Lateralized Effects in Troxler Fading and Parvo and Magnocellular Processing Tasks after Localized 1Hz rTMS.

Troxler Fading (TF) is a complex visual phenomenon with uncertain mechanisms. This study was performed to test hypotheses concerning the contributions of parvocellular and magnocelluar processing in extrastriate pathways to TF. The study used low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) delivered at target sites in the parietal, temporal and dorsolateral frontal cortex to alter performance on a TF paradigm and on tests sensitive to parvocellular and magnocellular processing. Nine, right-handed, healthy subjects completed 3 tasks, TF, Texture Detection (TD), and Motion Detection (MD), at baseline and after undergoing 15 minutes of low-frequency rTMS at each cortical site on separate occasions. Results revealed lateralized effects of rTMS on each test. Left temporal stimulation slowed the parvocellular, TD task and it accelerated TF. Right parietal stimulation markedly accelerated TF whereas left parietal stimulation slowed TF. Right frontal stimulation accelerated performance on the magnocellular, MD task. Taken together and in the context of other research studies, the findings suggest hemispheric specialization both for TF and for the parvocellular and magnocellular processing tasks.

Inherent physiological artifacts in EEG during tDCS.

Online imaging and neuromodulation is invalid if stimulation distorts measurements beyond the point of accurate measurement. In theory, combining transcranial Direct Current Stimulation (tDCS) with electroencephalography (EEG) is compelling, as both use non-invasive electrodes and image-guided dose can be informed by the reciprocity principle. To distinguish real changes in EEG from stimulation artifacts, prior studies applied conventional signal processing techniques (e.g. high-pass filtering, ICA). Here, we address the assumptions underlying the suitability of these approaches. We distinguish physiological artifacts - defined as artifacts resulting from interactions between the stimulation induced voltage and the body and so inherent regardless of tDCS or EEG hardware performance - from methodology-related artifacts - arising from non-ideal experimental conditions or non-ideal stimulation and recording equipment performance. Critically, we identify inherent physiological artifacts which are present in all online EEG-tDCS: 1) cardiac distortion and 2) ocular motor distortion. In conjunction, non-inherent physiological artifacts which can be minimized in most experimental conditions include: 1) motion and 2) myogenic distortion. Artifact dynamics were analyzed for varying stimulation parameters (montage, polarity, current) and stimulation hardware. Together with concurrent physiological monitoring (ECG, respiration, ocular, EMG, head motion), and current flow modeling, each physiological artifact was explained by biological source-specific body impedance changes, leading to incremental changes in scalp DC voltage that are significantly larger than real neural signals. Because these artifacts modulate the DC voltage and scale with applied current, they are dose specific such that their contamination cannot be accounted for by conventional experimental controls (e.g. differing stimulation montage or current as a control). Moreover, because the EEG artifacts introduced by physiologic processes during tDCS are high dimensional (as indicated by Generalized Singular Value Decomposition- GSVD), non-stationary, and overlap highly with neurogenic frequencies, these artifacts cannot be easily removed with conventional signal processing techniques. Spatial filtering techniques (GSVD) suggest that the removal of physiological artifacts would significantly degrade signal integrity. Physiological artifacts, as defined here, would emerge only during tDCS, thus processing techniques typically applied to EEG in the absence of tDCS would not be suitable for artifact removal during tDCS. All concurrent EEG-tDCS must account for physiological artifacts that are a) present regardless of equipment used, and b) broadband and confound a broad range of experiments (e.g. oscillatory activity and event related potentials). Removal of these artifacts requires the recognition of their non-stationary, physiology-specific dynamics, and individualized nature. We present a broad taxonomy of artifacts (non/stimulation related), and suggest possible approaches and challenges to denoising online EEG-tDCS stimulation artifacts.

Nerve Stimulation Enhances Task-Oriented Training for Moderate-to-Severe Hemiparesis 3-12 Months After Stroke: A Randomized Trial.

