Transcutaneous vagus nerve stimulation (tVNS) is a promising potential intervention for Alzheimer's disease (AD) due to its influence on brain functions and mechanisms important in disease progression. Regions of interest include projection to the nucleus of the solitary tract, locus coeruleus, and hippocampus. Deterioration of the hippocampus is one of the most prominent early characteristics of AD, particularly during the mild cognitive impairment (MCI) stage. tVNS could modify function of the hippocampus. We examined resting state functional connectivity from the bilateral hippocampus in response to tVNS in patients with MCI.

Fifty older adults (28 women, 60-89 years of age) diagnosed with MCI were assessed. MCI was confirmed via diagnostic consensus conference with a neurologist and neuropsychologist (sources of information: Montreal Cognitive Assessment Test [MoCA], Clinical Dementia Rating scale [CDR], Functional Activities Questionnaire (FAQ), Hopkins Verbal Learning Test - Revised [HVLT-R] and medical record review). Resting state functional magnetic resonance imaging (fMRI) was collected on a 3T Siemens Prisma scanner while participants received either unilateral tVNS (left tragus, n = 25) or sham stimulation (left ear lobe, n = 25). fMRI data were processed using CONN toolbox v18b and hippocampal seed to voxel (whole brain) analyses were conducted with voxel and cluster level multiple comparison correction.

Contrasting tVNS and sham stimulation, whole-brain seed-to-voxel analysis demonstrated significant changes in connectivity from the left hippocampus to several cortical and subcortical regions bilaterally. Specifically, there was increased connectivity to prefrontal regions and cingulate gyri, and decreased connectivity to anterior and medial temporal lobes. A seed-to-voxel analysis from the right hippocampus indicated significant decrease in connectivity to a single cluster of regions in the left anterior temporal lobe in response to tVNS.

In conclusion, tVNS modified connectivity from the hippocampus to multiple brain regions implicated in semantic and salience functions, in which disruption correlates with deterioration in AD. These findings indicate afferent target engagement of tVNS. Future work is needed to investigate the long-term effects of tVNS in patients with MCI and whether it could contribute to meaningful cognitive change and subsequent improvements in quality of life.

Non-motor symptoms, such as mild cognitive impairment and dementia, are an overwhelming cause of disability in Parkinson’s disease (PD). While subthalamic nucleus deep brain stimulation (STN DBS) is safe and effective for motor symptoms, declines in verbal fluency after bilateral DBS surgery have been widely replicated. However, little is known about cognitive outcomes following unilateral surgeries.

We enrolled 31 PD patients who underwent unilateral STN-DBS in a randomized, cross-over, double-blind study (SUNDIAL Trial). Targets were chosen based on treatment of the most symptomatic side (n = 17 left hemisphere and 14 right hemisphere). All participants completed a neuropsychological battery (FAS/CFL, AVLT, DKEFS Color-Word Test) at baseline, then 2, 4, and 6 months post-surgery. Outcomes include raw scores for verbal fluency, immediate and delayed recall, and DKEFS Color-Word Inhibition trial (Trial 3) completion time. At 2, 4, and 6 months, the neurostimulation type (directional versus ring mode) was randomized for each participant. We compared baseline scores for all cognitive outcome measures using Welch’s two-sample t-tests and used linear mixed effects models to examine longitudinal effects of hemisphere and stimulation on cognition. This test battery was converted to a teleneuropsychology administration because of COVID-19 mid-study, and this was included as a covariate in all statistical models, along with years of education, baseline cognitive scores, and levodopa equivalent medication dose at each time point.

At baseline, patients who underwent left hemisphere implants scored lower on verbal fluency than right implants (t(20.66) = -2.49, p = 0.02). There were not significant differences between hemispheres in immediate recall (p = 0.57), delayed recall (p = 0.22), or response inhibition (p = 0.51). Post-operatively, left STN DBS patients experienced significant declines in verbal fluency over the study period (p = 0.02), while patients with right-sided stimulation demonstrated improvements (p < .001). There was no main effect of stimulation parameters (directional versus ring) on verbal fluency, memory, or inhibition, but there was a three-way interaction between time, stimulation parameters, and hemisphere on inhibition, such that left STN DBS patients receiving ring stimulation completed the inhibition trial faster (p = 0.035). After surgery, right STN DBS patients displayed faster inhibition times than patients with left implants (p = 0.015).

