effects observed. Future investigations will need to consider timing, intervention duration and dosage (in terms of number of sessions and number of pulses) that may depend on the stage, the level, and the severity of the injury. There is a need for more real vs. sham rTMS studies, reporting similar designs with sufficient information for replication, to achieve a significant level of evidence regarding the use of rTMS in SCI.

Ultrasound-guided superficial serratus plane block for persistent post-mastectomy pain: four case reports.

BACKGROUND: Persistent post-mastectomy pain (PPMP) is common after surgery. Although multiple modalities have been used to treat this type of pain, including medications, physical therapy, exercise interventions, cognitive-behavioral psychology, psychosocial interventions, and interventional approaches, managing PPMP may be still a challenge for breast cancer survivors. Currently, serratus plane block (SPB) as a novel regional anesthetic technique shows promising results for controlling chronic pain. METHODS: We report four cases of patients with PPMP that were treated using superficial serratus plane block (SSPB) at our clinic. A retrospective review of effect of pain relief was collected through postprocedure interviews. RESULTS: We found that two of our patients were successfully treated with SSPB for pain after treatment for breast cancer. The third patient had an intercostobrachial nerve block that produced incomplete pain relief but had adequate pain relief with a SSPB. However, the fourth patient reported no pain relief after SSPB. CONCLUSION: These cases illustrate that the patients with PPMP could benefit from SSPB. Particularly, we find patients with a subjective sense of "tightness" relating to reconstructive surgeries may be a good candidate for SSPB. Further studies are warranted to evaluate this block for PPMP, as it is low risk and relatively simple to perform.

An Automated Workflow for the Electric Field Modeling of High-definition Transcranial Direct Current Stimulation (HD-tDCS) in Chronic Stroke with Lesions.

Transcranial Direct Current Stimulation is a popular noninvasive brain stimulation (NIBS) technique that modulates brain excitability by means of low-amplitude electrical current (usually <4mA) delivered to the electrodes on the scalp. The NIBS research has gained significant momentum in the past decade, prompting tDCS as an adjunctive therapeutic tool for neuromuscular disorders like stroke. However, due to stroke lesions and the differences in individual neuroanatomy, the targeted brain region may not show the same response upon NIBS across stroke patients. To this end, we conducted a study to test the feasibility of targeted NIBS. The hand motor hotspot (HMH) for each chronic stroke participant was identified using Neuronavigated Transcranial Magnetic Stimulation (TMS). After identifying the HMH as the neural target site, we applied High-definition TDCS with the current delivered at 2mA for 20 minutes. To simulate the effects of HD-tDCS in the brain, especially with stroke lesions, we used the computational modeling tool (ROAST). The lesion mask was identified using an automated tool (LINDA). This paper demonstrates that the stroke lesions can be incorporated in the computational modeling of electric field distribution upon HD-tDCS without manual intervention.

Altered Modulation of the Movement-Related Beta Desynchronization with Force in Stroke - a Pilot Study.

Conventional therapy improves motor recovery after stroke. However, 50% of stroke survivors still suffer from a significant level of long-term upper extremity impairment. Identifying a specific biomarker whose magnitude scales with the level of force could help in the development of more effective, novel, highly targeted rehabilitation therapies such as brain stimulation or neurofeedback. Four chronic stroke participants were enrolled in this pilot study to find such a neural marker using an Independent Component Analysis (ICA)-based source analysis approach, and investigate how it has been affected by the injury. Beta band desynchronization in the ipsilesional primary motor cortex was found to be most robustly scaling with force. This activity modulation with force was found to be significantly reduced, and to plateau at higher force than that of the contralesional (unaffected) side. A rehabilitation therapy that would target such a neuromarker could have the potential to strengthen the brain-to-muscle drive and improve motor learning and recovery.Clinical Relevance- This study identifies a neural marker that scales with motor output and shows how this modulation has been affected by stroke.

Graph-theoretical analysis of EEG functional connectivity during balance perturbation in traumatic brain injury: A pilot study.

