Transcutaneous auricular vagus nerve stimulation modifies cortical excitability in middle-aged and older adults.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABAAergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation.

Does predictive cueing of presentation time modulate alpha power and facilitate visual working memory performance in younger and older adults?

Selective attention and working memory (WM) are vulnerable to age-related decline. Older adults perform worse on, and are less able to modulate alpha power (8-12 Hz) than younger adults in tasks involving cues about 'where' or 'when' a memory set will appear. However, no study has investigated whether alpha power is modulated by cues predicting the presentation time of a memory set. Here, we recorded electroencephalography while 24 younger (18-33 years) and 23 older (60-77 years) adults completed a modified delay match-to-sample task where participants were cued to the duration of a memory set (0.1 s or 0.5 s). We found: (1) predictive cues increased WM storage; (2) no differences in preparatory alpha power between predictive and neutral cue types, but preparatory alpha suppression was weaker in older adults; (3) retention period oscillatory power differed between presentation times, but these differences were no longer present when comparing trial types from the onset of the memory set; and (4) oscillatory power in the preparatory and retention periods were unrelated to performance. Our results suggest that preparatory alpha power is not modulated by predictive cues towards presentation time, however, reductions in alpha/beta power during visual WM retention may be linked to encoding, rather than retention.

The Role of Alpha Power in the Suppression of Anticipated Distractors During Verbal Working Memory.

As working memory (WM) is limited in capacity, it is important to direct neural resources towards processing task-relevant information while ignoring distractors. Neural oscillations in the alpha frequency band (8-12 Hz) have been suggested to play a role in the inhibition of task-irrelevant information during WM, although results are mixed, possibly due to differences in the type of WM task employed. Here, we examined the role of alpha power in suppression of anticipated distractors of varying strength using a modified Sternberg task where the encoding and retention periods were temporally separated. We recorded EEG while 20 young adults completed the task and found: (1) slower reaction times in strong distractor trials compared to weak distractor trials; (2) increased alpha power in posterior regions from baseline prior to presentation of a distractor regardless of condition; and (3) no differences in alpha power between strong and weak distractor conditions. Our results suggest that parieto-occipital alpha power is increased prior to a distractor. However, we could not find evidence that alpha power is further modulated by distractor strength.

Resting state functional connectivity measures correlate with the response to anodal transcranial direct current stimulation.

Responses to non-invasive brain stimulation are highly variable between subjects. Resting state functional connectivity was investigated as a marker of plasticity induced by anodal transcranial direct current stimulation (tDCS). Twenty-six healthy adults (15 male, 26.4 ± 6.5 years) were tested. Experiment 1 investigated whether functional connectivity could predict modulation of corticospinal excitability following anodal tDCS. Experiment 2 determined test-retest reliability of connectivity measures. Three minutes of electroencephalography was recorded and connectivity was quantified with the debiased weighted phase lag index. Anodal (1 mA, 20 min) or sham tDCS was applied to the left primary motor cortex (M1), with a change in motor evoked potential amplitude recorded from the right first dorsal interosseous used as a marker of tDCS response. Connectivity in the high beta frequency (20-30 Hz) between an electrode approximating the left M1 (C3) and electrodes overlying the left parietal cortex was a strong predictor of tDCS response (cross-validated R2  = 0.69). Similar relationships were observed for alpha (8-13 Hz; R2  = 0.64), theta (4-7 Hz; R2  = 0.53), and low beta (14-19 Hz; R2  = 0.58) frequencies, however, test-retest reliability of connectivity measures was strongest for the high beta frequency model (ICC = 0.65; good reliability). Further investigation of the high beta model found that greater connectivity between C3 and a cluster of electrodes approximately overlying the left parietal cortex was associated with stronger responses to anodal (rho = 0.61, P = 0.03), but not sham tDCS (rho = 0.43, P = 0.14). Functional connectivity is a strong predictor of the neuroplastic response to tDCS and may be one important characteristic to assist targeted tDCS application.

The effects of age and biological sex on the association between I-wave recruitment and the response to cTBS: An exploratory study.