Declines in verbal fluency after bilateral stimulation are the most commonly reported cognitive sequalae of DBS for movement disorders. Here we found group level declines in verbal fluency after unilateral left STN implants, but not right STN DBS up to 6 months after surgery. Patients with right hemisphere implants displayed improvements in verbal fluency. Compared to bilateral DBS, unilateral DBS surgery, particularly in the right hemisphere, is likely a modifiable risk factor for verbal fluency declines in patients with Parkinson’s disease.

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.

Chronic insomnia is a highly prevalent disorder affecting approximately one-in-three Americans. Insomnia is associated with increased cognitive and brain arousal. Compared to healthy individuals, those with insomnia tend to show greater activation/connectivity within the default mode network (DMN) of the brain, consistent with the hyperarousal theory. We investigated whether it would be possible to suppress activation of the DMN to improve sleep using a type of repetitive transcranial magnetic stimulation (rTMS) known as continuous theta burst stimulation (cTBS).

Participants (n=9, 6 female; age=25.4, SD=5.9 years) meeting criteria for insomnia/sleep disorder on standardized scales completed a counterbalanced sham-controlled crossover design in which they served as their own controls on two separate nights of laboratory monitored sleep on separate weeks. Each session included two resting state functional magnetic resonance imaging (fMRI) sessions separated by a brief rTMS session. Stimulation involved a 40 second cTBS stimulation train applied over an easily accessible cortical surface node of the DMN located at the left inferior parietal lobe. After scanning/stimulation, the participant was escorted to an isolated sleep laboratory bedroom, fitted with polysomnography (PSG) electrodes, and allowed an 8-hour sleep opportunity from 2300 to 0700. PSG was monitored continuously and scored for standard outcomes, including total sleep time (TST), percentage of time various sleep stages, and number of arousals.

Consistent with our hypothesis, a single session of active cTBS produced a significant reduction of functional connectivity (p < .05, FDR corrected) within the DMN. In contrast, the sham condition produced no changes in functional connectivity from pre- to post-treatment. Furthermore, after controlling for age, we also found that the active treatment was associated with meaningful trends toward greater overnight improvements in sleep compared to the sham condition. First, the active cTBS condition was associated with significantly greater TST compared to sham (F(1,7)=14.19, p=.007, partial eta-squared=.67). Overall, individuals obtained 26.5 minutes more sleep on the nights that they received the active cTBS compared to the sham condition. Moreover, the active cTBS condition was associated with a significant increase in the percentage of time in rapid eye movement (REM%) sleep compared to the sham condition (F(1,7)=7.05, p=.033, partial eta-squared=.50), which was significant after controlling for age. Overall, active treatment was associated with an increase of 6.76% more of total sleep time in REM compared to sham treatment. Finally, active cTBS was associated with fewer arousals from sleep (t(8) = -1.84, p = .051, d = .61), with an average of 15.1 fewer arousals throughout the night than sham.

Overall, these findings suggest that this simple and brief cTBS approach can alter DMN brain functioning in the expected direction and was associated with trends toward improved objectively measured sleep, including increased TST and REM% and fewer arousals during the night following stimulation. These findings emerged after only a single 40-second treatment, and it remains to be seen whether multiple treatments over several days or weeks can sustain or even improve upon these outcomes.

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.

Aging is associated with disruptions in functional connectivity within the default mode (DMN), frontoparietal control (FPCN), and cingulo-opercular (CON) resting-state networks. Greater within-network connectivity predicts better cognitive performance in older adults. Therefore, strengthening network connectivity, through targeted intervention strategies, may help prevent age-related cognitive decline or progression to dementia. Small studies have demonstrated synergistic effects of combining transcranial direct current stimulation (tDCS) and cognitive training (CT) on strengthening network connectivity; however, this association has yet to be rigorously tested on a large scale. The current study leverages longitudinal data from the first-ever Phase III clinical trial for tDCS to examine the efficacy of an adjunctive tDCS and CT intervention on modulating network connectivity in older adults.

This sample included 209 older adults (mean age = 71.6) from the Augmenting Cognitive Training in Older Adults multisite trial. Participants completed 40 hours of CT over 12 weeks, which included 8 attention, processing speed, and working memory tasks. Participants were randomized into active or sham stimulation groups, and tDCS was administered during CT daily for two weeks then weekly for 10 weeks. For both stimulation groups, two electrodes in saline-soaked 5x7 cm2 sponges were placed at F3 (cathode) and F4 (anode) using the 10-20 measurement system. The active group received 2mA of current for 20 minutes. The sham group received 2mA for 30 seconds, then no current for the remaining 20 minutes.

