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This systematic review investigates how prefrontal transcranial magnetic stimulation (TMS) immediately influences neuronal excitability based on oxygenation changes measured by functional magnetic resonance imaging (fMRI) or functional near-infrared spectroscopy (fNIRS). A thorough understanding of TMS-induced excitability changes may enable clinicians to adjust TMS parameters and optimize treatment plans proactively. Five databases were searched for human studies evaluating brain excitability using concurrent TMS/fMRI or TMS/fNIRS. Thirty-seven studies (13 concurrent TMS/fNIRS studies, 24 concurrent TMS/fMRI studies) were included in a qualitative synthesis. Despite methodological inconsistencies, a distinct pattern of activated nodes in the frontoparietal central executive network, the cingulo-opercular salience network, and the default-mode network emerged. The activated nodes included the prefrontal cortex (particularly dorsolateral prefrontal cortex), insula cortex, striatal regions (especially caudate, putamen), anterior cingulate cortex, and thalamus. High-frequency repetitive TMS most consistently induced expected facilitatory effects in these brain regions. However, varied stimulation parameters (e.g., intensity, coil orientation, target sites) and the inter- and intra-individual variability of brain state contribute to the observed heterogeneity of target excitability and co-activated regions. Given the considerable methodological and individual variability across the limited evidence, conclusions should be drawn with caution.

Abstract Understanding and treating Alzheimer’s disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies.

Abstract Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (VS) of 5-HT1A receptor. While post-hoc comparisons showed no significant changes of 5-HT1A receptor VS in either group, higher 5-HT1A receptor VS after treatment correlated with greater difference in HAMD (r = −0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT1A receptor. Due to the small sample size, all results must, however, be regarded with caution.

Abstract Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

IntroductionIntermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults.MethodsTwenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional near-infrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation.ResultsAfter stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t(17) = 2.203, P = 0.042, d = 0.523] and 100% iTBS [t(17) = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t(17) = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation.ConclusionThe linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT.

IntroductionPost-stroke aphasia (PSA) is a language disorder caused by left hemisphere stroke. Electroacupuncture (EA) is a minimally invasive therapeutic option for PSA treatment. Tongli (HT5) and Xuanzhong (GB39), two important language-associated acupoints, are frequently used in the rehabilitation of patients with PSA. Preliminary evidence indicated functional activation in distributed cortical areas upon HT5 and GB39 stimulation. However, research on the modulation of dynamic and static functional connectivity (FC) in the brain by EA in PSA is lacking.MethodThis study aimed to investigate the PSA-related effects of EA stimulation at HT5 and GB39 on neural processing. Thirty-five participants were recruited, including 19 patients with PSA and 16 healthy controls (HCs). The BOLD signal was analyzed by static independent component analysis, generalized psychophysiological interactions, and dynamic independent component analysis, considering variables such as age, sex, and years of education.ResultsThe results revealed that PSA showed activated clusters in the left putamen, left postcentral gyrus (PostCG), and left angular gyrus in the salience network (SN) compared to the HC group. The interaction effect on temporal properties of networks showed higher variability of SN (F = 2.23, positive false discovery rate [pFDR] = 0.017). The interaction effect on static FC showed increased functional coupling between the right calcarine and right lingual gyrus (F = 3.16, pFDR = 0.043). For the dynamic FC, at the region level, the interaction effect showed lower variability and higher frequencies of circuit 3, with the strongest connections between the supramarginal gyrus and posterior cingulum (F = 5.42, pFDR = 0.03), middle cingulum and PostCG (F = 5.27, pFDR = 0.036), and triangle inferior frontal and lingual gyrus (F = 5.57, pFDR = 0.026). At the network level, the interaction effect showed higher variability in occipital network–language network (LN) and cerebellar network (CN) coupling, with stronger connections between the LN and CN (F = 4.29, pFDR = 0.042). Dynamic FC values between the triangle inferior frontal and lingual gyri were anticorrelated with transcribing, describing, and dictating scores in the Chinese Rehabilitation Research Center for Chinese Standard Aphasia Examination.DiscussionThese findings suggest that EA stimulation may improve language function, as it significantly modulated the nodes of regions/networks involved in the LN, SN, CN, occipital cortex, somatosensory regions, and cerebral limbic system.

Background: Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission.Objectives: We aimed to expand insights into the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivoxel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment-resistant depression (TRD).Methods: Twelve TRD patients (five females, mean age ± SD = 35 ± 11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after 3 weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx = mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach.Results: ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (pcorr. = 0.046, F = 13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations.Conclusion: This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.