The neuroplastic response to continuous theta burst stimulation (cTBS) is inherently variable. The measurement of I-wave latencies has been shown to strongly predict the magnitude and direction of the response to cTBS, whereby longer latencies are associated with stronger long-term depression-like responses. However, potential differences in this association relating to age and sex have not been explored. We performed cTBS and measured I-wave recruitment (via MEP latencies) in 66 participants (31 female) ranging in age from 11 to 78 years. The influence of age and sex on the association between I-wave recruitment and the response to cTBS was tested using linear regression models. In contrast to previous studies, there was not a significant association between I-wave latencies and cTBS response at the group level (p = 0.142, R2 = 0.033). However, there were interactions between I-waves and both age and sex when predicting cTBS response. Subgroup analysis revealed that preferential late I-wave recruitment predicted cTBS response in adolescent females, but not in adolescent or adult males or adult females. These data suggest that the generalisability of I-wave measurement in predicting the response to cTBS may be lower than initially believed. Prediction models should include age and sex, rather than I-wave latencies alone, as our findings suggest that, while each factor alone is not a strong predictor, these factors interact to influence the response to cTBS.

Do age-related differences in aperiodic neural activity explain differences in resting EEG alpha?

Alpha-band oscillatory activity in human electroencephalography (EEG) becomes slower and lower in amplitude with advanced age. However, the influence of aperiodic activity on these measures has received little consideration. We investigated whether age-related differences in aperiodic activity explains differences in resting EEG peak alpha frequency and power. We assessed aperiodic activity in 85 younger and 92 older adults by fitting the 1/f-like background activity evident in EEG power spectra using the spectral parameterization ("specparam") algorithm. Across the scalp, the aperiodic exponent and offset were smaller in older compared to younger participants, reflecting a flatter 1/f-like slope and a downward broadband shift in power spectra with age. After correcting for aperiodic activity, peak alpha frequency remained slower in older adults; however, peak alpha power no longer differed statistically between age groups. The large sample size utilized in this study, as well as the depth of analysis, provides further evidence that the aperiodic component of the resting EEG signal is altered with aging and should be considered when investigating neural oscillatory activity.

Extended Repetitive Transcranial Magnetic Stimulation Therapy for Post-stroke Depression in a Patient With a Pre-frontal Cortical Lesion: A Case Study.

Approximately one-third of stroke survivors experience post-stroke depression. Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has shown promise as a treatment for depression with few side effects and high tolerability. However, previous post-stroke depression trials have not considered the effect of lesion location, the persistence of clinical improvements, nor the value of ongoing maintenance treatments. These questions are important to determine the therapeutic value of rTMS as a treatment for post-stroke depression. We report a unique case study of a 71-year-old male who had experienced a left hemispheric ischemic stroke 4 years prior. The patient was screened with the Beck Depression Inventory and Patient Health Questionnaire and found to be experiencing moderate levels of depression. Ten daily sessions of left dorsolateral pre-frontal cortex rTMS were applied over a two-week period. A clinically meaningful reduction in depression was achieved. Approximately 10 weeks following rTMS treatment, improvements in depression were attenuating. Weekly maintenance rTMS was delivered to the left dorsolateral pre-frontal cortex for 10 sessions. At the conclusion of maintenance rTMS, clinical assessments indicated depressive symptoms had reduced to a minimal to nil level. Clinically meaningful improvements in depression were maintained at 3 months after rTMS treatment had ceased. These findings provide novel insight to suggest rTMS may reduce depressive symptoms in stroke survivors with a lesion at the site of stimulation. Ongoing maintenance treatments might prove beneficial to enhance persistence of clinical improvements.

Motor network connectivity predicts neuroplastic response following theta burst stimulation in healthy adults.