OBJECTIVE: The aim of the study was to determine whether somatosensory stimulation affects outcomes of motor training for moderate-to-severe upper limb hemiparesis less than 12 mos before stroke. DESIGN: Fifty-five adults participated in 18 intervention sessions pairing 2 hours of active (n = 33) or sham (n = 22) somatosensory stimulation with 4 hours of intensive task-oriented motor training. Wolf Motor Function Test, Action Research Arm Test, Fugl-Meyer Assessment, and Stroke Impact Scale were administered at baseline, postintervention, and 1- and 4-mo follow-up. RESULTS: Statistically significant between-groups differences favored the active condition on Wolf Motor Function Test at post (P = 0.04) and Action Research Arm Test at post (P = 0.02), 1 mo (P = 0.01), and 4 mos (P = 0.01) but favored the sham condition on Stroke Impact Scale at 1 mo (P = 0.03). There were no significant between-groups differences on Fugl-Meyer Assessment. CONCLUSIONS: Somatosensory stimulation can improve objective outcomes of motor training for moderate-to-severe hemiparesis less than 12 mos after stroke, although it needs to be determined whether the magnitude of between-groups differences in this study is clinically relevant. Future studies should investigate the intervention's impact on disability and functional recovery for this population as well as neurophysiological mechanisms underlying intervention effects.

Time configuration of combined neuromodulation and motor training after stroke: A proof-of-concept study.

BACKGROUND: Intensive motor training is a therapeutic intervention that supports recovery of movement function after stroke by capitalizing on the brain's capacity for neuroplastic change. Peripheral nerve stimulation and transcranial direct current stimulation are neuromodulation techniques that can upregulate neuroplasticity and, in turn, enhance outcomes of motor training after stroke. Few studies have investigated possible adjuvant effects between peripheral nerve stimulation, transcranial direct current stimulation, and intensive motor training. OBJECTIVE: This proof-of-concept study investigated whether timing variations in neuromodulation paired with robot-assisted motor training effect differential outcomes for subjects with chronic, moderate-to-severe upper extremity impairment after stroke. METHODS: Ten subjects in the chronic phase (>12 months after stroke) of recovery completed the study. Subjects received 10 daily sessions of transcranial direct current stimulation either at the start (n = 4) or at the end (n = 6) of peripheral nerve stimulation preceding intensive motor training. Pre-post changes in motor function (Fugl-Meyer Assessment; Stroke Impact Scale) and neuroplasticity (transcranial magnetic stimulation) were assessed by condition. RESULTS: Significant improvement in Stroke Impact Scale (p = 0.02) and no change in Fugl-Meyer Assessment were associated with the start condition. No changes in Stroke Impact Scale and Fugl-Meyer Assessment were associated with the end condition. Only 1 subject in the start group had measurable neuroplastic responses and demonstrated an increase in ipsilesional cortical map volume. Only 1 subject in the end group had measurable neuroplastic responses and demonstrated a decrease in ipsilesional cortical map volume. Opposite shifts in ipsilesional cortical centers of gravity occurred relative to condition. CONCLUSION: In cases of moderate-to-severe impairment after stroke, transcranial direct current stimulation at the start, rather than the end, of peripheral nerve stimulation prior to motor training may effect better functional outcomes. Future research with a larger sample size is needed to validate the findings of this proof-of-concept study.

Nerve Stimulation Enhances Task-Oriented Training in Chronic, Severe Motor Deficit After Stroke: A Randomized Trial.

