Chronic musculoskeletal pain is associated with neurobiological, physiological, and cellular measures. Importantly, we have previously demonstrated that a biobehavioral and psychosocial resilience index appears to have a protective relationship on the same biomarkers. Less is known regarding the relationships between chronic musculoskeletal pain, protective factors, and brain aging. This study investigates the relationships between clinical pain, a resilience index, and brain age. We hypothesized that higher reported chronic pain would correlate with older appearing brains, and the resilience index will attenuate the strength of the relationship between chronic pain and brain age.

Participants were drawn from an ongoing observational multisite study and included adults with chronic pain who also reported knee pain (N = 135; age = 58.3 ± 8.1; 64% female; 49% non-Hispanic Black, 51% non-Hispanic White; education Mdn = some college; income level Mdn = $30,000 - $40,000; MoCA M = 24.27 ± 3.49). Measures included the Graded Chronic Pain Scale (GCPS), characteristic pain intensity (CPI) and disability, total pain body sites; and a cognitive screening (MoCA). The resilience index consisted of validated biobehavioral (e.g., smoking, waist/hip ratio, and active coping) and psychosocial measures (e.g., optimism, positive affect, negative affect, perceived stress, and social support). T1-weighted MRI data were obtained. Surface area metrics were calculated in FreeSurfer using the Human Connectome Project's multi-modal cortical parcellation scheme. We calculated brain age in R using previously validated and trained machine learning models. Chronological age was subtracted from predicted brain age to generate a brain age gap (BAG). With higher scores of BAG indicating predicated age is older than chronological age. Three parallel hierarchical regression models (each containing one of three pain measures) with three blocks were performed to assess the relationships between chronic pain and the resilience index in relation to BAG, adjusting for covariates. For each model, Block 1 entered the covariates, Block 2 entered a pain score, and Block 3 entered the resilience index.

GCPS CPI (R2 change = .033, p = .027) and GCPS disability (R2 change = 0.038, p = 0.017) significantly predicted BAG beyond the effects of the covariates, but total pain sites (p = 0.865) did not. The resilience index was negatively correlated and a significant predictor of BAG in all three models (p < .05). With the resilience index added in Block 3, both GCPS CPI (p = .067) and GCPS disability (p = .066) measures were no longer significant in their respective models. Additionally, higher education/income (p = 0.016) and study site (p = 0.031) were also significant predictors of BAG.

In this sample, higher reported chronic pain correlated with older appearing brains, and higher resilience attenuated this relationship. The biobehavioral and psychosocial resilience index was associated with younger appearing brains. While our data is cross-sectional, findings are encouraging that interventions targeting both chronic pain and biobehavioral and psychosocial factors (e.g., coping strategies, positive and negative affect, smoking, and social support) might buffer brain aging. Future directions include assessing if chronic pain and resilience factors can predict brain aging over time.

Functional near infrared spectroscopy (fNIRS) is a form of non-invasive neuroimaging that uses light to measure changes in oxygenated and deoxygenated hemoglobin (Yucel et. al., 2021). Relative to fMRI, fNIRS is significantly cheaper and less susceptible to motion artifacts thereby enabling researchers to acquire data in more ecologically valid environments and has a higher temporal resolution that makes it well-suited for connectivity analyses (Tak and Ye, 2014). fNIRS is, however, uniquely limited by cortical anatomy. With a typical probe array having a penetrance depth of up to 3cm, the benefits of fNIRS may be limited by the neocortical atrophy that is characteristic in those with neurodegeneration. We present preliminary findings comparing fNIRS probe sensitivity in older adults diagnosed with posterior cortical atrophy (PCA) relative to cognitively intact older adults using Monte Carlo (MC) simulations. MC simulations offer probabilistic models that simulate photon movement through tissues of interest. We were particularly interested in fNIRS' sensitivity in the occipitoparietal cortices since these are regions characteristically affected in PCA.

We acquired high resolution structural (T1) MRI on 3 cognitively intact older adults and 3 individuals who received a clinical diagnosis of PCA according to Crutch et al. (2017) criteria. Individual T1 scans were preprocessed and transformed into a twodimensional (2D) surface using FreeSurfer. This continuous 2D surface was then segmented into its main tissue priors, as well as its pial surfaces. Segmented MRIs were then imported into AtlasViewer software and registered to our full head fNIRS probe array via an affine transformation. We embedded the GPU-accelerated Monte Carlo Extreme 3D light transport simulator software (Fang and Boas, 2009) into AtlasViewer which enabled us to launch 10 million photons from each optode, compared to the 1 million that AtlasViewer is set to by default, thereby providing more accurate results (Aasted et. al., 2015). We then assessed the sensitivity profile (log units), a mathematical estimate of optical density, of the inferior and superior occipital gyri, middle occipital gyrus, the superior and inferior parietal lobules, and left and right precunei.

Among the regions interrogated, five channels on our fNIRS probe were markedly different between the controls and those with PCA. Specifically, sensitivity values for channels covering the right inferior (hedges g = 8.04) and left superior occipital gyrus (hedges g = 2.46), the right inferior parietal lobule (hedges g = 8.89), and the right (hedges g = 9.43) and left (hedges g = 14.83) precunei were all markedly lower in those with PCA.

We provided preliminary evidence that the sensitivity of fNIRS appears to be markedly reduced in those with PCA. This is especially relevant for researchers using fNIRS in populations with neurodegeneration. Future work will evaluate these findings in a larger sample as well as in other neurologic conditions with the goal of helping researchers appropriately power their studies and interpret their results.

Executive function is known to decline in later life, largely attributed to structural and functional changes in the prefrontal cortex. However, other regions of the brain are integral to executive functioning, including the hippocampus. The hippocampus plays a large role in memory but its intricate connections to limbic regions including the prefrontal cortex likely underlies associations between the hippocampus and executive functions. Due to the hippocampus’ complex structure, hippocampal subregions may be differentially associated with executive function, but this possibility remains largely unexplored. Therefore, we examined the association between volume of the hippocampus and its subregions with executive function to understand these relationships across the adult lifespan.

