Intersession Interval Research Articles

Randomised controlled trial comparing different intersession intervals of intermittent theta burst delivered to the dorsal medial prefrontal cortex

BackgroundIntermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation (rTMS) that can be administered in a fraction of the time of standard rTMS. Applying multiple daily...

Characterizing patterns of diffusion tensor imaging variance in aging brains.

As large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Here we characterize the role of physiology, subject compliance, and the interaction of subject with the scanner in the understanding of DTI variability, as modeled in spatial variance of derived metrics in homogeneous regions. We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging (BLSA), with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. We assess variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as "interval"), motion, sex, and whether it is the first scan or the second scan in the session. Covariate effects are heterogeneous and bilaterally symmetric across ROIs. Inter-session interval is positively related ( ) to FA variance in the cuneus and occipital gyrus, but negatively ( ) in the caudate nucleus. Males show significantly ( ) higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In 62 out of 176 ROIs defined by the Eve type-1 atlas, an increase in motion is associated ( ) with a decrease in FA variance. Head motion increases during the rescan of DTI ( millimeters per volume). The effects of each covariate on DTI variance, and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis. This work provides a foundation for study planning to account for regional variations in metric variance.

Differential analgesic effects of high-frequency or accelerated intermittent theta burst stimulation of M1 on experimental tonic pain: Correlations with cortical activity changes assessed by TMS-EEG

Accelerated intermittent theta burst stimulation (AiTBS) has attracted much attention in the past few years as a new form of brain stimulation paradigm. However, it is unclear the relative efficacy of AiTBS on cortical excitability compared to conventional high-frequency rTMS. Using concurrent TMS and electroencephalogram (TMS-EEG), this study systematically compared the efficacy on cortical excitability and a typical clinical application (i.e. pain), between AiTBS with different intersession interval (ISIs) and 10-Hz rTMS. Participants received 10-Hz rTMS, AiTBS-15 (3 iTBS sessions with a 15-min ISI), AiTBS-50 (3 iTBS sessions with a 50-min ISI), or Sham stimulation over the primary motor cortex on four separate days. All four protocols included a total of 1800 pulses but with different session durations (10-Hz rTMS ​= ​18, AiTBS-15 ​= ​40, and AiTBS-50 ​= ​110 ​min). AiTBS-50 and 10-Hz rTMS were more effective in pain reduction compared to AiTBS-15. Using single-pulse TMS-induced oscillation, our data revealed low gamma oscillation as a shared cortical excitability change across all three active rTMS protocols but demonstrated completely opposite directions. Changes in low gamma oscillation were further associated with changes in pain perception across the three active conditions. In contrast, a distinct pattern of TMS-evoked potentials (TEPs) was revealed, with 10-Hz rTMS decreasing inhibitory N100 amplitude and AiTBS-15 reducing excitatory P60 amplitude. These changes in TEPs were also covarying with low gamma power changes. Sham stimulation indicated no significant effect on either cortical excitability or pain perception. These results are relevant only for provoked experimental pain, without being predictive for chronic pain, and revealed a change in low gamma oscillation, particularly around the very particular frequency of 40 ​Hz, shared between AiTBS and high-frequency rTMS. Conversely, cortical excitability (balance between excitation and inhibition) assessed by TEP recording was modulated differently by AiTBS and high-frequency rTMS paradigms.

Fast depressive symptoms improvement in bipolar I disorder after Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT): A two-site feasibility and safety open-label trial

BackgroundAlthough there are a few first-line treatment options for bipolar depression, none are rapid-acting. A new rTMS protocol, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®), has been shown to have a rapid antidepressant effect in major depressive disorder (MDD). We examined the preliminary safety, tolerability, and efficacy of SAINT for the treatment of depression in a small sample of persons with treatment-resistant bipolar I disorder. MethodsParticipants with treatment-resistant bipolar I disorder currently experiencing moderate to severe depression were treated with open-label SAINT. Resting-state functional MRI (fMRI) was used to generate individualized treatment targets for each participant based on the region of the left dorsolateral prefrontal cortex most anticorrelated with the subgenual anterior cingulate cortex. Participants were treated with 10 iTBS sessions daily, with 50-min intersession intervals, for up to 5 consecutive days. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate follow-up after treatment. ResultsWe treated 10 participants and found a mean reduction of 16.9 in MADRS scores, with a 50 % response rate and 40 % remission rate immediately following treatment. 60 % of participants met remission criteria within the 1-month period following treatment. No serious adverse events, manic episodes, or cognitive side effects were observed. LimitationsOur study has a limited sample size and larger samples are needed to confirm safety and efficacy. ConclusionsSAINT has shown preliminary feasibility, safety, tolerability, and efficacy in treating treatment-resistant bipolar I depression. Double-blinded sham-controlled trials with larger samples are needed to confirm safety and efficacy.