BACKGROUND AND PURPOSE: A sensory-based intervention called peripheral nerve stimulation can enhance outcomes of motor training for stroke survivors with mild-to-moderate hemiparesis. Further research is needed to establish whether this paired intervention can have benefit in cases of severe impairment (almost no active movement). METHODS: Subjects with chronic, severe poststroke hemiparesis (n=36) were randomized to receive 10 daily sessions of either active or sham stimulation (2 hours) immediately preceding intensive task-oriented training (4 hours). Upper extremity movement function was assessed using Fugl-Meyer Assessment (primary outcome measure), Wolf Motor Function Test, and Action Research Arm Test at baseline, immediately post intervention and at 1-month follow-up. RESULTS: Statistically significant difference between groups favored the active stimulation group on Fugl-Meyer at postintervention (95% confidence interval [CI], 1.1-6.9; P=0.008) and 1-month follow-up (95% CI, 0.6-8.3; P=0.025), Wolf Motor Function Test at postintervention (95% CI, -0.21 to -0.02; P=0.020), and Action Research Arm Test at postintervention (95% CI, 0.8-7.3; P=0.015) and 1-month follow-up (95% CI, 0.6-8.4; P=0.025). Only the active stimulation condition was associated with (1) statistically significant within-group benefit on all outcomes at 1-month follow-up and (2) improvement exceeding minimal detectable change, as well as minimal clinically significant difference, on ≥1 outcomes at ≥1 time points after intervention. CONCLUSIONS: After stroke, active peripheral nerve stimulation paired with intensive task-oriented training can effect significant improvement in severely impaired upper extremity movement function. Further confirmatory studies that consider a larger group, as well as longer follow-up, are needed. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02633215.

Randomized Trial of Peripheral Nerve Stimulation to Enhance Modified Constraint-Induced Therapy After Stroke.

BACKGROUND: Constraint-based therapy and peripheral nerve stimulation can significantly enhance movement function after stroke. No studies have investigated combining these interventions for cases of chronic, mild-to-moderate hemiparesis following stroke. OBJECTIVE: This study aims to determine the effects of peripheral nerve stimulation paired with a modified form of constraint-induced therapy on upper extremity movement function after stroke. Nineteen adult stroke survivors with mild-to-moderate hemiparesis more than 12 mo after stroke received 2 hours of either active (n = 10) or sham (n = 9) peripheral nerve stimulation preceding 4 hours of modified constraint-induced therapy (10 sessions). RESULTS: Active peripheral nerve stimulation enhanced modified constraint-induced therapy more than sham peripheral nerve stimulation (significance at P < 0.05), both immediately after intervention (Wolf Motor Function Test: P = 0.006 (timed score); P = 0.001 (lift score); Fugl-Meyer Assessment: P = 0.022; Action Research Arm Test: P = 0.007) and at 1-mo follow-up (Wolf Motor Function Test: P = 0.025 (timed score); P = 0.007 (lift score); Fugl-Meyer Assessment: P = 0.056; Action Research Arm Test: P = 0.028). CONCLUSION: Pairing peripheral nerve stimulation with modified constraint-induced therapy can lead to significantly more improvement in upper extremity movement function than modified constraint-induced therapy alone. Future research is recommended to help establish longitudinal effects of this paired intervention, particularly as it affects movement function and daily life participation. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to: (1) Understand the role that afferent input plays with regard to movement function; (2) Understand general concepts of delivering modified constraint-based therapy in stroke rehabilitation research; and (3) Understand the rationale for applying an adjuvant intervention to optimize outcomes of constraint-based therapy following stroke. LEVEL: Advanced ACCREDITATION: : The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.

Brain stimulation paired with novel locomotor training with robotic gait orthosis in chronic stroke: a feasibility study.

OBJECTIVES: 1) To investigate the feasibility of combining transcranial direct current stimulation (tDCS) to the lower extremity (LE) motor cortex with novel locomotor training to facilitate gait in subjects with chronic stroke and low ambulatory status, and 2) to obtain insight from study subjects and their caregivers to inform future trial design. METHODS: Double-blind, randomized controlled study with additional qualitative exploratory descriptive design. One-month follow-up.10 subjects with stroke were recruited and randomized to active tDCS or sham tDCS for 12 sessions. Both groups participated in identical locomotor training with a robotic gait orthosis (RGO) following each tDCS session. RGO training protocol was designed to harness cortical neuroplasticity. Data analysis included assessment of functional and participation outcome measures and qualitative thematic analysis. RESULTS: Eight subjects completed the study. Both groups demonstrated trends toward improvement, but the active tDCS group showed greater improvement than the sham group. Qualitative analyses indicated beneficial effects of this combined intervention. CONCLUSIONS: It is feasible to combine tDCS targeting the LE motor cortex with our novel locomotor training. It appears that tDCS has the potential to enhance the effectiveness of gait training in chronic stroke. Insights from participants provide additional guidance in designing future trials.