A patterned repetitive transcranial magnetic stimulation protocol, known as continuous theta burst stimulation (cTBS), can suppress corticospinal excitability via mechanisms that appear similar to long-term depression synaptic plasticity. Despite much potential, this technique is currently limited by substantial response variability. The purpose of this study was to investigate whether baseline resting state functional connectivity is a determinant of response to cTBS. Eighteen healthy young adults participated in up to three experimental sessions. Single-pulse transcranial magnetic stimulation was used to quantify change in corticospinal excitability following cTBS. Three minutes of resting electroencephalographic activity was recorded, and functional connectivity was estimated using the debiased weighted phase lag index across different frequency bands. Partial least squares regression identified models of connectivity between a seed region (C3) and the whole scalp that maximally accounted for variance in cTBS responses. There was no group-level effect of a single cTBS train or spaced cTBS trains on corticospinal excitability (p = 0.092). A low beta frequency band model of connectivity accounted for the largest proportion of variance in spaced cTBS response (R2 = 0.50). Based on the low beta frequency model, a-priori regions of interest were identified and predicted 39% of variance in response to spaced cTBS at a subsequent session. Importantly, weaker connectivity between the seed electrode (C3) and a cluster approximating a frontocentral region was associated with greater spaced cTBS response (p = 0.02). It appears M1-frontocentral networks may have an important role in determining the effects of cTBS on corticospinal excitability.

Load-dependent modulation of alpha oscillations during working memory encoding and retention in young and older adults.

Working memory (WM) is vulnerable to age-related decline, particularly under high loads. Visual alpha oscillations contribute to WM performance in younger adults, and although alpha decreases in power and frequency with age, it is unclear if alpha activity supports WM in older adults. We recorded electroencephalography (EEG) while 24 younger (aged 18-35 years) and 30 older (aged 50-86) adults performed a modified Sternberg task with varying load conditions. Older adults demonstrated slower reaction times at all loads, but there were no significant age differences in WM capacity. Regardless of age, alpha power decreased and alpha frequency increased with load during encoding, and the magnitude of alpha suppression during retention was larger at higher loads. While alpha power during retention was lower than fixation in older, but not younger adults, the relative change from fixation was not significantly different between age groups. Individual differences in alpha power did not predict performance for either age groups or at any WM loads. We demonstrate that alpha power and frequency are modulated in a similar task- and load-dependent manner during WM in both older and younger adults when WM performance is comparable across age groups. IMPACT STATEMENT: Aging is associated with a marked decrease in the power and frequency of alpha oscillations. Here, we demonstrate that when verbal working memory performance is matched across age groups, alpha power and frequency are modulated in a similar task- and load-dependent manner in both young and older adults.

Daily activities are associated with non-invasive measures of neuroplasticity in older adults.

OBJECTIVE: We aimed to determine the association between daily activities (sleep, sedentary behavior and physical activities) and neuroplasticity in older adults by measuring motor evoked potential amplitudes (MEPs) elicited after a single and spaced continuous theta burst stimulation (cTBS) paradigm, targeting the primary motor cortex. METHODS: MEPs were recorded from the right first dorsal interosseous muscle of 34 older adults (66.9 ± 4.5 years) by delivering single-pulse TMS before, between and at 0, 10, 20, 40 and 60 min after the application of spaced-cTBS separated by 10 min. Habitual activity was assessed by accelerometry for 24 h/day over 7-days. Multiple linear regression models determined if the time-use composition (sleep, sedentary behavior and physical activities) was associated with neuroplasticity response. RESULTS: More physical activity at the equal expense of sleep and sedentary behaviors was associated with greater motor cortical neuroplasticity. Associations appeared to be driven by more time spent in light- but not moderate-to-vigorous- physical activities. CONCLUSIONS: Engaging in light physical activity at the expense of sleep and sedentary behavior was associated with greater LTD-like motor cortex neuroplasticity (as measured with cTBS) in older adults. SIGNIFICANCE: These findings suggest the promotion of physical activity among older adults to support brain neuroplasticity.

Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex Following Ischemic Stroke.