Characterizing patterns of diffusion tensor imaging variance in aging brains.

As large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Here, we characterize the role of physiology, subject compliance, and the interaction of the subject with the scanner in the understanding of DTI variability, as modeled in the spatial variance of derived metrics in homogeneous regions. We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging, with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. We assess the variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as "interval"), motion, sex, and whether it is the first scan or the second scan in the session. Covariate effects are heterogeneous and bilaterally symmetric across ROIs. Inter-session interval is positively related ( ) to FA variance in the cuneus and occipital gyrus, but negatively ( ) in the caudate nucleus. Males show significantly ( ) higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In 62 out of 176 ROIs defined by the Eve type-1 atlas, an increase in motion is associated ( ) with a decrease in FA variance. Head motion increases during the rescan of DTI ( mm per volume). The effects of each covariate on DTI variance and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis. This work provides a foundation for study planning to account for regional variations in metric variance.

Non MRI Guided Accelerated Intermittent Theta Burst Stimulation is Effective in Patients with Treatment Resistant Depression and Suicidality

IntroductionThe U.S. Food & Drug Administration (FDA) has cleared SNT (Stanford Neuromodulation Therapy) for treatment of major depressive disorder (MDD) in adults who have failed to achieve improvement from at least two prior trials of antidepressants. SNT protocol requires both structural and functional connectivity MRIs which is limited by high cost and lack of availability, its use without neuronavigation is still considered an off label use and need more investigation.Objectives1-To investigate efficacy of SNT like accelerated off-label protocol without Neuronavigation in treating patients with TRD and suicidality.2-To investigate durabiliy ( up to one month ) of SNT like accelerated off-label protocol without Neuronavigation in treating patients with TRD and suicidalityMethods Two cases diagnosed as treatment resistant unipolar depression with suicidal ideations received accelerated intermittent theta burst stimulation (a iTBS); with figure of eight coil administered to the left dorsolateral prefrontal cortex (DL-PFC) determined using Beam method. Stimulation was at 90% MT for 1800 pulses with an intersession interval of fifty minutes. Patients received ten sessions every day for five consecutive days for a total of fifty sessions (90,000 pulses). The following scales were applied at the baseline and at the end of each day of five treatment days:The Montgomery and Asberg Depression Rating Scale (MADRS) The Beck Depression Inventory, Columbia Suicide Severity Rating Scale (C-SSRS) and Young Mania Rating Scale (YMRS).ResultsThe two cases at the end of the fifth day were completely improved regarding both suicidal ideations and depression without emerging of hypomania. Follow up was done weekly for one month with durable results.ConclusionsSNT protocol without neuronavigation needs to be well investigated in suppressing both suicidality and depression in patients with TRD.Disclosure of InterestNone Declared

Repetitive Transcranial Alternating Current Stimulation to Improve Working Memory: An EEG-fNIRS Study.