The study included 32 healthy, community-dwelling participants (age range = 18-81, mean age = 51.06 ± 20.98, 91% white, 72% female) who received a 3-Tesla magnetic resonance imaging (MRI) scan and completed a cognitive battery. We calculated an executive composite based on Trail Making Test Part B and the interference score from the Stroop Color and Word Test. Freesurfer (version 5.3) as used to quantify total hippocampal volume and subfield volumes for CA1, CA2-3, CA4-dentate gyrus, subiculum, and presubiculum. We conducted mixed-effects regression analyses with total hippocampal and subfield volume, age group (young, middle-aged, and older), and their interaction predicting the executive function composite, controlling for total intracranial volume.

Larger hippocampal subregion volumes in CA1 (p = 0.03), the subiculum (p = 0.01), and the CA4-dentate gyrus (p = 0.04) predicted better executive function. Total hippocampal volume and the presubiculum were not significantly associated with the executive function composite. The age group interaction was not significant for any of the models. Follow-up analyses by hemisphere showed that the effects were right lateralized in CA1and CA4-dentate gyrus, and bilateral in the subiculum.

These data support the literature demonstrating the involvement of the hippocampus in executive function and demonstrates variation across hippocampal subfields. The lack of significant age interactions suggests these relationships may not differ across the lifespan, although this finding would need to be replicated in larger samples. These findings support previous literature showing CA4-dentate gyrus’ association with neurogenesis may facilitate better executive function by increasing connection strength among CA1, CA2-3, and the frontal cortex. This study contributes to our understanding of how specific hippocampal subregions relate to executive function, which has both clinical and research implications.

Improving the timeline for intervention in Alzheimer's disease (AD) has considerable potential to delay and mitigate disability and suffering. Neuropsychological assessment is useful for distinguishing AD from normal aging and other dementias but is less useful in preclinical detection due to its limited sensitivity. The N400 (N4), a language-based EEG event-related potential (ERP) related to semantic functioning, is a promising candidate marker of AD with potential to improve early detection and monitoring of AD. For example, studies have shown that individuals with AD show a reduced N4 "effect"—a smaller difference in the size of the N4 to semantically congruent vs. incongruent word-pairs. The goal of this study is to assess the presence of the N4 effect in healthy seniors, and those with amnestic mild cognitive impairment (MCI) or mild AD, and to evaluate associations between performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the N4 across these samples.

Fifty older adults (intact=27, combined MCI/mild AD group=23; "impaired") completed neuropsychological testing, including the RBANS, as part of a larger study. Participants were re-contacted and returned for EEG assessment between several weeks to one year later. During EEG recording, participants completed a word-pair judgement paradigm, which involved distinguishing between semantically congruent and incongruent word-pairs. Data was collected and analyzed according to customized N4 analysis scripts provided as part of ERPCORE, an online resource for acquiring and analyzing common ERP components (Kappenman et al., 2021; https://osf.io/thsqg/). The change in N4 amplitude between congruent and incongruent trials (the N4 effect) was used as an index of participants' semantic functioning. Participants' N4 effect was quantified using the mean amplitude from 300-550 milliseconds poststimulus at electrode Cz.

Repeated measures ANOVAs indicated a significant effect of trial type on the N400 amplitude in the intact individuals (F(1, 26)=77.66, p<.001), which remained significant in the sample as a whole (F(1, 48)=65.18, p<.001). Although intact participants numerically showed a larger N4 effect (intact: M=-4.02, SD=2.37; impaired: M=-2.60, SD=3.40), the expected group-by-trial interaction was not significant (F(1, 48)=3.01, p=.089). Correlational analyses revealed no significant associations between the N4 effect and the RBANS Total Scale scores (r=-.14, p=.32), nor for the Immediate Memory (r=-.002, p=.99), Visuospatial/Constructional (r=-.069, p=.63), Language (r=-.15, p=.30) Attention (r=-.21, p=.14), or Delayed Memory (r=-.18 p=.58) indexes.

Results confirmed the presence of the N4 effect in intact participants and in the sample as a whole. Although the N4 effect was numerically smaller in the impaired group as expected, this difference was not significant in the present sample. Likewise, we observed no evidence for associations between the size of N4 effect and performance on RBANS indexes. Overall, the present study provides mixed evidence for the utility of the N4 as a biomarker in mild AD. Factors that may have contributed to the lack of associations between the N4 effect and the RBANS include the limited sample size and variable lengths of time between participants' initial cognitive assessments and EEG testing.

Self-concept is a mental representation of the self—an internal sense of personal identity. This complex representation is unique to the human mind. Behavioral studies on self-concept have demonstrated that self-relevant information is remembered better than other types of information, a phenomenon commonly known as the “self-reference effect” (SRE). However, the underlying neural mechanisms of SRE remain largely unknown.

Here, we recorded neural activity from ∼600 neurons from 15 neurosurgical epilepsy patients, who were implanted with depth electrodes for seizure monitoring. The SRE paradigm consisted of an incidental learning (encoding) task and subsequent memory recognition test. During the incidental learning task, participants were asked to rate various personality traits in three distinct encoding conditions: the self, a friend, and a celebrity. In the recognition part of the task, participants were asked to distinguish between traits that were presented during the encoding phase (old) and traits that were not presented (new).

Our behavioral findings showed the highest memory accuracy on the recognition test for traits that were associated with the “self” condition, which is consistent with previous studies on SRE. Additionally, we found that traits associated with the “friend” category were more accurately recognized than those associated with a celebrity, indicating that personally familiar information—even if not self-related— improves memory recognition. Through single-unit analyses from target brain regions, including the medial temporal lobe (MTL) and medial prefrontal cortex (mPFC), we identified unique patterns of neural activity during the memory encoding phase, specifically increased responses during self-referential encoding in a subset of the neuronal population.

Future analyses will explore the relationship between increased MTL activity during self-referential encoding and improved memory recognition of traits rated in relation to the self, and network interactions between MTL and mPFC in self-oriented memory processes.

