A Randomized Placebo Controlled Clinical Trial Demonstrating Safety & Efficacy of EnXtra® in Healthy Adults.

Objective: The present randomized, placebo-controlled study aimed to assess the long-term safety and perceivable mental acuity benefits of EnXtra® in healthy individuals.Methods: Study participants were administered EnXtra® with or without caffeine for a period of 12 weeks. The cardiovascular safety was evaluated by assessing change in QT interval, blood pressure and heart rate. Further, other efficacy variables evaluated were change in perceived alertness and calmness by Bond and Lader mood scales, Sleep disturbance by Pittsburgh sleep quality Index and daytime sleepiness by Epworth sleepiness scale.Results: None of the study group showed any significant change in the ECG or haemodynamic parameters as compared to baseline (p > 0.05). Post consumption, alertness and calmness scores were significantly increased in the EnXtra®, and EnXtra® plus caffeine group (p < 0.001) as compared to placebo. Daytime sleep scores decreased in the EnXtra® group however change was not significant. Sleep quality remained undisturbed in all three arms.Conclusion: The findings demonstrated the psychostimulant efficacy of EnXtra® with no safety concerns on long-term usage.

Effect of Alpinia galanga on Mental Alertness and Sustained Attention With or Without Caffeine: A Randomized Placebo-Controlled Study.

OBJECTIVE: Although Alpinia galanga has been reported to improve cognitive performance in animals, it has not been thoroughly studied for its potential psychostimulant effect in humans. A randomized, double-dummy, double-blind, placebo-controlled cross-over study was conducted to determine the effect of A galanga on mental alertness and sustained attention in comparison with caffeine and placebo in participants with a habitual caffeine intake. METHODS: Fifty-nine participants (18-40 years and body mass index of ≥18.5 and <25.00 kg/m2) with moderate caffeine consumption were enrolled. The participants had a Generalized Anxiety Disorder-7 score ≤7, Patient Health Questionnaire-9 score ≤14 and a Jin Fan's Attention Network Test alertness score of 50 ± 20 ms. The interventional product (placebo, A galanga proprietary extract [E-AG-01], caffeine, and a combination of E-AG-01 with caffeine) was administered to the participants, followed by sequential administration of the remaining interventions on the consecutive study visits; the effects on mental alertness, sustained attention, and sleep architecture, along with safety and tolerability, were analyzed by validated methods. RESULTS: In the E-AG-01 group, the alertness score was increased by 11.65 ± 23.94, 12.50 ± 19.73, and 12.62 ± 0.68 ms from baseline at 1, 3 (p = 0.042), and 5 hours, respectively, indicating its efficacy to enhance mental alertness and the increase in alertness score as compared to placebo. In the composite group (E-AG-01 with caffeine), mean response time was significantly reduced, by 15.55 ms (p = 0.026) at 3 hours. CONCLUSIONS: A galanga (E-AG-01) induces a beneficial effect in mental alertness and the combination of A galanga with caffeine impedes the caffeine crash and improves sustained attention at 3 hours. Thus, these stimulant effects might yield a new usage for A galanga as a key ingredient in energy drinks or similar products.

Effects of topical nasal anesthetic on fiberoptic endoscopic examination of swallowing with sensory testing (FEESST).

Objections to the use of topical nasal anesthesia (TNA) during fiberoptic endoscopic evaluation of swallowing (FEES) with sensory testing (FEESST) have been raised, primarily because of the possibility of desensitizing the pharyngeal and laryngeal mucosa and affecting both the sensory and motor aspects of the swallow. Furthermore, it has been suggested that TNA is not necessary during FEES as it does not improve patient comfort or make the procedure easier for the endoscopist. The purpose of this double-blind, randomized, controlled, crossover clinical trial was to determine how gel TNA during flexible endoscopic evaluation of swallowing with sensory testing affects sensation, swallowing, and comfort rating scores in healthy non-dysphagic participants. Laryngopharyngeal sensory thresholds and swallowing durations were compared between two conditions: TNA and sham. Transition duration decreased statistically significantly during the TNA condition compared to the sham for 10 ml only (p < 0.05). All other swallowing measures did not change between the conditions. Laryngopharyngeal sensory thresholds and perceptions did not change between conditions. No change was observed for subject comfort scores, ease of exam, or quality of view. Future studies should evaluate TNA administration variables, including concentration, dosage amount, and method of application, to determine the optimal strategy for providing comfort while avoiding altered swallowing.

Effects of functional electrical stimulation on gait recovery post-neurological injury during inpatient rehabilitation.