Transcranial electrical stimulation has demonstrated the potential to enhance cognitive functions such as working memory, learning capacity, and attentional allocation. Recently, it was shown that periodic stimulation within a specific duration could augment the human brain's neuroplasticity. This study investigates the effects of repetitive transcranial alternating current stimulation (tACS; 1 mA, 5 Hz, 2 min duration) on cognitive function, functional connectivity, and topographic changes using both electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Fifteen healthy subjects were recruited to measure brain activity in the pre-, during-, and post-stimulation sessions under tACS and sham stimulation conditions. Fourteen trials of working memory tasks and eight repetitions of tACS/sham stimulation with a 1-minute intersession interval were applied to the frontal cortex of the participants. The working memory score, EEG band-wise powers, EEG topography, concentration changes of oxygenated hemoglobin, and functional connectivity (FC) were individually analyzed to quantify the behavioral and neurophysiological effects of tACS. Our results indicate that tACS increases: i) behavioral scores (i.e., 15.08, ) and EEG band-wise powers (i.e., theta and beta bands) compared to the sham stimulation condition, ii) FC of both EEG-fNIRS signals, especially in the large-scale brain network communication and interhemispheric connections, and iii) the hemodynamic response in comparison to the pre-stimulation session and the sham condition. Conclusively, the repetitive theta-band tACS stimulation improves the working memory capacity regarding behavioral and neuroplasticity perspectives. Additionally, the proposed fNIRS biomarkers (mean, slope), EEG band-wise powers, and FC can be used as neuro-feedback indices for closed-loop brain stimulation.

Investigating optimal spacing schedules for incidental acquisition of L2 collocations

Abstract Research investigating lag effects in second language (L2) collocation learning is very limited. To date, no intervention study has examined the relationship between intersession intervals (ISIs) and retention intervals (RIs) in relation to incidental acquisition of collocations. To fill this gap, the current study collected data from two groups of students in Saudi Arabia (Experiment 1, n = 73; Experiment 2, n = 69), using a pretest-treatment-delayed posttest design. The participants learned 25 incongruent adjective-noun collocations incidentally during five reading sessions at either a 3.5-day ISI (Experiment 1) or a 7-day ISI (Experiment 2). Two control groups received no treatment. Learning rates were assessed at the form recall and meaning recall levels of sensitivity following an RI of 14 days in Experiment 1 and an RI of 28 days in Experiment 2. Results show that both spacing schedules were equally effective for the incidental acquisition of collocations.

Effect of follicular wave synchronization using a progesterone-releasing intravaginal device-based protocol on in vitro embryo production in Bos taurus cows subjected to 14-day intervals ovum pick-up

Follicular wave synchronization (FWS) before ovum pick-up (OPU) is one of the strategies used to improve the efficiency of in vitro embryo production (IVP). This study aimed to evaluate the effect of FWS on the total follicular number, cumulus-oocyte complex (COC) recovery, and in vitro embryo development in Angus cows (n = 33) subjected to OPU with 14-day intersession intervals. Additionally, it was also evaluated the presence of carryover effects given the short intersession interval used. The experiment was run as a 2-treatment (FWS vs. Control) x 2-period (1 vs. 2) crossover design. Animals in the FWS group received an intravaginal progesterone implant (1gr), estradiol benzoate (2 mg), and D-cloprostenol (150 μg) on day 0 and the OPU was performed on day 5. Control group animals did not receive any hormone treatment. The FWS increased the number of 6–10 mm follicles (P = 0.05), but it decreased the COC recovery rate (P < 0.01). The FWS did not affect the total or frozen embryo numbers (P = 0.49 and P = 0.17; respectively), but it increased the total blastocyst cell number (P < 0.01). A carryover effect was found on the total and < 6 mm follicles number (P = 0.10 and P < 0.01; respectively), and on the regular, atretic, viable, and total number of COC (P = 0.01, P = 0.08, P = 0.02 and P < 0.01; respectively). We concluded that the FWS increased the quality of embryos after OPU with 14-day intersession intervals in Angus cows and that this kind of OPU/IVP scheme enabled the existence of a carryover effect, especially on the follicle number and COC morphology.

Specific patterns of neural activity in the hippocampus after massed or distributed spatial training

Training with long inter-session intervals, termed distributed training, has long been known to be superior to training with short intervals, termed massed training. In the present study we compared c-Fos expression after massed and distributed training protocols in the Morris water maze to outline possible differences in the learning-induced pattern of neural activation in the dorsal CA1 in the two training conditions. The results demonstrate that training and time lags between learning opportunities had an impact on the pattern of neuronal activity in the dorsal CA1. Mice trained with the distributed protocol showed sustained neuronal activity in the postero-distal component of the dorsal CA1. In parallel, in trained mice we found more active cells that tended to constitute spatially restricted clusters, whose degree increased with the increase in the time lags between learning trials. Moreover, activated cell assemblies demonstrated increased stability in their spatial organization after distributed as compared to massed training or control condition. Finally, using a machine learning algorithm we found that differences in the number of c-Fos positive cells and their location in the dorsal CA1 could be predictive of the training protocol used. These results suggest that the topographic organization and the spatial location of learning activated cell assemblies might be critical to promote the increased stability of the memory trace induced by distributed training.