Attention is the backbone of cognitive systems and is requisite for many cognitive processes vital to everyday functioning, including memory, problem solving, and the cognitive control of behavior. Attention is commonly impaired following traumatic brain injury and is a critical focus of rehabilitation efforts. The development of reliable methods to assess rehabilitation-related changes are paramount. The Attention Network Test (ANT) has been used previously to identify 3 independent, yet interactive attention networks—alerting, orienting, and executive control (EC). We examined the behavioral and neurophysiological robustness and temporal stability of these networks across multiple sessions to assess the ANT’s potential utility as an effective measure of change during attention rehabilitative interventions.

15 healthy young adults completed 4 sessions of the ANT (1 session/7-day period). ANT networks were assessed within the task by contrasting opposing stimulus conditions: cued vs. non-cued trials probed alerting, valid vs. invalid spatial cues probed orienting, and congruent vs. incongruent targets probed EC. Differences in median correct-trial reaction times (RTs) and error rates (ERs) between the condition pairs were assessed to determine attention network scores; robustness of networks effects, as determined by one-sample t-tests at each session, against a mean of 0, determining the presence of significant network effects at each session. Sixty-four-channel electroencephalography (EEG) data were acquired concurrently and processed using Matlab to create condition-related event-related potentials (ERPs)—particularly the cue- and probe-related P1, N1, and P3 deflection amplitudes, measured by using signed-area calculation in regions of interest (ROIs) determined by observation of spherical-spline voltages. This enabled us to examine the robustness of cue- and probe-attention-network ERPs.

All three attention networks showed robust effects. However, only the EC RT and ER network scores remained significantly robust [t(14)s>13.9,ps<.001] across all sessions, indicating that EC is robust in the face of repeated exposure. Session 1 showed the greatest EC-RT robustness effect which became smaller during the subsequent sessions per ANOVAs on Session x Congruency [F(3,42)=10.21,p<.0001], reflecting persistence despite practice effects. RT robustness of the other networks varied across sessions. Alerting and EC ERs were similarly robust across all 4 sessions, but were more variable for the orienting network. ERP results: The cue-locked P1-orienting (valid vs. invalid) was generally larger to valid- than invalid-cues, but the robustness across sessions was variable (significant in only sessions 1 and 4 [t(14)s>2.13,ps<.04], as reflected in a significant main effect of session [p=.0042]. Next, target-locked EC P3s were generally smaller to congruent than incongruent targets [F(1,14)=9.40,p=.0084], showing robust effects only in sessions 3 and 4 [ps<.005].

The EC network RT and ER scores were consistently robust across all sessions, suggesting that this network may be less vulnerable to practice effects across session than the other networks and may be the most reliable probe of attentional rehabilitation. ERP measures were more variable across attention networks with respect to robustness. Behavioral measures of EC-network may be most reliable for assessing progress related to attentional-rehabilitation efforts.

Timing, or the decision of when to act, is essential to mammalian behaviors from escaping predators to driving a car. It requires cognitive functions such as working memory for time-based rules and attention to the passing of time. Thus, it can be used as a proxy for higher order executive functions that are difficult to measure but are impaired in many neurological disorders. Therefore, insights from studies of interval timing, tasks which require estimating time intervals of several seconds, have great value for our understanding of human disease. Crucial to timing is the basal ganglia, which integrates cortical activity with midbrain dopamine signals and sends out signals to the spinal cord that regulate movement, motivation, and other behaviors. We have previously found that within the basal ganglia, medium spiny neurons of the striatum exhibit ramping activity in time-related tasks. In other words, they gradually increase or decrease firing frequency across a timed interval, and this is thought to encode time. Yet it is still unknown how the encoding of time is translated into time-based motor responses. To answer this question, we turned to the external globus pallidus (GPe) because it is a regulatory hub within the basal ganglia and is thus well positioned to regulate timing behavior. We sought to examine how the GPe functions in response to time-based demands.

We recorded from neuronal ensembles using 16 channel electrode arrays implanted in the GPe of five mice while they performed an interval timing task called the switch interval timing task. Spike sorting was then used to identify signal from individual neurons.

Data were compiled from 43 neurons over several trials. Principal component analysis of neural firing activity was then conducted and revealed a downward ramping pattern in GPe neurons during interval timing trials. Data were then separated based on trials in which mice made correct decisions and those in which mice made a mistake. We found that when mice make correct timing decisions, there is downward ramping activity in the GPe, yet when mice make timing mistakes, this ramping pattern is lost.

Our findings suggest that the GPe processes timing signals through ramping activity, before projecting to the output nuclei of the basal ganglia. This is a novel finding and contributes to a growing understanding of the temporal code of the basal ganglia. The full extent of this code is still unknown, but this insight contributes to a better understanding of how the globus pallidus represents cognition. If we can better explain the neural correlates of timing, we can use this knowledge to inform therapeutic interventions for basal ganglia dysfunction, which could have profound implications for diseases like Parkinson’s disease, which affects millions around the world.

Epilepsy includes recurrent, unprovoked seizures and affects 470,000 children in the US, of which 7% have drug-resistant epilepsy due to failing two or more antiseizure medication trials. For some patients with drug-resistant epilepsy, surgery has been successful in reducing seizure burden. Functional MRI (fMRI) and intracranial mapping of neurocognitive functions, especially language, are increasingly done to assess potential functional loss from epilepsy surgery. However, these procedures vary by medical institute. The purpose of this review was to examine published literature on fMRI and intracranial mapping procedures for pediatric epilepsy surgery workup toward development of a standardized protocol that can be used across institutes as a guide to standard-of-care best practices for predicting loss of function associated with epilepsy surgery.

Our literature review includes information from 8 electronic databases for peer-reviewed, English language studies of evaluation for pediatric epilepsy surgery candidacy. Thirty-one studies were selected based on inclusion criteria. Only studies including fMRI and intracranial mapping conducted with pediatric patients being worked up for epilepsy surgery were selected.