Traumatic brain injury (TBI) often results in balance impairment, increasing the risk of falls, and the chances of further injuries. However, the underlying neural mechanisms of postural control after TBI are not well understood. To this end, we conducted a pilot study to explore the neural mechanisms of unpredictable balance perturbations in 17 chronic TBI participants and 15 matched healthy controls (HC) using the EEG, MRI, and diffusion tensor imaging (DTI) data. As quantitative measures of the functional integration and segregation of the brain networks during the postural task, we computed the global graph-theoretic network measures (global efficiency and modularity) of brain functional connectivity derived from source-space EEG in different frequency bands. We observed that the TBI group showed a lower balance performance as measured by the center of pressure displacement during the task, and the Berg Balance Scale (BBS). They also showed reduced brain activation and connectivity during the balance task. Furthermore, the decrease in brain network segregation in alpha-band from baseline to task was smaller in TBI than HC. The DTI findings revealed widespread structural damage. In terms of the neural correlates, we observed a distinct role played by different frequency bands: theta-band modularity during the task was negatively correlated with the BBS in the TBI group; lower beta-band network connectivity was associated with the reduction in white matter structural integrity. Our future studies will focus on how postural training will modulate the functional brain networks in TBI.

Relationship between DTI Brain Connectivity and Functional Performance in Individuals with Traumatic Brain Injury.

this study examines the relationship between brain structural connectivity, and physical and cognitive performances in individuals with Traumatic Brain Injury (TBI). Nine moderate to severe TBI participants were included in the study, and regression analysis was performed to explore if DTI connectivity of 16 regions of interest can predict individuals' : 1) Maximum Voluntary Contraction (MVC), 2) time component of Wolf Motor Function Test (WMFT), 3) Reaction Time (RT) during bimanual force matching task, 4) Performance Error Measurement (PEM) during bimanual force matching task, and 5) cognitive assessment of task switching using Trail Making (TM) test. Results showed that slower WMFT, PEM, and TM can be predicted by weaker cerebrospinal tract connectivity. Higher Caudate connectivity predicted higher WMFT and slower RT, and higher right Cingulum predicted faster TM. Current results suggest that measures of cognitive-motor interference may be better indicators of functional performance than single cognitive and motor performance tests.

EEG Correlates of Central Origin of Cancer-Related Fatigue.

The neurophysiological mechanism of cancer-related fatigue (CRF) remains poorly understood. EEG was examined during a sustained submaximal contraction (SC) task to further understand our prior research findings of greater central contribution to early fatigue during SC in CRF. Advanced cancer patients and matched healthy controls performed an elbow flexor SC until task failure while undergoing neuromuscular testing and EEG recording. EEG power changes over left and right sensorimotor cortices were analyzed and correlated with brief fatigue inventory (BFI) score and evoked muscle force, a measure of central fatigue. Brain electrical activity changes during the SC differed in CRF from healthy subjects mainly in the theta (4-8 Hz) and beta (12-30 Hz) bands in the contralateral (to the fatigued limb) hemisphere; changes were correlated with the evoked force. Also, the gamma band (30-50 Hz) power decrease during the SC did not return to baseline after 2 min of rest in CRF, an effect correlated with BFI score. In conclusion, altered brain electrical activity during a fatigue task in patients is associated with central fatigue during SC or fatigue symptoms, suggesting its potential contribution to CRF during motor performance. This information should guide the development and use of rehabilitative interventions that target the central nervous system to maximize function recovery.

Altered Cortical and Postural Response to Balance Perturbation in Traumatic Brain Injury - An EEG Pilot Study.