Electric field distribution predicts efficacy of accelerated intermittent theta burst stimulation for late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for late-life depression (LLD) but may have lower rates of response and remission owing to age-related brain changes. In particular, rTMS induced electric field strength may be attenuated by cortical atrophy in the prefrontal cortex. To identify clinical characteristics and treatment parameters associated with response, we undertook a pilot study of accelerated fMRI-guided intermittent theta burst stimulation (iTBS) to the right dorsolateral prefrontal cortex in 25 adults aged 50 or greater diagnosed with LLD and qualifying to receive clinical rTMS. Participants underwent baseline behavioral assessment, cognitive testing, and structural and functional MRI to generate individualized targets and perform electric field modeling. Forty-five sessions of iTBS were delivered over 9 days (1800 pulses per session, 50-min inter-session interval). Assessments and testing were repeated after 15 sessions (Visit 2) and 45 sessions (Visit 3). Primary outcome measure was the change in depressive symptoms on the Inventory of Depressive Symptomatology-30-Clinician (IDS-C-30) from Visit 1 to Visit 3. Overall there was a significant improvement in IDS score with the treatment (Visit 1: 38.6; Visit 2: 31.0; Visit 3: 21.3; mean improvement 45.5%) with 13/25 (52%) achieving response and 5/25 (20%) achieving remission (IDS-C-30 < 12). Electric field strength and antidepressant effect were positively correlated in a subregion of the ventrolateral prefrontal cortex (VLPFC) (Brodmann area 47) and negatively correlated in the posterior dorsolateral prefrontal cortex (DLPFC). Response and remission rates were lower than in recently published trials of accelerated fMRI-guided iTBS to the left DLPFC. These results suggest that sufficient electric field strength in VLPFC may be a contributor to effective rTMS, and that modeling to optimize electric field strength in this area may improve response and remission rates. Further studies are needed to clarify the relationship of induced electric field strength with antidepressant effects of rTMS for LLD.

Test-retest reliability of suppression head impulse paradigm (SHIMP) in healthy individuals

Objective The Video Head Impulse Test (vHIT) is an efficient tool to assess VOR. vHIT has been widely used to detect the presence of peripheral vestibular impairment. vHIT uses two paradigms: HIMP (Head Impulse Paradigm) and SHIMP (Suppression Head Impulse Paradigm). The current study aimed to determine the test-retest reliability of the Suppression Head Impulse Paradigm (SHIMP) in normal individuals. Method Twenty-eight healthy young individuals aged 18–30 years with normal hearing sensitivity and normal middle ear function participated in the study. The participants also had no signs and symptoms or history of vestibular problems. The SHIMP paradigm was performed twice (sessions I and II) with an inter-session interval of twodays. Results Paired sample t-test showed no significant difference in VOR gain and asymmetry values between sessions I and II. Cronbach’s alpha also showed a good test-retest reliability for VOR gain and asymmetry values. Kappa Coefficient showed good reliability for the presence of anticompensatory saccades. Conclusion VOR Gain functions and the presence of anti-compensatory saccades are highly reliable parameters when tested with SHIMP. Thus, any deviance in the gain parameters indicates a vestibular impairment rather than variability in the SHIMP test paradigm.