Our review revealed that the most common task used in fMRI and intracranial mapping procedures is visual-object naming, but type of naming tasks and the way they are administered varies widely across medical institutes and includes published measures and those created on site. Variability makes examining findings across studies and designing best practice for these procedures challenging.

Creating gold-standard procedures for fMRI and intracranial mapping administration for epilepsy surgery evaluations is critical in optimizing treatment and functional outcomes for our pediatric patients. Our review is an initial step in this process.

Concurrent electroencephalography (EEG) during neuropsychological assessment offers a promising method to understand realtime neural and cognitive processes during task performance. For example, previous studies using experimental tasks suggest that midline-frontal theta power (MFT) could serve as a measure of mental exertion and subjective difficulty. The RBANS provides an opportunity to examine this issue in neuropsychological assessment, as a widely-used screening battery that was explicitly developed with subtests that vary according to difficulty within its five domains. This study investigated the effects of task difficulty, cognitive domain, and age on elicitation of MFT during rest and RBANS administration.

EEG was recorded during eyes-closed and eyes-open resting periods and RBANS administration in a sample of 45 healthy younger adults (n = 21; mean age = 23.29, SD = 3.27, range = 19-33; 48% female) and older adults (n = 24; mean age = 70.58, SD = 5.77, range = 59-83; 83% female). MFT was defined as the highest peak above the overall power spectrum within 4-8Hz from electrode Fz, and operationalized as a binary variable (present/absent). A multilevel generalized logistic regression model was run to assess the main effects of Age (Younger, Older), Difficulty (Easy, Hard), Domain (Rest, Immediate Memory, Visuospatial/Constructional, Language, Attention, Delayed Memory), and their potential interactions, on the presence of MFT.

In the full sample, the Coding, Figure Recall, and Picture Naming subtests were numerically most likely to elicit MFT (71.1%, 66.7%, and 62.2%, respectively), whereas Semantic Fluency, Eyes-Closed Rest, and List Recall had the lowest likelihoods (37.7%, 31%, 28.9%). Older adults were also numerically less likely to exhibit MFT (37.50% present) compared to younger adults (62.24% present). An analysis of deviance revealed a significant effect of Age (F(1,43) = 7.22, p = .01) and a significant interaction between Difficulty and Domain (F(5,220) = 4.78, p < .001). Specifically, Hard subtests in the Visuospatial/Constructional (Figure Copy; b = -2.63, p < .05) and Language (Semantic Fluency; b = -2.92, p < .01) Domains were less likely to elicit MFT than the Easy subtests (i.e., Line Orientation and Picture Naming, respectively).

Results indicated that MFT can be reliably measured during neuropsychological assessment, and varies in relation to both age and task-related factors. Consistent with previous studies, older adults exhibited less MFT than younger adults in general, possibly suggesting a failure to recruit the relevant networks. Further, present findings suggest that the presence of MFT varies not only by the type of task but also by the level of difficulty. Future research with larger samples can clarify whether and how the amount of MFT elicited during specific subtests relates to objective and subjective difficulty. Overall, MFT can reliably be elicited by cognitive tasks and bears further study as a measure of real-time neural expenditure.

Functional near-infrared spectroscopy (fNIRS) is a non-invasive functional neuroimaging method that takes advantage of the optical properties of hemoglobin to provide an indirect measure of brain activation via task-related relative changes in oxygenated hemoglobin (HbO). Its advantage over fMRI is that fNIRS is portable and can be used while walking and talking. In this study, we used fNIRS to measure brain activity in prefrontal and motor region of interests (ROIs) during single- and dual-task walking, with the goal of identifying neural correlates.

Nineteen healthy young adults [mean age=25.4 (SD=4.6) years; 14 female] engaged in five tasks: standing single-task cognition (serial-3 subtraction); single-task walking at a self-selected comfortable speed on a 24.5m oval-shaped course (overground walking) and on a treadmill; and dual-task cognition+walking on the same overground course and treadmill (8 trials/condition: 20 seconds standing rest, 30 seconds task). Performance on the cognitive task was quantified as the number of correct subtractions, number of incorrect subtractions, number of self-corrected errors, and percent accuracy over the 8 trials. Walking speed (m/sec) was recorded for all walking conditions. fNIRS data were collected on a system consisting of 16 sources, 15 detectors, and 8 short-separation detectors in the following ROIs: right and left lateral frontal (RLF, LLF), right and left medial frontal (RMF, LMF), right and left medial superior frontal (RMSF, LMSF), and right and left motor (RM, LM). Lateral and medial refer to ROIs’ relative positions on lateral prefrontal cortex. fNIRS data were analyzed in Homer3 using a spline motion correction and the iterative weighted least squares method in the general linear model. Correlations between the cognitive/speed variables and ROI HbO data were applied using a Bonferroni adjustment for multiple comparisons.

Subjects with missing cognitive data were excluded from analyses, resulting in sample sizes of 18 for the single-task cognition, dual-task overground walking, and dual-task treadmill walking conditions. During dual-task overground walking, there was a significant positive correlation between walking speed and relative change in HbO in RMSF [r(18)=.51, p<.05] and RM [r(18)=.53, p<.05)]. There was a significant negative correlation between total number of correct subtractions and relative change in HbO in LMSF ([r(18)=-.75, p<.05] and LM [r(18)=-.52, p<.05] during dual-task overground walking. No other significant correlations were identified.

These results indicate that there is lateralization of the cognitive and motor components of overground dual-task walking. The right hemisphere appears to be more active the faster people walk during the dual-task. By contrast, the left hemisphere appears to be less active when people are working faster on the cognitive task (i.e., serial-3 subtraction). The latter results suggest that automaticity of the cognitive task (i.e., more total correct subtractions) is related to decreased brain activity in the left hemisphere. Future research will investigate whether there is a change in cognitive automaticity over trials and if there are changes in lateralization patterns in neurodegenerative disorders that are known to differentially affect the hemispheres (e.g., Parkinson’s disease).