30-60% of traumatic brain injury (TBI) patients suffer from long-term balance deficit. Even though motor preparation and execution are altered and slowed in TBI, their relative contribution and importance to posture instability remain poorly understood. This study investigates the impaired cortical dynamics and neuromuscular response in TBI in response to balance perturbation and its relation to balance deficit. 12 TBI and 6 healthy control (HC) participants took the Berg Balance Scale (BBS) test and participated in a balance perturbation task where they were subjected to random anterior/posterior translation, while brain (EEG), muscle (EMG) activities, and center of pressure (COP) were continuously recorded. Using independent component analysis (ICA), the component most responsible for the N1 component of the perturbation evoked potential (PEP) was selected and its amplitude and latency were extracted. Balance task performance was measured by computing the COP displacement during the task. TBI had a significantly lower BBS, larger COP displacement and lower N1 amplitude compared to the HC group. No group differences was found for N1 latency and muscle activity onset delay to the perturbation. BBS was correlated with the COP displacement and N1 amplitude, and COP displacement was correlated with N1 latency. TBI balance deficit may be associated with more impaired than delayed cortical response to balance perturbation.

Design of a low-cost MRI compatible plantarflexion force measurement device.

Investigating the neural correlates of ankles' joint rotation is critical to better understand the underlying deficit in balance or posture control in the clinical population. This work describes the design and characteristics of a low-cost MRI compatible isometric plantarflexion force measurement device. The device is fully adjustable to the particular height and shoe size of participants. Each individual force sensor has an operational linear range up to 80-100kg amounting to a force range up to 180kg when combining the two sensors, which is well above the maximal force for the majority of the population. Preliminary neuroimaging tests suggest that performing submaximal ankle plantar flexions on the device induce minimal motion artifacts on fMRI signal that are within an acceptable range.

Unsupervised Stochastic Strategies for Robust Detection of Muscle Activation Onsets in Surface Electromyogram.

Surface electromyographic (sEMG) data impart valuable information concerning muscle function and neuromuscular diseases especially under human movement conditions. However, they are subject to trial-wise and subject-wise variations, which would pose challenges for investigators engaged in precisely estimating the onset of muscle activation. To this end, we posited two unsupervised statistical approaches- scree-plot elbow detection (SPE) heavily relying on the threshold choice and the more robust profile likelihood maximization (PLM) that obviates parameter tuning-for accurately detecting muscle activation onsets (MAOs). The performance of these algorithms was evaluated using the sEMG dataset provided in the article by Tenan et al. and the simulated sEMG created as explained therein. These sEMG signals are reported to have been collected from the biceps brachii and vastus lateralis of 18 participants while performing a biceps curl or knee extension, respectively. The acquired sEMG signals were first preconditioned with the Teager-Kaiser energy operator, and then, either supplied to the SPE or to the PLM or to a state-of-the-art algorithm. The mean and median errors, between the MAO time in milliseconds estimated by each of the algorithms and the gold standard onset time, were computed. The outcome of a PLM variant, namely, PLM-Laplacian, has been found to have good agreement with the gold standard, i.e., an absolute median error of 9 and 21 ms in the simulated and the actual sEMG data, respectively; whereas, the errors produced by the other algorithms are statistically significantly larger than that incurred by the PLM-Laplacian according to Wilcoxon rank-sum test. In addition, the advocated approach does not necessitate parameter settings, lending itself to be flexible and adaptable to any application, which is a unique advantage over several other methods. Research is underway to further validate this technique by imposing various experimental conditions.

"Go! to Sleep": A Web-Based Therapy for Insomnia.