Long-term cortical reorganization following stroke in a single subject with severe motor impairment.

BACKGROUND: Stroke continues to be a major public health concern in the United States. Motor recovery in the post-acute stages of stroke is possible due to neuroplasticity, or the capacity of the brain to reorganize. OBJECTIVE: This case study tracks neuroplastic and motor change in a subject with severe hemiparesis following an extensive middle cerebral artery stroke. He had absence of ipsilesional motor evoked potentials in early evaluations. This report is unique in that the duration of follow-up evaluation extends nearly 2 years, with evaluations being performed at 7, 9, 10, 13, 20, and 21 months post-stroke. METHODS: At each evaluation we used transcranial magnetic stimulation to track neuroplastic change and the Fugl-Meyer Assessment and the Wolf Motor Function Test to evaluate upper extremity motor performance. RESULTS: The contralesional hemisphere showed dynamic change throughout the study period. In contrast, the ipsilesional hemisphere demonstrated notable change only between 13 and 21 months post-stroke, with the most dramatic change occurring between 20 and 21 months post-stroke. Motor performance generally improved throughout the study period. CONCLUSIONS: Our findings demonstrate that substantial neuroplasticity-mediated motor recovery can occur nearly 2 years after stroke in an individual with severe post-stroke motor impairment.

Focal electrical stimulation as an effective sham control for active rTMS and biofeedback treatments.

A valid sham control is important for determining the efficacy and effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an experimental and clinical tool. Given the manner in which rTMS is applied, separately or in combination with self-regulatory approaches, and its intended impact on brain states, a valid sham control of this type may well serve as a meaningful control for biofeedback studies, where efforts to develop a credible control have often been less than ideal. This study examined the effectiveness of focal electrical stimulation of the frontalis muscle as a sham technique for blinding participants to high-frequency rTMS over the dorso-lateral prefrontal cortex (DLPFC) at durations, intensities, and schedules of stimulation similar to many clinical applications. In this within-subjects single blind design, 19 participants made guesses immediately after receiving 54 counterbalanced rTMS sessions (sham, 10 Hz, 20 Hz); 7 (13 %) of the guesses were made for sham, 31 (57 %) were made for 10 Hz, and 16 (30 %) were made for 20 Hz. Participants correctly guessed the sham condition 6 % (CI 1, 32 %) of the time, which is less than the odds of chance (i.e., of guessing at random, 33 %); correctly guessed the 10 Hz condition 66 % (CI 43, 84 %) of the time, which was greater than chance; and correctly guessed the 20 Hz condition 41 % (CI 21, 65 %) of the time, which was no different than chance. Focal electrical stimulation therefore can be an effective sham control for high-frequency rTMS of the DLPFC, as well as for active biofeedback interventions. Participants were unaware that electrical stimulation was, in fact, sham rTMS.

Behavioral, neurophysiological, and descriptive changes after occupation-based intervention.

OBJECTIVE: We evaluated the effects of occupation-based intervention on poststroke upper-extremity (UE) motor recovery, neuroplastic change, and occupational performance in 1 research participant. METHOD: A 55-yr-old man with chronic stroke and moderately impaired UE motor function participated in 15 sessions of occupation-based intervention in a hospital setting designed to simulate a home environment. We tested behavioral motor function (Fugl-Meyer Assessment, Stroke Impact Scale, Canadian Occupational Performance Measure) and neuroplasticity (transcranial magnetic stimulation [TMS]) at baseline and at completion of intervention. We collected descriptive data on occupational participation throughout the study. RESULTS: All behavioral outcomes indicated clinically relevant improvement. TMS revealed bihemispheric corticomotor reorganization. Descriptive data revealed enhanced occupational performance. CONCLUSION: Occupation-based intervention delivered in a hospital-based, homelike environment can lead to poststroke neuroplastic change, increased functional use of the affected UE, and improved occupational performance.