High-definition transcranial direct current stimulation (HD-tDCS) is a non-invasive form of brain stimulation used to modulate neuronal activity in a brain region of interest. Growing research has shown that HD-tDCS is a promising treatment for cognitive decline in neurodegenerative disease. Most HD-tDCS studies have used amplitudes of 2mA or less, with little investigation into tolerability at greater intensities since anecdotal lore generally suggests them to be poorly tolerated. Therefore, we examined the tolerability of HD-tDCS and common side effect profile in older adults who received total amplitudes of 3mA to 10mA (delivered using multiple electrodes delivering 2-4mA). We developed a series of methods (e.g., participant instructions, task engagement, techniques to lower impedance) and hypothesized they would equate the experience between active and sham HD-tDCS. We also compared symptom endorsement between those receiving active stimulation at 3mA+ total versus those receiving 2mA or lower; again, hypothesizing no difference in reported symptoms.

295 older adults (Mage = 71.12±9.42) (Normal Cognition = 75, Amnestic MCI [aMCI] = 172, Dementia of the Alzheimer's Type [DAT] = 27, Other = 21) were enrolled across six HD-tDCS studies. All participants received one to thirty 20- to 30-minute sessions of active or sham stimulation at total amplitudes between 2mA and 10mA. All participants completed a standardized side effect questionnaire after each session asking whether they experienced burning, tingling, itching, scalp pain, trouble concentrating, sleepiness, headache, mood changes, neck pain, skin redness, or any other symptoms. When symptoms were endorsed, participants rated the severity of the symptom (mild, moderate, severe).

We used Fisher's Exact tests to compare the frequency and severity of side effects in active (3mA or higher) vs. sham stimulation. Those receiving sham were significantly more likely to report tingling than those receiving active HD-tDCS. Conversely, those receiving active stimulation more frequently endorsed mood changes and skin redness relative to the sham group, though moderate-severe ratings were endorsed in only 2.9% and 0.4% of the sessions, respectively. Relative to those receiving 2mA, participants receiving higher intensities of active stimulation experienced skin redness more frequently, whereas the 2mA reported higher frequencies of itching and scalp pain. A burning sensation was endorsed at equal rates between these groups; however, the higher intensity active group reported it as moderate or severe more frequently than the 2mA active group. Despite these minor differences, most side effects following 3mA+ were reported at low frequencies and were typically mild when endorsed.

Our findings demonstrate that HD-tDCS is well-tolerated for total amplitudes up to 10mA in older adults with little tangible difference in the reported experience relative to sham. Findings support the use of higher HD-tDCS amplitudes, at least when key methodological procedures are followed.

High-definition transcranial direct current stimulation (HD-tDCS) is a non-invasive brain stimulation technique shown to modulate neuronal networks. In order for HD-tDCS to be used in randomized, placebo-controlled clinical trials, it is critical to have methods that enable blinding. Some research has shown that sham stimulation is an effective blind in tDCS. However, few studies have investigated the double-blinding of HD-tDCS, especially at intensities greater than 2mA. We address this knowledge gap by examining the blinding and double-blinding of HD-tDCS among a mixed neurologic sample of older adults.

A sample of 240 older adults (Mage = 72.21±8.94) with various clinical diagnoses (Normal Cognition = 34, Amnestic MCI [aMCI] = 172, Dementia-Alzheimer’s Type [DAT] = 27, Other = 7) were recruited through five double-blind, randomized controlled trials. All participants were stimulation naive at their first session and received one to thirty sessions of 20- or 30-minutes of active (n=1472) or sham (n=681) stimulation at total amplitudes of 2mA, 4mA, or 6mA. At the start of each stimulation session, a study team member entered a code into the tDCS unit, and the electrical current was gradually ramped up to the specified (blinded) amplitude over a period of 30 seconds. The current remained at this level for the specified amount of time in the active condition (e.g., 20-minutes) but was ramped down over the next 30 seconds for those in the sham condition. This ramp up/down process was repeated in the final minute (e.g., 20th minute) in the sham session to provide both primacy and recency effects. After each active or sham session, participants were asked whether they received 'real’ or sham stimulation. One study also asked a study team member if they believed the participant received real or sham stimulation at two primary outcome endpoints.

We used Fisher’s Exact tests to evaluate the efficacy of our blinding and double-blinding procedures. In stimulation naive participants receiving their first session, there were no differences in accuracy, suggesting adequate blinding. We also examined participant blinding across all sessions to determine whether repeated HD-tDCS exposure might impact blinding. Across all sessions, participants in the sham condition were more likely to endorse being in the 'real’ (active) condition, again suggesting adequate blinding. There were no significant group differences for active versus sham in the frequency of the study team correctly stating the participant’s condition, suggesting sufficient double-blinding. No significant differences were found in study team blinding when data from the 2mA versus 4mA to 6mA were analyzed separately.

These results suggest that the HD-tDCS sham method is an effective blind and double-blind for HD-tDCS in clinical trials, even at total amplitudes as high as 6mA.

Episodic memory functioning is distributed across two brain circuits, one of which courses through the dorsal anterior cingulate cortex (dACC). Thus, delivering non-invasive neuromodulation technology to the dACC may improve episodic memory functioning in patients with memory problems such as in amnestic mild cognitive impairment (aMCI). This preliminary study is a randomized, double-blinded, sham-controlled clinical trial to examine if high definition transcranial direct current stimulation (HD-tDCS) can be a viable treatment in aMCI.

Eleven aMCI participants, of whom 9 had multidomain deficits, were randomized to receive 1 mA HD-tDCS (N=7) or sham (N=4) stimulation. HD-tDCS was applied over ten 20-minute sessions targeting the dACC. Neuropsychological measures of episodic memory, verbal fluency, and executive function were completed at baseline and after the last HD-tDCS session. Changes in composite scores for memory and language/executive function tests were compared between groups (one-tailed t-tests with a = 0.10 for significance). Clinically significant change, defined as > 1 SD improvement on at least one test in the memory and non-memory domains, was compared between active and sham stimulation based on the frequency of participants in each.