BACKGROUND: In preclinical models, behavioral training early after stroke produces larger gains compared with delayed training. The effects are thought to be mediated by increased and widespread reorganization of synaptic connections in the brain. It is viewed as a period of spontaneous biological recovery during which synaptic plasticity is increased. OBJECTIVE: To look for evidence of a similar change in synaptic plasticity in the human brain in the weeks and months after ischemic stroke. METHODS: We used continuous theta burst stimulation (cTBS) to activate synapses repeatedly in the motor cortex. This initiates early stages of synaptic plasticity that temporarily reduces cortical excitability and motor-evoked potential amplitude. Thus, the greater the effect of cTBS on the motor-evoked potential, the greater the inferred level of synaptic plasticity. Data were collected from separate cohorts (Australia and UK). In each cohort, serial measurements were made in the weeks to months following stroke. Data were obtained for the ipsilesional motor cortex in 31 stroke survivors (Australia, 66.6 ± 17.8 years) over 12 months and the contralesional motor cortex in 29 stroke survivors (UK, 68.2 ± 9.8 years) over 6 months. RESULTS: Depression of cortical excitability by cTBS was most prominent shortly after stroke in the contralesional hemisphere and diminished over subsequent sessions (P = .030). cTBS response did not differ across the 12-month follow-up period in the ipsilesional hemisphere (P = .903). CONCLUSIONS: Our results provide the first neurophysiological evidence consistent with a period of enhanced synaptic plasticity in the human brain after stroke. Behavioral training given during this period may be especially effective in supporting poststroke recovery.

Reduced vision-related quality of life in people living with dystonia.

Purpose: Dystonia is a neurological movement disorder with negative impact on function and quality of life. It is currently unclear whether vision-related quality of life is affected. The aim of this study was to determine whether vision-related quality of life is reduced by dystonia.Materials and methods: A vision-related quality of life questionnaire was delivered online to probe visual function in people living with dystonia. Scores for each of six domains were compared to normative data of 819 healthy participants using one sample t-tests. Respondents were divided into two groups based on whether they had botulinum toxin injections and compared using independent samples t-tests.Results: There were 42 completed responses. There was a difference from norm for two domains; ocular symptoms (t(41) = 2.31, p = 0.026) and role performance (t(41) = 2.85, p = 0.007). There was variation in responses for all six domains. No difference in scores for the botulinum toxin injection group was found for either domain (both p > 0.74).Conclusions: Some people with dystonia experience reduced vision-related quality of life, which has potential to contribute to their disability. Health professionals should be aware of vision-related issues when managing people with dystonia and consider appropriate rehabilitative interventions to reduce disability and enhance quality of life.Implications for rehabilitationDystonia is a neurological movement disorder resulting in abnormal postures and movements.Vision-related quality of life is reduced by dystonia which may contribute to disability and reduced function.Strategies to improve vision-related quality of life should be included in rehabilitation programmes for people living with dystonia.

Resting State Functional Connectivity Is Associated With Motor Pathway Integrity and Upper-Limb Behavior in Chronic Stroke.

Background. Resting state functional connectivity (RSFC) is a developmental priority for stroke recovery. Objective. To determine whether (1) RSFC differs between stroke survivors based on integrity of descending motor pathways; (2) RSFC is associated with upper-limb behavior in chronic stroke; and (3) the relationship between interhemispheric RSFC and upper-limb behavior differs based on descending motor pathway integrity. Methods. A total of 36 people with stroke (aged 64.4 ± 11.1 years, time since stroke 4.0 ± 2.8 years) and 25 healthy adults (aged 67.3 ± 6.7 years) participated in this study. RSFC was estimated from electroencephalography (EEG) recordings. Integrity of descending motor pathways was ascertained using transcranial magnetic stimulation to determine motor-evoked potential (MEP) status and magnetic resonance imaging to determine lesion overlap and fractional anisotropy of the corticospinal tract (CST). For stroke participants, upper-limb motor behavior was assessed using the Fugl-Meyer test, Action Research Arm Test and grip strength. Results. ß-Frequency interhemispheric sensorimotor RSFC was greater for MEP+ stroke participants compared with MEP- (P = .020). There was a significant positive correlation between ß RSFC and upper-limb behavior (P = .004) that appeared to be primarily driven by the MEP+ group. A hierarchical regression identified that the addition of ß RSFC to measures of CST integrity explained greater variance in upper-limb behavior (R2 change = 0.13; P = .01). Conclusions. This study provides insight to understand the role of EEG-based measures of interhemispheric network activity in chronic stroke. Resting state interhemispheric connectivity was positively associated with upper-limb behavior for stroke survivors where residual integrity of descending motor pathways was maintained.

Age-related decline of neuroplasticity to intermittent theta burst stimulation of the lateral prefrontal cortex and its relationship with late-life memory performance.