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) FOR POST- STROKE ANXIETY AND DEPRESSION FOLLOWING SARS-COV2 INFECTION AND NEUROCOVID-19 CONTRACTION

Transcranial direct current stimulation (tDCS) is effective in the management of patients with depression and anxiety. However, it is not known if it is effective in the case of anxiety and depression following SARS-CoV2 and NeuroCOVID-19 infection. The aim of this study was to determine the efficacy of stimulating the brain with the use of a tDCS protocol ameliorated by a functional neuromarker, and here based on HBI methodology to reduce anxiety and depression following SARS-CoV2 infection and NeuroCOVID-19 contraction. A 47-year-old patient manifested severe anxiety and depression following a stroke following SARS-CoV2 infection and Neuro- COVID-19 contraction. The anxiety and depression were diagnosed using the HAD-Scale (Zigmond, Snaith 1983). A score of 8 to 10 is broad ly accepted as indicating mild symptoms, a score between 11- 16 suggests moderate anxiety or depression, and a score of 16 or more indicates severe anxiety or depressive symptoms. The patient received anodal tDCS to the left DLPFC using two different application protocols. Initially, a stimulation session of 2 milliamperes (mA) intensity for 20 minutes was administered every working day for 2 weeks. After 3 weeks, she subsequently received 7 daily sessions of periodic stimulations of an intensity of 2 mA for 13 minutes each with 20 minutes intersession intervals for 1 week. It was found that tDCS delivered via the dorsolateral prefrontal cortex (DLPFC) was effective in the reduction of post-stroke anxiety and depression following SARS- CoV2 infection and NeuroCOVID-19 contraction. Immediately follow- ing the final session of the initial protocol of stimulation, the Had Score was reduced for anxiety from 18 to 6 points, and for depression from 17 to 5 points and the symptoms disappeared. The HBI methodology allowed for the detection of a functional neuromarker of anxiety and depression and the development of a tDCS protocol. It was found that tDCS delivered via the dorsolateral prefrontal cortex (DLPFC) was effective in the reduction of post-stroke anxiety and depression following SARS-CoV2 infection and NeuroCOVID-19 contraction.

Spacing Effects in Task Repetition Research

AbstractThis article provides a conceptual review of the principles of input spacing as they might relate specifically to oral task repetition research and presents some of the common methodological considerations from the broader input spacing literature. The specific considerations discussed include the interaction between intersession intervals and retention intervals, the manipulation of posttests as a between‐participants variable, the number of task repetitions, absolute versus relative spacing, the criterion of learning, task type versus exact task repetition, and blocked versus interleaved practice. Each of these considerations is discussed with links, as appropriate, to the relevant empirical input spacing and task repetition literature. The purpose of this review is to highlight how, in many cases, these methodological considerations have been overlooked by task repetition researchers, including in studies where input spacing has and has not been a direct focus, and to suggest ways of addressing these methodological shortcomings in future research.

Time-course of age-related temporal order memory decline in an object recognition paradigm in mice

Temporal order memory refers to the ability to remember the order of occurrence of items across time. It is a critical feature of episodic memory that is often tested in rodents using spontaneous object recognition paradigms. However, impact of aging over performances of temporal order memory decline is barely known. Herein, we characterized here the effect of normal aging on the temporal order memory performances in NMRI mice between 3 and 19months of age, with an inter-session interval of 24h.We found that temporal order memory was impaired as soon as7 months of age. These results provide strong evidence that temporal order memory is particularly vulnerable to the deleterious effect of normal aging.

The Problem and Potential of TMS' Infinite Parameter Space: A Targeted Review and Road Map Forward.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive, effective, and FDA-approved brain stimulation method. However, rTMS parameter selection remains largely unexplored, with great potential for optimization. In this review, we highlight key studies underlying next generation rTMS therapies, particularly focusing on: (1) rTMS Parameters, (2) rTMS Target Engagement, (3) rTMS Interactions with Endogenous Brain Activity, and (4) Heritable Predisposition to Brain Stimulation Treatments.MethodsWe performed a targeted review of pre-clinical and clinical rTMS studies.ResultsCurrent evidence suggests that rTMS pattern, intensity, frequency, train duration, intertrain interval, intersession interval, pulse and session number, pulse width, and pulse shape can alter motor excitability, long term potentiation (LTP)-like facilitation, and clinical antidepressant response. Additionally, an emerging theme is how endogenous brain state impacts rTMS response. Researchers have used resting state functional magnetic resonance imaging (rsfMRI) analyses to identify personalized rTMS targets. Electroencephalography (EEG) may measure endogenous alpha rhythms that preferentially respond to personalized stimulation frequencies, or in closed-loop EEG, may be synchronized with endogenous oscillations and even phase to optimize response. Lastly, neuroimaging and genotyping have identified individual predispositions that may underlie rTMS efficacy.ConclusionsWe envision next generation rTMS will be delivered using optimized stimulation parameters to rsfMRI-determined targets at intensities determined by energy delivered to the cortex, and frequency personalized and synchronized to endogenous alpha-rhythms. Further research is needed to define the dose-response curve of each parameter on plasticity and clinical response at the group level, to determine how these parameters interact, and to ultimately personalize these parameters.