No statistical or clinically significant change (N-1 X2; p = 0.62) was seen in episodic memory for the active HD-tDCS (MDiff = 4.4; SD = 17.1) or sham groups (MDiff = -0.5; SD = 9.7). However, the language and executive function composite showed statistically significant improvement (p = 0.04; MDiff = -15.3; SD = 18.4) for the active HD-tDCS group only (Sham MDiff = -5.8; SD = 10.7). Multiple participants (N=4) in the active group had clinically significant enhancement in language and executive functioning tests, while nobody in the sham group did (p = 0.04).

HD-tDCS targeting the dACC had no direct benefit for episodic memory deficits in aMCI based on preliminary findings for this ongoing clinical trial. However, significant improvement in language and executive function skills occurred in response to HD-tDCS, suggesting HD-tDCS in this configuration has promising potential as an intervention for language and executive function deficits in MCI.

The aim of the present study was to analyse the effects of the transcranial random noise stimulation (tRNS) technique when placed on the left dorsolateral prefrontal cortex (L-DPFC) and left inferior frontal gyrus (L-IFG), for the improvement of verbal fluency performance and creativity skills in a group of multilingual healthy adults.

Fifty healthy adults, aged 18-47 years, participated in the study. All of them were native Spanish speakers of which three were bilingual (Spanish and English) and 47 were multilingual (Spanish, Basque and English). The study had a randomized, counterbalanced, double-blind, sham-controlled design. The participants were randomly allocated to either a tRNS active group or a placebo-control group. All participants were tested individually in one session divided into three parts: (1) baseline, (2) online, and (3) offline assessment. In the active condition, a 1.5mA current (100-500 Hz) was delivered for 20 minutes (online phase). Participants’ verbal fluency was assessed through semantic and phonemic verbal fluency tasks in three different languages (Spanish, Basque and English), while creativity was assessed in their native language with the Remote Associations Test (RAT, pre and post forms) for convergent thinking, and with the Unusual Uses subtest (UU, pre and post forms) for divergent thinking. In addition, the linguistic profile of the participants was evaluated with the Language Experience and Proficiency Questionnaire (LEAP-Q), and their processing speed and cognitive flexibility were assessed with the Stroop Color and Word Test (SCWT).

The results showed significant differences in phonemic fluency between the groups during the online assessment in Spanish (F= 5.31, p = 0.026), and in the offline assessments in Spanish (F=6.44, p = 0.015) and English (F=10.80, p = 0.002), with participants in the active condition performing better. While no differences were observed in the performance of the groups in verbal fluency in Basque, neither in the online (F=1.06, p = 0.31), nor in the offline assessment (F=2.62, p = 0.11). Furthermore, no significant differences were observed between groups in semantic verbal fluency tasks in any of the languages, neither during stimulation nor offline. However, there were no differences between conditions in the online (Spanish, F=0.86, p = 0.35; English, F=2.95, p = 0.09; and Basque, F=0.01 p = 0.94) and offline (Spanish, F=2.53, p = 0.11; English, F=0.74, p = 0.39; and Basque, F=1.39, p = 0.24) semantic tasks. In creativity, significant differences were observed between groups on the RAT (F=9.58, p = 0.003), while no differences were observed in the performance of any of the three dimensions of the UU (Originality, F=0.44, p = 0.51; Flexibility, F=0.42, p = 0.51; Fluency, F=0.69, p = 0.41). In the SCWT, statistically significant differences were only observed in the colour-word part (F=7.60, p = 0.008) during the online assessment, showing a better performance of the participants under the tRNS condition compare to the sham condition.

The results obtained in this study suggest that the excitatory effects of tRNS over the L-DLPFC L-IFG could contribute to the improvement of phonemic verbal fluency and verbal convergent thinking, in healthy individuals.

Repetitive transcranial magnetic stimulation (TMS) is an evidenced based treatment for adults with treatment resistant depression (TRD). The standard clinical protocol for TMS is to stimulate the left dorsolateral prefrontal cortex (DLPFC). Although the DLPFC is a defining region in the cognitive control network of the brain and implicated in executive functions such as attention and working memory, we lack knowledge about whether TMS improves cognitive function independent of depression symptoms. This exploratory analysis sought to address this gap in knowledge by assessing changes in attention before and after completion of a standard treatment with TMS in Veterans with TRD.

Participants consisted of 7 Veterans (14.3% female; age M = 46.14, SD = 7.15; years education M = 16.86, SD = 3.02) who completed a full 30-session course of TMS treatment and had significant depressive symptoms at baseline (Patient Health Questionnaire-9; PHQ-9 score >5). Participants were given neurocognitive assessments measuring aspects of attention [Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV) subtests: Digits Forward, Digits Backward, and Number Sequencing) at baseline and again after completion of TMS treatment. The relationship between pre and post scores were examined using paired-samples t-test for continuous variables and a linear regression to covary for depression and posttraumatic stress disorder (PTSD), which is often comorbid with depression in Veteran populations.

There was a significant improvement in Digit Span Forward (p=.01, d=-.53), but not Digit Span Backward (p=.06) and Number Sequencing (p=.54) post-TMS treatment. Depression severity was not a significant predictor of performance on Digit Span Forward (f(1,5)=.29, p=.61) after TMS treatment. PTSD severity was also not a significant predictor of performance on Digit Span Forward (f(1,5)=1.31, p=.32).

Findings suggested that a standard course of TMS improves less demanding measures of working memory after a full course of TMS, but possibly not the more demanding aspects of working memory. This improvement in cognitive function was independent of improvements in depression and PTSD symptoms. Further investigation in a larger sample and with direct neuroimaging measures of cognitive function is warranted.

Subthreshold depressive symptoms are both prevalent and associated with negative outcomes in older adults, including conversion to major depressive disorder and other medical conditions. Antidepressants are not recommended as first-line or sole intervention for subthreshold depression; thus, finding other efficacious interventions is important. In depressed adults, transcranial direct current stimulation (tDCS) applied to the frontal lobe has antidepressant properties and pairing tDCS with cognitive training results in additional benefit due to enhancement of frontal cortical activity. However, these studies have primarily targeted depressed adults under age 65 years and less is known about whether this intervention combination is beneficial or affects subthreshold depressive symptoms in older adults.