BACKGROUND: Insomnia is a common complaint of individuals presenting to healthcare providers and is associated with decreased quality of life and higher healthcare utilization. In-person cognitive behavioral therapy (CBT) is an effective treatment for insomnia but is hindered by cost and limited access to treatment. Initial research suggests that Web-based CBT may mitigate these obstacles. INTRODUCTION: This study tests the effectiveness of a Web-based program for insomnia based on principles of CBT and stress management. MATERIALS AND METHODS: We conducted a randomized trial with wait-list controls among adults with primary insomnia (n = 88). Two hundred sixty-three adults with comorbid insomnia were also included and analyzed separately. The intervention was a 6-week online program, and effectiveness was measured via the Insomnia Severity Index (ISI). RESULTS: Baseline ISI score for the intervention group (n = 43) was 17.0; 16.6 for the control group (n = 45). At first follow-up, the intervention group (n = 25) had a mean change from baseline of -7.3 (95% CI: -9.0, -5.6), sustained through second follow-up, while the control group (n = 35) had a change of -1.3 (-2.7, 0.1). The between-group difference was statistically significant (p < 0.001). Participants in the comorbid insomnia group had a baseline ISI score of 16.7 with improvement similar to the primary insomnia group (-6.9; -7.6, -6.2). DISCUSSION: We observed clinically meaningful improvements in insomnia severity in adults with primary or comorbid insomnia. Sustained improvement over 4 months underscores the effectiveness of a well-constructed online CBT for insomnia program. CONCLUSIONS: Go! to Sleep

The effect of motor overflow on bimanual asymmetric force coordination.

Motor overflow, typically described in the context of unimanual movements, refers to the natural tendency for a 'resting' limb to move during movement of the opposite limb and is thought to be influenced by inter-hemispheric interactions and intra-cortical networks within the 'resting' hemisphere. It is currently unknown, however, how motor overflow contributes to asymmetric force coordination task accuracy, referred to as bimanual interference, as there is need to generate unequal forces and corticospinal output for each limb. Here, we assessed motor overflow via motor evoked potentials (MEPs) and the regulation of motor overflow via inter-hemispheric inhibition (IHI) and short-intra-cortical inhibition (SICI) using transcranial magnetic stimulation in the presence of unimanual and bimanual isometric force production. All outcomes were measured in the left first dorsal interosseous (test hand) muscle, which maintained 30% maximal voluntary contraction (MVC), while the right hand (conditioning hand) was maintained at rest, 10, 30, or 70% of its MVC. We have found that as higher forces are generated with the conditioning hand, MEP amplitudes at the active test hand decreased and inter-hemispheric inhibition increased, suggesting reduced motor overflow in the presence of bimanual asymmetric forces. Furthermore, we found that subjects with less motor overflow (i.e., reduced MEP amplitudes in the test hemisphere) demonstrated poorer accuracy in maintaining 30% MVC across all conditions. These findings suggest that motor overflow may serve as an adaptive substrate to support bimanual asymmetric force coordination.

A Web-Based Mindfulness Stress Management Program in a Corporate Call Center: A Randomized Clinical Trial to Evaluate the Added Benefit of Onsite Group Support.

OBJECTIVE: The objective of this study is to determine the effectiveness of an 8-week web-based, mindfulness stress management program (WSM) in a corporate call center and added benefit of group support. METHODS: One hundred sixty-one participants were randomized to WSM, WSM with group support, WSM with group and expert clinical support, or wait-list control. Perceived stress, burnout, emotional and psychological well-being, mindfulness, and productivity were measured at baseline, weeks 8 and 16, and 1 year. RESULTS: Online usage was low with participants favoring CD use and group practice. All active groups demonstrated significant reductions in perceived stress and increases in emotional and psychological well-being compared with control. Group support improved participation, engagement, and outcomes. CONCLUSION: A self-directed mindfulness program with group practice and support can provide an affordable, effective, and scalable workplace stress management solution. Engagement may also benefit from combining web-based and traditional CD delivery.

Evidence of significant central fatigue in patients with cancer-related fatigue during repetitive elbow flexions till perceived exhaustion.