Objective: To determine the effects of nonsurgical, minimally or noninvasive therapies on urge urinary incontinence (UUI) symptoms and quality of life (QoL) in individuals with neurogenic bladder (NGB). Data Sources: Cochrane library, EMBASE, MEDLINE, PEDro, Scopus, and Web of Science databases were searched from inception to September 2021. Review Methods: Randomized controlled trials that compared therapies such as intravaginal electrical stimulation (IVES), transcutaneous electrical nerve stimulation (TENS), neuromuscular electrical stimulation (NMES), transcutaneous tibial nerve stimulation (TTNS), pelvic floor muscle training (PFMT), and behavioural therapy (BT) to control were included. Study screening, data extraction, and study quality assessments were performed by two independent authors. Results: Fourteen trials with 804 participants were included in the study after screening of 4281 potentially relevant articles. Meta-analyses revealed a significant effect of electrical stimulation on UUI due to multiple sclerosis (standardized mean difference (SMD): −0.614; 95% confidence interval (CI): −1.023, −0.206; p = 0.003) and stroke (SMD: −2.639; 95% CI: −3.804, −1.474; p = 0.000). The pooled analyses of TTNS (weighted mean difference (WMD): −12.406; 95% CI: −16.015, −8.797; p = 0.000) and BT (WMD: −9.117; 95% CI: −14.746, −3.487; p = 0.002) revealed significant effects of these interventions on QoL in people with Parkinson’s disease. However, meta-analyses revealed nonsignificant effects for PFMT (WMD: −0.751; 95% CI: −2.426, 0.924; p = 0.380) and BT (WMD: −0.597; 95% CI: −1.278, 0.083; p = 0.085) on UUI due to Parkinson’s disease. Conclusions: Our meta-analyses found electrical stimulation to be beneficial for improving the symptoms of UUI among people with multiple sclerosis and those with stroke. Our review also revealed that TTNS and BT might improve QoL for people with NGB due to Parkinson’s disease, although the effects of PFMT and BT on UUI warrant further investigation.

BackgroundSince the emergence of the COVID-19 pandemic, there have been lots of published work examining the association between COVID-19 and mental health, particularly, anxiety and depression in the general populations and disease subpopulations globally. Depression is a debilitating disorder affecting individuals' level of bio-psychological-social functioning across different age groups. Since almost all studies were cross-sectional studies, there seems to be a lack of robust, large-scale, and technological-based interventional studies to restore the general public's optimal psychosocial wellbeing amidst the COVID-19 pandemic. Transcranial pulse stimulation (TPS) is a relatively new non-intrusive brain stimulation (NIBS) technology, and only a paucity of studies was conducted related to the TPS treatment on older adults with mild neurocognitive disorders. However, there is by far no study conducted on young adults with major depressive disorder nationwide. This gives us the impetus to execute the first nationwide study evaluating the efficacy of TPS on the treatment of depression among young adults in Hong Kong.MethodsThis study proposes a two-armed single-blinded randomised controlled trial including TPS as an intervention group and a waitlist control group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 3- month follow-up (T3).RecruitmentA total of 30 community-dwelling subjects who are aged 18 and above and diagnosed with major depressive disorder (MDD) will be recruited in this study. All subjects will be computer randomised into either the intervention group or the waitlist control group, balanced by gender and age on a 1:1 ratio.InterventionAll subjects in each group will have to undertake functional MRI (fMRI) before and after six 30-min TPS sessions, which will be completed in 2 weeks' time.OutcomesBaseline measurements and post-TPS evaluation of the psychological outcomes (i.e., depression, cognition, anhedonia, and instrumental activities of daily living) will also be conducted on all participants. A 3-month follow-up period will be usedto assess the long-term sustainability of the TPS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyse data. Missing data were managed by multiple mutations. The level of significance will be set to p < 0.05.Significance of the StudyResults of this study will be used to inform health policy to determine whether TPS could be considered as a top treatment option for MDD.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT05006365.

Objective: The objective of this meta-analysis was to summarize evidence on the therapeutic effects of non-invasive brain stimulation (NIBS) on core symptoms of multiple sclerosis (MS). Specifically, findings from studies deploying transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) protocols were summarized in this review. Methods: We systematically searched articles published in four databases, until 31 May 2021, which compared the effects of active tDCS or rTMS with sham intervention in MS patients. We used a random-effects model for this meta-analysis. Meta-regression and subgroup meta-analysis were used to examine the effects of stimulation dose and different stimulation protocols, respectively. Results: Twenty-five randomized controlled trials (RCTs) were included in this review, consisting of 19 tDCS and 6 rTMS studies. tDCS led to a significant and immediate reduction of fatigue with a large effect size (Hedges’s g = −0.870, 95% confidence intervals (CI) = [−1.225 to −0.458], number needed to treat (NNT) = 2). Particularly, a subgroup analysis showed that applying tDCS over the left DLPFC and bilateral S1 led to fatigue reductions compared to sham stimulation. Furthermore, tDCS had favorable effects on fatigue in MS patients with low physical disability but not those with high physical disability, and additionally improved cognitive function. Finally, whereas rTMS was observed to reduce muscle spasticity, these NIBS protocols showed no further effect on MS-associated pain and mood symptoms. Conclusion: tDCS in MS alleviates fatigue and improves cognitive function whereas rTMS reduces muscle spasticity. More high-quality studies are needed to substantiate the therapeutic effects of different NIBS protocols in MS.