This stage 2 trial investigated the therapeutic effect of single channel, peroneal functional electrical stimulation (FES) for improving gait and muscle activity in people with neurological injuries who were enrolled in an inpatient rehabilitation program. Twenty-six patients (16 male; M age = 51.3 yr., SD = 16.2; 2-33 days post-injury) completed the study. Participants were randomly assigned to an experimental group (n = 13) or control group (n = 13). The experimental group received FES and the control group received sensory stimulation during 45-min. gait training sessions three times a week for the duration of their stay in a rehabilitation facility (average of four sessions for both groups). Changes in gait speed, tibialis anterior muscle electromyography (EMG), and FIM™ locomotion scores were compared between groups. No significant differences were found, as both groups demonstrated similar improvements. The current results with this small sample suggest a low dose of gait training with single channel FES did not augment gait nor EMG activity beyond gait training with sensory stimulation; therefore, clinicians will likely be better served using a larger dose of FES or multichannel FES in this clinical population.

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.

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.

Stimulation Induced Changes in Ratio Scaling Between and Within Hemispheres.

OBJECTIVES: This paper examines if ratio scaling, the principle behind the psychophysical Power Law, is similarly performed by the left and right cerebral hemispheres and how magnitude estimates derived in each hemisphere are integrated. METHOD: Three models of hemispheric integration were tested (dominance, summation, and inhibition) using a cross-modal matching procedure in right-handed, male subjects. Visual stimuli were presented to one or both hemispheres using a tachistoscopic method to test each model. Olfactory stimuli were also presented to one or both nares (hemispheres) to test the dominance and summation models. RESULTS: A dominance model was not supported as there was little difference in ratio scaling between hemispheres for either visual or olfactory stimuli. A summation model was supported for olfactory but not visual integration. Inter-hemispheric inhibition did not account for hemispheric integration. CONCLUSIONS: The most interesting findings stemmed from a comparison of experimental conditions within rather than between hemispheres. Ratio scaling parameters, the sizes of the exponents and constants, appeared to be driven by the amount of stimulation provided to a hemisphere - a greater amount being associated with higher exponents and lower constants. Variability in ratio scaling, how well data fit power functions, corresponded to whether the hemispheres received equal amounts of stimulation - equal stimulation producing a better fit than unequal stimulation. We conclude that stimulus induced cerebral activation influences the form of power functions; whereas equivalency of stimulation between hemispheres influenced the fit.

Can Crossover and Altered Magnitude Estimation in Neglect Be Explained by Contextual Effects?

Three studies that used experimental manipulations of stimulus context and correlational analyses were conducted to examine how contextual effects influence magnitude estimation and the crossover effect on line bisection. Previous work had shown that although orienting attention to one end of a line prior to bisection determines the direction in which crossover occurs, bias in magnitude estimation actually produces the crossover effect. The influence of contextual effects on magnitude estimation, however, was not examined in these previous models of crossover. Consequently, the purpose of the present investigation was to examine these effects. Subjects in the current studies were healthy controls and people who had right and left hemisphere injury due to stroke, both with and without spatial neglect. Study 1 examined the crossover effect for lines bisected with and without a stimulus context. Study 2 examined both stimulus order as well as response order context effects on magnitude estimation. Study 3 examined how much variance in magnitude estimation was accounted for by stimulus contextual effects and how stimulus context influenced the crossover effect. The results showed that contextual bias was ubiquitous but relatively small in the magnitude estimates of normal subjects. Contextual bias was exaggerated to a similar degree in subjects with right or left hemisphere injury due to stroke, but the amount of variance accounted by contextual bias was still quite small. A novel finding of study 2 was that contextual effects can be induced by previous responses to stimuli as well as by the magnitude of preceding stimuli in subjects with unilateral brain injury. This may be a contextual effect related to response perseveration. Finally, studies 1 and 3 indicated that contextual effects strengthened the crossover effect on line bisection, primarily on relatively short lines. Contextual effects, however, cannot fully account for the crossover effect, because crossover bisections were observed also in the absence of a stimulus context. It is concluded that the crossover effect is explained by biases in attentional orientation and magnitude estimation. Contextual effects represent one source of bias in magnitude estimation that influences the crossover effect by promoting contralateral errors on short line lengths (<2 cm).

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.

On How Psychophysical Thresholds are Altered by Unilateral Brain Injury Due to Stroke.