OBJECTIVE: To investigate whether fatigue induced by an intermittent motor task in patients with cancer-related fatigue (CRF) is more central or peripheral. METHODS: Ten patients with CRF who were off chemo and radiation therapies and 14 age-matched healthy controls were enrolled. Participants completed a Brief Fatigue Inventory (BFI) and performed a fatigue task consisting of intermittent elbow-flexion contractions at submaximal (40% maximal voluntary contraction) intensity till self-perceived exhaustion. Twitch force was elicited by an electrical stimulation applied to the biceps brachii muscle. The relative degree of peripheral (muscle) vs. central contribution to fatigue induced by the intermittent motor task (IMT) was assessed using twitch force ratio (TF ratio) defined as post IMT twitch force to pre IMT twitch force. The total number of trials (intermittent contractions) and total duration of all trials performed by each subject were also quantified. RESULTS: BFI scores were higher (p < 0.001) in CRF than controls, indicating greater feeling of fatigue in CRF patients than controls. A significantly smaller number of trials and shorter total duration of the trials (p < 0.05) were observed in CRF than control participants. The TF ratio (0.81 ± 0.05) in CRF was higher (p < 0.05) compared with that of controls (0.62 ± 0.05), suggesting CRF patients experienced a significantly lower degree of muscle (peripheral) fatigue at the time of perceived exhaustion. CONCLUSION: Consistent with prior findings for fatigue under submaximal sustained contraction, our results indicate that motor fatigue in CRF is more of central than peripheral origin during IMT. Significant central fatigue in CRF patients limits their ability to prolong motor performance.

Kinesthetic imagery training of forceful muscle contractions increases brain signal and muscle strength.

The purpose of this study was to compare the effect of training using internal imagery (IMI; also known as kinesthetic imagery or first person imagery) with that of external imagery (EMI; also known as third-person visual imagery) of strong muscle contractions on voluntary muscle strengthening. Eighteen young, healthy subjects were randomly assigned to one of three groups (6 in each group): internal motor imagery (IMI), external motor imagery (EMI), or a no-practice control (CTRL) group. Training lasted for 6 weeks (~15 min/day, 5 days/week). The participants' right arm elbow-flexion strength, muscle electrical activity, and movement-related cortical potential (MRCP) were evaluated before and after training. Only the IMI group showed significant strength gained (10.8%) while the EMI (4.8%) and CTRL (-3.3%) groups did not. Only the IMI group showed a significant elevation in MRCP on scalp locations over both the primary motor (M1) and supplementary motor cortices (EMI group over M1 only) and this increase was significantly greater than that of EMI and CTRL groups. These results suggest that training by IMI of forceful muscle contractions was effective in improving voluntary muscle strength without physical exercise. We suggest that the IMI training likely strengthened brain-to-muscle (BTM) command that may have improved motor unit recruitment and activation, and led to greater muscle output. Training by IMI of forceful muscle contractions may change the activity level of cortical motor control network, which may translate into greater descending command to the target muscle and increase its strength.

Brain white matter shape changes in amyotrophic lateral sclerosis (ALS): a fractal dimension study.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder. Current diagnosis time is about 12-months due to lack of objective methods. Previous brain white matter voxel based morphometry (VBM) studies in ALS reported inconsistent results. Fractal dimension (FD) has successfully been used to quantify brain WM shape complexity in various neurological disorders and aging, but not yet studied in ALS. Therefore, we investigated WM morphometric changes using FD analyses in ALS patients with different clinical phenotypes. We hypothesized that FD would better capture clinical features of the WM morphometry in different ALS phenotypes than VBM analysis. High resolution MRI T1-weighted images were acquired in controls (n = 11), and ALS patients (n = 89). ALS patients were assigned into four subgroups based on their clinical phenotypes.VBM analysis was carried out using SPM8. FD values were estimated for brain WM skeleton, surface and general structure in both controls and ALS patients using our previously published algorithm. No significant VBM WM changes were observed between controls and ALS patients and among the ALS subgroups. In contrast, significant (p<0.05) FD reductions in skeleton and general structure were observed between ALS with dementia and other ALS subgroups. No significant differences in any of the FD measures were observed between control and ALS patients. FD correlated significantly with revised ALS functional rating scale (ALSFRS-R) score a clinical measure of function. Results suggest that brain WM shape complexity is more sensitive to ALS disease process when compared to volumetric VBM analysis and FD changes are dependent on the ALS phenotype. Correlation between FD and clinical measures suggests that FD could potentially serve as a biomarker of ALS pathophysiology, especially after confirmation by longitudinal studies.