(1) Background: Adiponectin is an adipocyte-secreted hormone that has antidepressant- and anxiolytic-like effects in preclinical studies. Here, we investigated the antidepressant- and anxiolytic-like effects of sub-chronic treatment with AdipoRon, an adiponectin receptor agonist, and its potential linkage to changes in hippocampal adult neurogenesis and synaptic plasticity. (2) Methods: Different cohorts of wild-type C57BL/6J and CamKIIα-Cre male mice were treated with sub-chronic (7 days) AdipoRon, followed by behavioral, molecular, and electrophysiological experiments. (3) Results: 7-day AdipoRon treatment elicited antidepressant- and anxiolytic-like effects but did not affect hippocampal neurogenesis. AdipoRon treatment reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal activation in the ventral dentate gyrus, and long-term potentiation of the perforant path. The knockdown of N-methyl-D-aspartate (NMDA) receptor subunits GluN2A and GluN2B in the ventral hippocampus did not affect the antidepressant- and anxiolytic-like effects of AdipoRon. (4) Conclusions: Increasing adiponectin signaling through sub-chronic AdipoRon treatment results in antidepressant- and anxiolytic-like effects independent of changes in hippocampal structural and synaptic function.

Abstract Numerous studies demonstrate ketamine’s influence on resting-state functional connectivity (rsFC). Seed-based and static rsFC estimation methods may oversimplify FC. These limitations can be addressed with whole-brain, dynamic rsFC estimation methods. We assessed data from 27 healthy subjects who underwent two 3 T resting-state fMRI scans, once under subanesthetic, intravenous esketamine and once under placebo, in a randomized, cross-over manner. We aimed to isolate only highly robust effects of esketamine on dynamic rsFC by using eight complementary methodologies derived from two dynamic rsFC estimation methods, two functionally defined atlases and two statistical measures. All combinations revealed a negative influence of esketamine on dynamic rsFC within the left visual network and inter-hemispherically between visual networks (p

Aims/hypothesis: Diabetes mellitus (DM) is associated with comorbid brain disorders. Neuroimaging studies in DM revealed neuronal degeneration in several cortical and subcortical brain regions. Previous studies indicate more pronounced brain alterations in type 2 diabetes mellitus (T2DM) than in type 1 diabetes mellitus (T1DM). However, a comparison of both types of DM in a single analysis has not been done so far. The aim of this meta-analysis was to conduct an unbiased objective investigation of neuroanatomical differences in DM by combining voxel-based morphometry (VBM) studies of T1DM and T2DM using dual disorder anatomical likelihood estimation (ALE) quantification.Methods: PubMed, Web of Science and Medline were systematically searched for publications until June 15, 2020. VBM studies comparing gray matter volume (GMV) differences between DM patients and controls at the whole-brain level were included. Study coordinates were entered into the ALE meta-analysis to investigate the extent to which T1DM, T2DM, or both conditions contribute to gray matter volume differences compared to controls.Results: Twenty studies (comprising of 1,175 patients matched with 1,013 controls) were included, with seven studies on GMV alterations in T1DM and 13 studies on GMV alterations in T2DM. ALE analysis revealed seven clusters of significantly lower GMV in T1DM and T2DM patients relative to controls across studies. Both DM subtypes showed GMV reductions in the left caudate, right superior temporal lobe, and left cuneus. Conversely, GMV reductions associated exclusively with T2DM (>99% contribution) were found in the left cingulate, right posterior lobe, right caudate and left occipital lobe. Meta-regression revealed no significant influence of study size, disease duration, and HbA1c values.Conclusions/interpretation: Our findings suggest a more pronounced gray matter atrophy in T2DM compared to T1DM. The increased risk of microvascular or macrovascular complications, as well as the disease-specific pathology of T2DM may contribute to observed GMV reductions.Systematic Review Registration: [PROSPERO], identifier [CRD42020142525].

Introduction: Neuroimaging studies on neural processes associated with mirror-induced visual illusion (MVI) are growing in number. Previous systematic reviews on these studies used qualitative approaches.Objective: The present study conducted activation likelihood estimation (ALE) meta-analysis to locate the brain areas for unfolding the neural processes associated with the MVI.Method: We searched the CINAHL, MEDLINE, Scopus, and PubMed databases and identified eight studies (with 14 experiments) that met the inclusion criteria.Results: Contrasting with a rest condition, strong convergence in the bilateral primary and premotor areas and the inferior parietal lobule suggested top-down motor planning and execution. In addition, convergence was identified in the ipsilateral precuneus, cerebellum, superior frontal gyrus, and superior parietal lobule, clusters corresponding to the static hidden hand indicating self-processing operations, somatosensory processing, and motor control. When contrasting with an active movement condition, additional substantial convergence was revealed in visual-related areas, such as the ipsilateral cuneus, fusiform gyrus, middle occipital gyrus (visual area V2) and lingual gyrus, which mediate basic visual processing.Conclusions: To the best of our knowledge, the current meta-analysis is the first to reveal the visualization, mental rehearsal and motor-related processes underpinning the MVI and offers theoretical support on using MVI as a clinical intervention for post-stroke patients.