We are reporting secondary data analyses from Nissim et al. (2019), who recruited 30 non-demented healthy older adults and randomized them to receive active or sham tDCS in combination with cognitive training for 2 weeks. Active tDCS was delivered bifrontally over F3 (cathode) and F4 (anode) for 20-min at 2 mA intensity through two 5x7 cm2 saline saturated sponge electrodes using the Soterix Medical 1x1 tDCS clinical trials device. Sham tDCS had identical set-up with 2 mA stimulation for 30-sec with 30-sec ramp up and down. Cognitive training was administered for 40-min daily using attention/processing speed and working memory modules from BrainHQ. The first 20-min of cognitive training was paired with active or sham tDCS. To allow room for symptom improvement, we only included participants with Beck Depression Inventory, 2nd edition (BDI-II) scores of 5 or greater ("minimal" depression severity). We identified 15 participants who met this cut-off (70.93 ± 5.41 years old, 10 females, 16.4 years ± 2.32 years education, MoCA = 27.27 ± 2.34; 7 active, 8 sham).

tDCS conditions did not significantly differ in age, sex, years of education, MoCA scores, number of completed intervention days, or baseline BDI-II (active: 7.71 ± 2.93, sham: 11.38 ± 6.44). There were no differences in sensation ratings between groups or in confidence ratings for condition received (suggesting successful blinding). Results indicated the combination of active (and not sham) tDCS with cognitive training was associated with reduced depressive symptoms (2.7 vs. 1.4 points, active vs. sham). Including covariates (age, sex, education, MoCA scores, and number of completed intervention days) in the model further strengthened this discrepancy (3.7 vs. 0.51 points, active vs. sham).

While preliminary, these results suggest this intervention combination may be a potential method for improving subthreshold depressive symptoms in older adults via targeting prefrontal neural circuitry and promoting neuroplasticity of the underlying neural network. While baseline BDI-II scores did not significantly differ, the active tDCS group had a lower score than sham, but saw greater improvement in BDI-II scores post-intervention despite having less room for change. Adequate treatment of subthreshold depressive symptoms may prevent or reduce negative outcomes associated with depressive symptoms in at-risk older adults. Larger randomized clinical trials are needed to better understand tDCS plus cognitive training antidepressant effects in this age group.

This study builds on the work by Rehman et al (2022) who argued that transcranial magnetic stimulation (TMS) treatment not only helps treat depression but also decreases sleep problems such as difficulty falling asleep,staying asleep, and waking too early. The present study further explores differences in sleep onset latency, meaning the time it takes to fall asleep, and duration of sleep per night in the pre and post treatment phases of rTMS. The information regarding major attributes of sleep is critical because recent research shows that about 90% of patients with major depressive disorder (MDD) also struggle with sleep disorders (Li et al., 2022), and sleeping for less than seven hours may eventually lead to sleep deprivation (Hirshkowitz et al., 2015), with increased risk of physical and mental health problems (Sheehan et al, 2019). Sleep onset latency estimates vary from individual to individual but typical sleep latency is considered between 10 to 20 minutes (Jung et al, 2013). As it has been shown that overall sleep problems improve with rTMS, we hypothesized that self-reported sleep onset latency will decrease, and sleep duration will increase.

All participants met inclusion criteria for MDD diagnosis and completed a full course of TMS treatment (N=470; Mean age=53.45, SD=13.73). The sample was mostly male (81%) and ethnically diverse: 77.7% non-Hispanic White, 13.3% Black Americans, 1.9% Asian, 0.2 % Asian Indian, and 1.9% other ethnicities. Sleep problems were assessed using the following questions at the pre and post treatment stages: the number of minutes it takes to fall asleep and duration of sleep each night.

A Wilcoxon matched-pairs signed-rank test was conducted to determine whether there was a difference in sleep onset latency and hours of sleep per night between pre and post intervention. The results indicated a significant difference in time to fall asleep between pre and post treatment (pre-treatment M = 1.19, SD = 0.99, post-treatment M = 0.93, SD = 0.91; z = -5.01, p < .001. In addition, there was a significant increase in the minutes of sleep per night in pre (M = 6.11, SD = 2.07) compared to the post treatment (M = 6.32, SD = 1.77), z = -2.56, p = .010.

Reduced sleep is known to negatively impact mood, cognitive ability, work performance, and immune function (Besedovsky et al., 2012; Killgore, 2010; Massar et al, 2019; Vandekerckhove & Wang, 2018). Similarly, longer sleep onset latency can cause an individual to enter the first sleep stage later than expected and complete fewer sleep cycles. The results of the present study show the effectiveness of rTMS in decreasing sleep onset latency and increasing the duration of sleep. Given the comorbidity and bidirectionality between sleep disturbances and mood disorders (Fang et al., 2019; Palagini et al., 2019), further researching treatments such as rTMS to improve sleep as a means to also improve mood is crucial. We propose acquiring knowledge about sleep attributes as an essential part of clinicians’ work early on in the rTMS treatment in order to monitor an individual’s global functioning level in light of improved sleep.

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation therapy most widely used in depression, has shown evidence of secondary benefits for cognition in both neurologic and neuropsychiatric conditions. The recent development of more efficient stimulation protocols, such as accelerated high-dose intermittent theta burst (iTBS)-rTMS, has substantially reduced treatment burden by shortening the treatment course by >50%. This study aimed to establish the safety, feasibility, acceptability, and preliminary efficacy of iTBS-rTMS as a tool for bolstering cognition in individuals with amnestic mild cognitive impairment (aMCI).