OBJECTIVE: This study examined whether and how the absolute thresholds and the just noticeable difference thresholds for eleven, sensory/perceptual continua are altered by unilateral left and right hemisphere lesions due to stroke relative to healthy subjects. METHODS: The three subject groups were those with unilateral right hemisphere lesions (n=21), with unilateral left hemisphere lesions (n=13), and age-matched control subjects (n=76). Absolute thresholds of sensory detection and just noticeable difference thresholds were assessed for perceptual continua spanning the visual, tactile, proprioceptive, thermal, and gustatory sensory modalities. For stroke subjects, brain lesions were analyzed using subtraction techniques and volume analysis with the MRIcro and MRIcroN software programs. Stroke subjects also complete tests for spatial neglect, stroke severity and functional independence. RESULTS: There was no significant difference among subject groups regarding gender, race, hand dominance, age, or educational composition. There was no significant difference between subjects with right and left hemisphere lesions on measures of function, stroke severity, or lesion volume except for those with spatial neglect. The RHL group had a higher percentage of impaired perceptual continua (16%) than both normal controls (4%) and the LHL group (9%). If a stoke subject had an impaired threshold on one side of the body, they were ~5 times more likely to have an impaired threshold on the other side of the body. This result was more consistent and even exaggerated (~8 times more likely) in the small percentage of normal control subjects who demonstrated "impaired" sensory thresholds. Lesion volume was positively correlated with stroke severity and sensory threshold impairment, and it was negatively correlated with functional independence. CONCLUSIONS: When subjects, have difficulty detecting and discriminating sensory experiences, they tend to do so on both sides of the body. Unilateral right hemisphere stroke appeared to increase the relative frequency of altered thresholds occurring on the contralesional side of the body even though they made errors on both sides.

Transcranial Direct Current Stimulation (tDCS) Can Alter Cortical Excitability of the Lower Extremity in Healthy Participants: A Review and Methodological Study.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been used to alter cortical excitability of the lower extremity (LE) and to influence performance on LE tasks like ankle tracking accuracy; but no study, to our knowledge, ever reported a significant change in cortical excitability relative to sham-tDCS. Additionally, because several different electrode montages were used in previous studies, it is difficult to know how stimulation should be applied to achieve this effect. Our objective was to determine whether active-tDCS alters cortical excitability of the LE and ankle tracking accuracy relative to sham-tDCS in healthy participants. The efficacy of two electrode montages and two conductance mediums were compared. METHODS: A triple-blind, fully randomized, within-subjects study was conducted with healthy participants (N=18, 24.2 (6.6) years). Cortical recruitment curves and measures of ankle tracking accuracy for the dominant lower extremity were obtained before and after participants received active-tDCS at 2 milliamps for 20 minutes using montage-medium combinations of M1-SO:Saline, M1-SO:Gel, C1-C2:Saline, and C1-C2:Gel and a sham-tDCS condition (M1-SO: Saline). RESULTS: The motor evoked potential maximum of the recruitment curve was significantly lower for active than sham-tDCS, but only for the M1-SO:Saline combination. No other significant differences in the recruitment curve parameters or in ankle tracking were found. CONCLUSIONS: This is the first study to our knowledge to demonstrate a significant difference in cortical excitability of the LE between active and sham-tDCS conditions. Given the order in which the experimental procedures occurred, the result is consistent with the concept of a homeostatic plasticity response.

Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study.

Apathy is a common and disabling behavioral concomitant of many neurodegenerative conditions. The presence of apathy with Mild Cognitive Impairment (MCI) is linked with heightened rates of conversion to Alzheimer's disease. Improving apathy may slow the neurodegenerative process. The objective was to establish the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving apathy in older adults with MCI. An 8-week, double-blind, randomized, sham-controlled cross-over study was conducted in nine subjects (66 ± 9 years) with apathy and MCI. Subjects were randomized to rTMS or sham treatment (5 days/week) for 2 weeks following which they underwent a 4-week treatment-free period. Subjects then crossed-over to receive the other treatment for 2 weeks. The primary (apathy (AES-C)) and secondary (cognition (3MS & MMSE), executive function (TMT-A & TMT-B), and clinical global impression (CGI)) outcomes were assessed at baseline, 2, 6, and 8 weeks. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment at 2 weeks. There was significantly greater improvement in 3MS, MMSE, TMT-A, and CGI-I with rTMS compared to the sham treatment. This study establishes that rTMS is efficacious in improving apathy in subjects with MCI.

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.

Bias in magnitude estimation following left hemisphere injury.