OBJECTIVE: Advanced age is accompanied by a deterioration in memory performance that can profoundly influence activities of daily living. However, the neural processes responsible for age-related memory decline are not fully understood. Here, we used transcranial magnetic stimulation (TMS) in combination with electroencephalography (EEG) to assess age-related changes in neuroplasticity in the human prefrontal cortex. METHODS: TMS-evoked cortical potentials (TEPs) were recorded before and following the neuroplasticity-inducing intermittent theta burst stimulation (iTBS), applied to the left lateral prefrontal cortex in healthy young (n = 33, mean age 22 ± 3 years) and older adults (n = 33, mean age 68 ± 7 years). RESULTS: iTBS increased the amplitude of the positive TEP component at 60 ms after the TMS pulse (P60) in young, but not older adults. This age-related decline in P60 plasticity response was associated with poorer visuospatial associative (but not working) memory performance in older adults. CONCLUSIONS: These findings suggest that neuroplasticity in the human lateral prefrontal cortex is reduced in older relative to young adults, and this may be an important factor in age-related memory decline. SIGNIFICANCE: This may have important implications for the early detection of cognitive decline and dementia.

Characterization of Young and Old Adult Brains: An EEG Functional Connectivity Analysis.

Brain connectivity studies have reported that functional networks change with older age. We aim to (1) investigate whether electroencephalography (EEG) data can be used to distinguish between individual functional networks of young and old adults; and (2) identify the functional connections that contribute to this classification. Two eyes-open resting-state EEG recording sessions with 64 electrodes for each of 22 younger adults (19-37 years) and 22 older adults (63-85 years) were conducted. For each session, imaginary coherence matrices in delta, theta, alpha, beta and gamma bands were computed. A range of machine learning classification methods were utilized to distinguish younger and older adult brains. A support vector machine (SVM) classifier was 93% accurate in classifying the brains by age group. We report decreased functional connectivity with older age in delta, theta, alpha and gamma bands, and increased connectivity with older age in beta band. Most connections involving frontal, temporal, and parietal electrodes, and more than half of connections involving occipital electrodes, showed decreased connectivity with older age. Slightly less than half of the connections involving central electrodes showed increased connectivity with older age. Functional connections showing decreased strength with older age were not significantly different in electrode-to-electrode distance than those that increased with older age. Most of the connections used by the classifier to distinguish participants by age group belonged to the alpha band. Findings suggest a decrease in connectivity in key networks and frequency bands associated with attention and awareness, and an increase in connectivity of the sensorimotor functional networks with aging during a resting state.

Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia.

There is increasing evidence that the cerebellum has a role in the pathophysiology of primary focal hand dystonia and might provide an intervention target for non-invasive brain stimulation to improve function of the affected hand. The primary objective of this study was to determine if cerebellar transcranial direct current stimulation (tDCS) improves handwriting and cyclic drawing kinematics in people with hand dystonia, by reducing cerebellar-brain inhibition (CBI) evoked by transcranial magnetic stimulation (TMS). Eight people with dystonia (5 writer's dystonia, 3 musician's dystonia) and eight age-matched controls completed the study and underwent cerebellar anodal, cathodal and sham tDCS in separate sessions. Dystonia severity was assessed using the Writer's Cramp Rating Scale (WRCS) and the Arm Dystonia Disability Scale (ADDS). The kinematic measures that differentiated the groups were; mean stroke frequency during handwriting and fast cyclic drawing and average pen pressure during light cyclic drawing. TMS measures of cortical excitability were no different between people with FHD and controls. There was a moderate, negative relationship between TMS-evoked CBI at baseline and the WRCS in dystonia. Anodal cerebellar tDCS reduced handwriting mean stroke frequency and average pen pressure, and increased speed and reduced pen pressure during fast cyclic drawing. Kinematic measures were not associated with a decrease in CBI within an individual. In conclusion, cerebellar anodal tDCS appeared to improve kinematics of handwriting and circle drawing tasks; but the underlying neurophysiological mechanism remains uncertain. A study in a larger homogeneous population is needed to further investigate the possible therapeutic benefit of cerebellar tDCS in dystonia.