Accelerated Resting-State fMRI-Guided Theta Burst Stimulation to the Right DLPFC for Late-Life Depression: A Pilot Study

<h3>Introduction</h3> Repetitive transcranial magnetic stimulation (rTMS) is FDA-approved for treatment of major depressive disorder; however, its efficacy in late-life depression (LLD) may be reduced due to age-related changes (see Figure 1). rTMS of the dorsolateral prefrontal cortex (DLPFC) has been shown to affect mood control via modulation of the subgenual cingulate cortex (SgCC). The area within the DLPFC having maximum anticorrelated activity to the SgCC is currently believed the most efficacious target for rTMS for depression. While trials of accelerated neuronavigated rTMS to the left DLPFC for depression have shown large effects for depression,¹ there has not yet been a validation of this technique specifically for LLD. Additionally, no studies have tested accelerated intermittent theta burst stimulation (iTBS) to the right DLPFC for depression, although it may have benefit for both depression and anxiety.² We proposed a pilot study of accelerated resting-state functional MRI (rsfMRI)-guided iTBS for LLD and hypothesized that this intervention would result in a significant improvement in depressive and generalized anxiety disorder symptoms. <h3>Methods</h3> A total of 18 elderly patients (ages 50-79 years) with a clinical diagnosis of moderate to severe major depressive disorder of at least 6 months' duration were recruited from local clinics. Each patient underwent rsfMRI and behavioral assessment prior to treatment. Change in depressive symptoms was measured by the Inventory of Depressive Symptoms (IDS-30-C). Change in anxiety symptoms was measured by the Generalized Anxiety Disorder-7 (GAD-7). Each participant's unique stimulation target was found by preprocessing resting-state data within Analysis of Functional NeuroImages (AFNI). A connectivity map of the bilateral SgCC as defined by the Brainnetome atlas was computed and smoothed to 12mm. The maximally anti-correlated voxel within the DLPFC search region (Brodmann areas 9 and 46) was located. A 3mm sphere around the target voxel was warped to subject space and exported to a neuronavigation system. Each participant received 45 sessions of iTBS to their fMRI target with a Magventure MagPro X100 stimulator with Cool-B70 coil (see Figure 2). Stimulation parameters were: 5Hz burst frequency, 50Hz intraburst frequency, 2 second train duration, 8 second intertrain interval, 60 trains/session, 5 sessions/day, 50 minute intersession interval, for 9 days totaling 81,000 pulses. After the 15th and 45th treatments, participants repeated clinical and imaging assessments (see Figure 3). Depression scores were elicited by phone interview at one and three months after treatment. Means and standard deviations of depressive and anxious symptoms were calculated for each visit. Repeated measures analysis of variances (ANOVA) was used to assess change in symptoms over time. Changes in connectivity between nodes in the default mode network (DMN), salience network (SN), and frontoparietal network (FPN) were analyzed with independent components analysis (ICA) in Statistical Parametric Mapping (SPM). <h3>Results</h3> Mean age of the 18 patients (2M, 16F) was 63 ± 7.4 years. Mean duration of depression was 166 ± 154.4 months. Nine patients had comorbid GAD and five patients had comorbid posttraumatic stress disorder. Four of the 18 patients had previously undergone ECT. Mean depression (IDS-30-C) scores decreased throughout the study protocol (Visit 1: 39.31 ± 9.24; Visit 2: 30.74 ± 10.44; Visit 3: 20.79 ± 8.13) and remained below pre-treatment values at one month (19.84 ± 15.63) and three months (20.34 ± 14.15) (F(4,28) = 7.15, p = .0004, ??_p² = 0.5) (see Figure 4). Mean GAD-7 scores (N=18) also decreased with treatment (Visit 1: 9.95 ± 5.89; Visit 2: 9.58 ± 5.28; Visit 3: 6.53 ± 5.00) (F(2,36) = 7, p < .006, ??_p² = 0.28) (see Figure 5). Preliminary analysis of changes in connectivity from Visit 1 to Visit 3 indicate significantly increased within-network connectivity in the DMN (p = .003), and decreased between-network connectivity between the DMN and FPC (p = .011). <h3>Conclusions</h3> In this single-arm, uncontrolled pilot study, accelerated rsfMRI-guided iTBS to the right DLPFC in patients with LLD was effective in reducing both symptoms of depression and generalized anxiety. Connectivity changes in DMN and FPN network components were also observed. Future work should confirm these effects in a larger sample size and controlled study design. <h3>Secondary Rationale</h3> Reason for Late-Breaking Status: Data collection was continued beyond the regular submission deadline to attain greater statistical power to inform study conclusions. <h3>This research was funded by</h3> UNM Successful Aging Pilot Grant, Mind Research Network Center of Biomedical Research Excellence (COBRE) Pilot Grant (NIH/NIGMS 5P30GM122734-03)