Improvement in arousal, visual neglect, and perception of stimulus intensity following cold pressor stimulation.

The relationship between arousal, perception, and visual neglect was examined in this case study. Cold pressor stimulation (CPS: immersing the foot in iced water) was used to manipulate arousal and to determine its effects on contralesional neglect, perception of stimulus intensity (magnitude estimation), reaction time, and an electrophysiological correlate of ascending reticular activating system activity (i.e., the P50 potential). Measures that normalized from baseline following CPS included contralesional neglect on a clock drawing test, perception of stimulus magnitude, and P50 amplitude. The P50 amplitude returned to its abnormally low baseline level 20 min after CPS ended, indicating that CPS increased arousal.

Cold pressor stimulation diminishes P50 amplitude in normal subjects.

The present study examined how cold pressor stimulation influences electrophysiological correlates of arousal. We measured the P50 auditory evoked response potential in two groups of subjects who immersed their foot in either cold (0-2°C) or room temperature (22-24°C) water for 50 seconds. The P50, which was recorded before and after stimulation, is sleep-state dependent and sensitive to states of arousal in clinical populations. We found a significant reduction in P50 amplitude after exposure to cold, but not room temperature water. In comparison with other studies, these results indicate that cold pressor stimulation in normal subjects may evoke a regulatory process that modulates the P50 amplitude, perhaps to preserve the integrity of sensory perception, even as autonomic and subjective aspects of arousal increase.

Variable changes in PET activity before and after rTMS treatment for tinnitus.

OBJECTIVES/HYPOTHESIS: The objective was to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) improves tinnitus by decreasing neural activity in auditory processing regions of the temporal cortex and the utility of positron emission tomography (PET) for targeting treatment. STUDY DESIGN: Randomized, sham-controlled crossover. METHODS: Patients received a five-day course of active and sham 1-Hz rTMS (1800 pulses at 110% of motor threshold) to the temporal cortex, with a week separating active and sham treatment. Visual analogue ratings of tinnitus loudness (VARL) were assessed at baseline and the end of each treatment week; regional brain blood flow (rBBF) and glucose metabolism (via PET) were measured before and after treatment in regions of interest (ROI) beneath the stimulating coil and control sites. RESULTS: The VARL for both ears significantly decreased after active but not sham treatment. Responders comprised 43% of patients, experiencing at least a 33% drop in tinnitus loudness. The site most consistently associated with a positive response was the secondary auditory cortex (Brodmann Area 22) in either hemisphere. PET asymmetries were variable across patients and not always accessible to rTMS. Whereas PET activity decreased significantly beneath the stimulating coil following active treatment, similar changes occurred at control sites and after sham stimulation. Change in tinnitus perception did not correlate significantly with change in PET activity at the treatment site ROI. CONCLUSIONS: Active TMS led to a significant reduction in tinnitus loudness, but PET scans failed to support the hypothesis that low-frequency rTMS improves tinnitus by reducing cortical activation at the stimulation site, questioning the utility of PET for targeting rTMS.

Maintenance repetitive transcranial magnetic stimulation can inhibit the return of tinnitus.

OBJECTIVES/HYPOTHESIS: A single patient was tested to examine the safety and feasibility of using maintenance sessions of low-frequency repetitive transcranial magnetic stimulation (1 Hz rTMS) to reduce tinnitus loudness and prevent its return over time. STUDY DESIGN: Interrupted time series with multiple replications. METHODS: Tinnitus loudness was assessed using a visual analogue rating (VAR) with 0 = no tinnitus, and 100 = loudest tinnitus experienced; 1,800 TMS pulses delivered at 1 Hz and 110% of motor threshold were administered over the posterior, superior lateral temporal gyrus of the subject's right hemisphere until subjective tinnitus fell to a VAR of 25. TMS was reapplied as tinnitus returned to a VAR of 25 or higher. Cerebral metabolism was measured using positron emission tomography before and after treatment. RESULTS: In this patient, tinnitus could be reduced to a VAR of 6 or lower each time it reoccurred using one to three maintenance sessions of rTMS. Tinnitus loudness remained at or below a VAR of 25 and was reported to be unobtrusive in daily life when last assessed 4 months after the third and final round of maintenance treatment. Asymmetric increased cerebral metabolism in the right hemisphere reduced following treatment and as tinnitus improved. Maintenance treatment was well tolerated with no side effects. CONCLUSIONS: Although a case study cannot establish treatment efficacy, this study demonstrates for the first time that it is feasible to use maintenance rTMS to manage chronic tinnitus. Maintenance rTMS might impede cortical expansion of the tinnitus frequency into adjacent cortical areas, but group studies are necessary to confirm this speculation.