Twenty-four patients with aMCI were enrolled in an open-label phase I trial of iTBS-rTMS; 2 withdrew prior to initiating treatment due to personal circumstances. All participants had received a diagnosis of MCI due to possible AD from a healthcare provider (i.e., neurologist or neuropsychologist) and met actuarial neuropsychological criteria for aMCI. This sample of older adults (range: 61.5-85.2 years, M = 74.1, SD = 5.71) was predominantly White/non-Hispanic (n = 23; Black/non-Hispanic: n = 1), roughly half female (n = 13), with a college education (range: 12-20 years, M = 15.9, SD = 2.5). Participants received 24 sessions of iTBS-rTMS to the left dorsolateral prefrontal cortex over 3 days (8 sessions each, lasting roughly 2 hours per day). Participants rated their perceptions and experience of common side effects during and after each treatment session as well as retrospectively at post-treatment and 4-week follow-up. They completed structural and functional brain MRI, neuropsychiatric evaluations, and neuropsychological assessments before and after treatment and were administered a subset of these measures at 4-week follow-up. MoCA scores were used to monitor for adverse neurocognitive effects, and the fluid cognition composite score from the NIH Toolbox Cognition Battery was used to test preliminary efficacy.

We achieved a high retention rate (95%), with 21 of the 22 participants completing all study procedures. There were no clinically significant adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participant reports indicated high tolerability and acceptability, with a modal rating of 0 (on a scale from 0=not at all to 10=extremely) for six common side effects (i.e., headache, pain, scalp irritation, facial twitching, fatigue, fear/anxiety), assessed both during and after each treatment session. They reported very low desire to quit despite some participants rating the treatment as moderately tiring. We observed significant, large effect-size (d = 0.98) improvements in fluid cognition from pre- to post-treatment.

Our findings support the safety, feasibility, and acceptability of iTBS-rTMS treatment in patients with aMCI. Further, although not explicitly dosed for efficacy, we provide preliminary evidence of improved fluid cognition as a function of treatment, highlighting the potential of this treatment for improving trans-domain cognitive impairment. These promising results can directly inform future trials aimed at optimizing treatment parameters, broadening the indication to other MCI subtypes, and testing the augmentation of established cognitive rehabilitation interventions when combined with rTMS.

Poor mood and quality of life is common among patients with medically intractable seizures. Many of these patients are not candidates for seizure focus resection and continue to receive standard medical care. Responsive neurostimulation (RNS) has been an effective approach to reduce seizure frequency for nonsurgical candidates. Previous research using RNS clinical trial participants has demonstrated improved mood and quality of life when patients received RNS-implantation earlier in their medically resistant epilepsy work-up (Loring et al., 2021). We aimed to describe the level of depression and quality of life in adults with medical resistant epilepsy, treated with RNS, presenting to an outpatient clinic.

This pilot study was conducted among 11 adult epilepsy patients treated with RNS at the epilepsy specialty clinic at Baylor College of Medicine. Ages of participants ranged from 18-56 (M=32.01, SD=12.37) with a mean education of 12.43 (SD=0.85). The majority of the participants identified as White (White=72.2%; Hispanic/Latino/a=14.3%, Other=7.1%). We also present pre- and post-RNS preliminary results of a subset of 4 patients for whom pre and post implantation data was available. Depression symptoms were assessed through the Beck Depression Inventory, 2nd Edition (BDI-II) and quality of life was determined using the Quality of Life in Epilepsy (QoLiE-31).

Patients reported minimal symptoms of depression (M=5.45, SD=4.03) and good overall quality of life (M=71.18, SD=14.83) after RNS. Participants’ scores on their overall quality of life ranged from 50 to 95 (100=better quality of life). The QoLiE-31 showed high scores on emotional wellbeing (M=69.45, SD=14.56) and cognitive functioning (M=65.36, SD=16.66) domains. Post-hoc analysis revealed a significant difference in the cognitive functioning domain of QoLiE-31 before (M=44.75, SD=12.58) and after (M=51.0, SD=11.58) RNS implantation(t(3)=-3.78, p=0.016. Additionally, overall QoLiE score approached statistical significance when comparing pre-RNS (M=44.75 SD=9.29) to post-RNS (M=49.75 SD=11.62; t(3)=-2.01, p = 0.069). No significant differences were evident on seizure worry, energy/fatigue, medication effects, and social functioning domains of QoLiE-31 before and after RNS treatment.

These pilot study results suggest low levels of depression with this population post-RNS implantation. Additionally, there is preliminary evidence to suggest improved patient-rated cognitive functioning and overall quality of life. While this is a small study population, the results have important implications for patients with intractable epilepsy, even with those form who surgical resection may not be possible. Future studies with large enough samples to examine moderating and mediating factors to mood and quality of life changes post-RNS will be important.

Neuroimaging is commonly used in medicine to identify neuropathology and is widely considered to be a reliable and valid diagnostic modality. Personality testing is commonly used to identify psychopathology but is generally perceived to have less clinical efficacy than neuroimaging. The purpose of the current study was to compare the clinical efficacy of personality tests to neuroimaging using meta-analysis.

Multiple databases were searched for original research utilizing either personality tests or neuroimaging. The search interval covered articles published within the last 10 years. Studies were selected based on the criteria of having a clinical group and a healthy control sample with a reported diagnostic outcome. For this meta-analysis, neuroimaging studies focusing on diagnostic utility for Alzheimer’s dementia were included. Personality testing studies were included if they broadly reported a clinical outcome, due to fewer studies in this area. Studies were coded using a complex multi-comparison, outcome, and subgroup schema, and were analyzed under random-effects modeling.

Out of the 240 studies identified for the personality domain, 13 were selected for the meta-analysis. Out of 6522 studies identified for the neuroimaging domain, 21 studies were selected for the meta-analysis. Results indicated a significant difference between the neuroimaging and personality testing effect sizes. Specifically, neuroimaging [Hedge’s g = -1.623, 95% CI = -1.973 to -1.273, p<.001] yielded a greater effect size in comparison to the personality tests effect size [Hedge’s g = -0.658, 95% CI = -0.751 to -0.565, p<.001]. The effect size for clinical utility of neuroimaging was close to double that of the effect for personality tests diagnostic utility.

Findings from this meta-analysis showed a significant difference in the effect sizes obtained from neuroimaging studies compared to the studies of personality tests. While both neuroimaging and personality testing demonstrated meaningful clinical utility, neuroimaging studied had a larger effect size.