There is a growing interest both in identifying the neural mechanisms of magnitude estimation and in identifying forms of bias that can explain aspects of behavioral syndromes like unilateral neglect. Magnitude estimation is associated with activation of temporo-parietal cortex in both cerebral hemispheres of normal subjects; however, it is unclear if and how left hemisphere lesions bias magnitude estimation because the infrequency of neglect and the presence of aphasia in these subjects confound examination. In contrast, we examined magnitude estimation using 12 different types of sensory stimuli that spanned five sensory domains in two patients with very different clinical presentations following unilateral left hemisphere stroke. One patient had neglect sub-acutely without aphasia. The other had aphasia chronically after a temporo-parietal lesion but not neglect. The neglect patient was re-examined 48 h after being treated with modafinil (Provigil) for decreased arousal. Both patients demonstrated bias in magnitude estimation relative to normal subjects (n=83). Alertness improved in the neglect patient after taking modafinil. His neglect also resolved and his magnitude estimates more closely resembled those of normal subjects. This is the first evidence, to our knowledge, that left hemisphere injury can bias magnitude estimation in a manner similar but not identical to that associated with right hemisphere injury.

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.

Cognitive assessment for CI therapy in the outpatient clinic.

OBJECTIVE: To evaluate in a preliminary fashion whether several standard cognitive assessments predict treatment outcomes on real-world functional activities following Constraint-Induced Movement therapy (CI therapy) for either the upper extremity (UE) or the lower extremity (LE) for chronic stroke hemiparesis in the outpatient therapy clinic. METHODS: 15 UE and 14 LE patients in the clinic underwent a short battery of cognitive assessments that evaluated sustained attention, episodic memory, executive control abilities, and general cognitive function. Spearman correlation analysis was used to evaluate whether each cognitive test predicted treatment outcome on the limb-specific Motor Activity Log (MAL). RESULTS: Two assessments (delayed verbal memory and Trail Making Test form B) significantly correlated with LE MAL change that followed therapy. CONCLUSIONS: We tentatively conclude from this exploratory and preliminary study that cognitive performance may predict treatment changes in response to CI therapy for the LE. Moderate to large correlations that we observed between other cognitive assessments and CI therapy outcomes recommend replicating this study with a larger and more cognitively diverse sample of stroke patients to learn if these findings are generalizable.

Common neuropsychological deficits associated with stroke survivors' impaired performance on a useful field of view test.

Useful field of view is a measure of information processing in peripheral vision that has potential for predicting impaired driving performance. The present study was performed to examine whether common neuropsychological deficits resulting from stroke might be associated with useful field of view impairment. 46 stroke survivors had impaired useful field of view test performance when compared to individuals without stroke (t30.6= -4.33, p<.001). The impairments in useful field of view of stroke survivors were associated with impaired peripheral fields, slowed processing speeds, and diminished attention. Such impairment was not localized to lesions in any particular brain area. Results allow the inference that common neuropsychological impairments may have contributed to inefficient extraction of visual information from peripheral vision.

Arousal and attention deficits in patients with tinnitus.

We investigated the effects of tinnitus on measures of arousal and attention at various levels of the neuraxis to derive a profile of the pathophysiology of tinnitus. Individuals with tinnitus of at least 6 months' duration (14 male, 15 female) and healthy controls (14 male, 21 female) were tested for arousal and habituation to repetitive stimulation at the brainstem-thalamus level by measuring the P50 potential, a scalp-recorded, auditory-evoked response, using pairs of click stimuli. We used the psychomotor vigilance task, a reaction-time test, to assess attentional processes mediated by thalamocortical functions. We then correlated deficits in arousal and attention, as measured by these tests, with perceived tinnitus severity. Results showed no difference between tinnitus patients and controls in level of arousal or habituation to repetitive sensory stimulation, as measured by the amplitude of the P50 potential and the ability to suppress a second, closely paired stimulus, respectively. However, reaction-time assessments showed that patients with tinnitus have attentional deficits relative to controls (p = .02). We found no significant correlation between sleep disturbance or tinnitus severity and reaction-time testing.

Influence of reference frames on asymmetries in Troxler's effect.

In 1804, Troxier discovered that, when an observer fixates on a point in central vision and attends to a peripheral stationary stimulus, the peripheral stimulus eventually fades from awareness. This phenomenon is known as Troxler's effect and is allegedly influenced by spatial attention. Asymmetries in Troxler's effect along horizontal and vertical meridian were a recent discovery. However, viewer- and environment-centered reference frames were aligned in prior studies, making it impossible to assess whether asymmetries correspond to viewer- versus environment-centered coordinate systems. This study was undertaken to (a) replicate the asymmetries in the upright condition among 39 participants without health issues and (b) use the asymmetrics to test contrasting predictions made by viewer- and environment-centered coordinate systems when they are decoupled using an experimental head-tilt condition. The horizontal and vertical asymmetries were replicated and consistent with a viewer-centered rather than an environment-centered reference frame.