Participants underwent resting-state fMRI at baseline and post-intervention. CONN toolbox was used to preprocess imaging data and conduct region of interest (ROI-ROI) connectivity analyses. The Artifact Detection Toolbox, using intermediate settings, identified outlier volumes. Two participants were excluded for having greater than 50% of volumes flagged as outliers. ROI-ROI analyses modeled the interaction between tDCS group (active versus sham) and occasion (baseline connectivity versus postintervention connectivity) for the DMN, FPCN, and CON controlling for age, sex, education, site, and adherence.

Compared to sham, the active group demonstrated ROI-ROI increases in functional connectivity within the DMN following intervention (left temporal to right temporal [T(202) = 2.78, pFDR < 0.05] and left temporal to right dorsal medial prefrontal cortex [T(202) = 2.74, pFDR < 0.05]. In contrast, compared to sham, the active group demonstrated ROI-ROI decreases in functional connectivity within the FPCN following intervention (left dorsal prefrontal cortex to left temporal [T(202) = -2.96, pFDR < 0.05] and left dorsal prefrontal cortex to left lateral prefrontal cortex [T(202) = -2.77, pFDR < 0.05]). There were no significant interactions detected for CON regions.

These findings (a) demonstrate the feasibility of modulating network connectivity using tDCS and CT and (b) provide important information regarding the pattern of connectivity changes occurring at these intervention parameters in older adults. Importantly, the active stimulation group showed increases in connectivity within the DMN (a network particularly vulnerable to aging and implicated in Alzheimer’s disease) but decreases in connectivity between left frontal and temporal FPCN regions. Future analyses from this trial will evaluate the association between these changes in connectivity and cognitive performance post-intervention and at a one-year timepoint.

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.

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.

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.

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.

Sensory-motor decoupling at the cortical level involving cholinergic circuitry has also been reported in Parkinson’s Disease (PD). Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been used previously to probe cortical cholinergic circuits in well-characterised subgroups of patients with PD. In the current study, we compared SAI in a cohort of PD patients at various stages of disease and explored correlations between SAI and various clinical measures of disease severity.

The modified Hoehn and Yahr (H&Y) scale was used to stage disease in 22 patients with PD. Motor and cognitive function were assessed using the MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale) part III and MoCA (Montreal Cognitive Assessment) score, respectively. Objective gait assessment was performed using an electronic walkway (GAITRite®). SAI was measured as the average percentage inhibition of test motor-evoked potentials (MEPs) conditioned by electrical stimulation of the contralateral median nerve at the wrist.

SAI was significantly reduced in patients with advanced PD (H&Y stage 3) compared to early PD patients (H&Y stage 1) on pairwise comparison. The visuospatial executive function and orientation domains of cognition demonstrated significant negative associations with SAI.

Cortical sensory-motor integration is progressively diminished as disease progresses. The observation that a reduction in SAI is associated with a reduction in cognitive function possibly reflects the progressive involvement of cortical cholinergic circuits in PD with increasing motor stage. Future longitudinal studies are necessary to confirm this preliminary result.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to be an effective treatment for depression. However, there has been little research to determine optimal parameters for treatment.

This study compared two rTMS treatment regimes for the treatment of major depression. Seventy-seven participants were randomized to either spaced or daily treatment. Spaced rTMS was given 3 days/week for 6 weeks (18 treatments in total) and daily rTMS was given 5 days/week for 4 weeks (20 treatments in total). All participants were assessed at baseline and after 4 weeks of treatment. Participants in the spaced treatment group were also assessed after 6 weeks of treatment. All participants were treated at 110% of the resting motor threshold with high-frequency rTMS (10 Hz) to the left dorsolateral prefrontal cortex (DLPFC) followed by low-frequency rTMS to the right DLPFC.

Participants in the daily treatment group showed more improvement by week 4 than those in the spaced treatment group; however, both groups had similar improvement by treatment completion. There was significant improvement in both groups in ratings of depression and anxiety, with no significant differences between groups.

Our study indicates that the efficacy of rTMS is related to the number of treatments given and that spacing the treatments neither improves nor reduces efficacy.