Uncovering Characteristic Response Paths of a Population

We propose an approach for uncovering characteristic response paths of a population from an individual-level multivariate time series data set. The approach is based on a model that accommodates a set of arbitrary distributions for endogenous variables and interstep intervals and variables. The model enables reliable estimation of individual-level parameters by uncovering and statistically pooling clusters of similar individuals. We show that using such a model one can distribute the response of an outcome variable to an impulse over all possible preceding activity sequences. When a few such sequences explain most of the response, they describe the population’s characteristic response paths from the impulse to the outcome. We apply the proposed approach to a customer touchpoint data set from a large multichannel specialty retailer. This application uncovers six customer segments, each with unique characteristic paths to purchase. These paths provide insights into the behavior of customers and the optimal over-time communication strategy for different customer segments. Summary of Contribution: Uncovering users’ paths through physical and virtual spaces has been of considerable interest in the computing and operations research domain. The existing research suggests a demand for visualizing the primary paths of agents through geographic, online, and activity spaces. Thus far, most of the research have developed approaches that are unique to specific domains providing insight into the domain in the process. There is a need for a general statistically robust approach that can be applied to a broad range of domains to uncover variable sequences that lead to outcomes of interest. We propose a computational approach to uncover characteristic response paths of a population from an individual-level multivariate time series data set. The approach is based on a statistical model that accommodates arbitrary and mixed set of distributions for the endogenous variables, accommodates intersession intervals and variables, and reliably estimates individuals’ parameters through statistical pooling by uncovering clusters of similar members. These features make the proposed model suitable for a large variety of real-world datasets. We show that using such a model one can extract characteristic paths over possible activity sequences starting from an impulse leading up to a target variable of interest.

Lag effects in grammar learning: A desirable difficulties perspective

AbstractThis paper examined lag effects in the learning of second language (L2) grammar. Moreover, following the Desirable Difficulty Framework for L2 practice, the present study investigated whether lag effects could be explained by other sources of difficulty. Using digital flashcards, 117 English language learners (aged 10–18) learned two grammatical structures over two different sessions at a 1-day or 7-day intersession interval (ISI). Learners’ performance was analyzed at two retention intervals (RIs) of 7 and 28 days, respectively. Linguistic difficulty was compared by examining two different structures, while learner-related difficulty was analyzed by comparing learners who differed in terms of age, proficiency, and time required to complete the training. Results showed no main effect of ISI, a main effect of RI, and a small but significant ISI × RI interaction. Linguistic difficulty and age did not interact with ISI or RI. However, longer lags led to significantly higher scores for faster learners and learners of higher proficiency, while shorter lags promoted significantly higher scores for slower learners and learners of lower proficiency. The findings provide some support for the Desirable Difficulty Framework in its potential to explain L2 lag effects.