Repetitive transcranial magnetic stimulation for tinnitus: a pilot study.

OBJECTIVES/HYPOTHESIS: Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to alleviate tinnitus perception, presumably by inhibiting cortical activity associated with tinnitus. We conducted a pilot study to assess effectiveness of neuronavigated rTMS and its effects on attentional deficits and cortical asymmetry in four patients with chronic tinnitus using objective and subjective measures and employing an optimization technique refined in our laboratory. STUDY DESIGN: Randomized, placebo-controlled (sham stimulation) crossover study. METHODS: Patients received 5 consecutive days of active, low-frequency rTMS or sham treatment (using a 45-degree coil-tilt method) before crossing over. Subjective tinnitus was assessed at baseline, after each treatment, and 4 weeks later. Positron emission tomography/computed tomography (PET/CT) scans were obtained at baseline and immediately after active treatment to examine change in cortical asymmetry. Attentional vigilance was assessed at baseline and after each treatment using a simple reaction time test. RESULTS: All patients had a response to active (but not sham) rTMS, as indicated by their best tinnitus ratings; however, tinnitus returned in all patients by 4 weeks after active treatment. All patients had reduced cortical activity visualized on PET immediately after active rTMS. Mean reaction time improved (P < .05) after active but not sham rTMS. CONCLUSIONS: rTMS is a promising treatment modality that can transiently diminish tinnitus in some individuals, but further trials are needed to determine the optimal techniques required to achieve a lasting response. It is unclear whether the improved reaction times were caused by tinnitus reduction or a general effect of rTMS. PET/CT scans immediately after treatment suggest that improvement may be related to reduction of cortical asymmetry associated with tinnitus.

Repetitive transcranial magnetic stimulation for tinnitus: a case study.

OBJECTIVES/HYPOTHESIS: Correlate subjective improvements in tinnitus severity with restoration of cortical symmetry and sustained attention after neuronavigated low-frequency, repetitive transcranial magnetic stimulation (rTMS). STUDY DESIGN: Case study. METHODS: Positron emission tomography and computed tomography imaging (PET-CT) guided rTMS was performed on a 43-year-old white male with more than a 30 year history of bilateral tinnitus. rTMS was administered to the area of increased cortical activation visualized on PET-CT at a rate of 1 Hz for 30 minutes (1,800 pulses/session) for each of 5 consecutive days, with optimization applied on day 5 using single pulses of TMS to temporarily alter tinnitus perception. Subjective tinnitus severity was rated before and after rTMS using the tinnitus severity index with analogue scale. Attention and vigilance were assessed before and after therapy using the psychomotor vigilance task (PVT), a simple reaction time test that is sensitive to thalamocortical contributions to sustained attention. Posttherapy PET-CT was used to evaluate any change in asymmetric cortical activation. RESULTS: The most marked reduction in tinnitus severity occurred after rTMS optimization; this persisted up to 4 weeks after rTMS. PVT testing showed the patient exhibited a statistically significant improvement in mean slowest 10% reaction times after rTMS (P = .004). PET-CT imaging 2 days after the cessation of rTMS showed no changes in cortical blood flow or metabolic asymmetries. CONCLUSIONS: Low-frequency rTMS applied to the primary auditory cortex can reduce tinnitus severity, with rTMS optimization yielding the most favorable results. Beneficial changes occurring in the patient's slowest reaction times suggest that attentional deficits associated with tinnitus may also respond to low-frequency rTMS.