Predicting Alzheimer’s disease severity by means of TMS–EEG coregistration

Clinical manifestations of Alzheimer's disease (AD) are associated with a breakdown in large-scale communication, such that AD may be considered as a “disconnection syndrome.” An established method to test effective connectivity is the combination of transcranial magnetic stimulation with electroencephalography (TMS–EEG) because the TMS-induced cortical response propagates to distant anatomically connected regions. To investigate whether prefrontal connectivity alterations may predict disease severity, we explored the relationship of dorsolateral prefrontal cortex connectivity (derived from TMS–EEG) with cognitive decline (measured with Mini Mental State Examination and a face–name association memory task) in 26 patients with AD. The amplitude of TMS–EEG evoked component P30, which was found to be generated in the right superior parietal cortex, predicted Mini Mental State Examination and face–name memory scores: higher P30 amplitudes predicted poorer cognitive and memory performances. The present results indicate that advancing disease severity might be associated with effective connectivity increase involving long-distance frontoparietal connections, which might represent a maladaptive pathogenic mechanism reflecting a damaged excitatory–inhibitory balance between anterior and posterior regions

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These RSNM targets were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ( sgACC-derived targets ). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes

Response and Remission Rates Following High-Frequency vs. Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Over Right DLPFC for Treating Major Depressive Disorder (MDD): A Meta-Analysis of Randomized, Double-Blind Trials

Background: High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is the most widely applied treatment protocol for major depressive disorder (MDD), while low-frequency (LF) rTMS over the right DLPFC (R-DLPFC) also exhibits similar, if not better, efficacy for MDD. Therefore, a meta-analysis is warranted to compare the efficacy of the two protocols for MDD.Method: We searched the literature from 1990 through to August 1, 2017 using MEDLINE, and the literature from 1995 through to August 1, 2017 using EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS, and ProQuest Dissertations and Theses (PQDT). We included randomized controlled trials (RCT) comparing the efficacy of HF rTMS over the L-DLPFC and LF rTMS over the R-DLPFC for MDD, which used response and/or remission rates as the primary endpoints, with and without sham-controlled.Results: (1) The meta-analysis of the response rates was based on 12 studies, including 361 patients with MDD (175 for HF (> 5 Hz) over the L-DLPFC, and 186 for LF (<5 Hz) over the R-DLPFC; odds ratio = 1.08; 95%, confidence interval = 0.88–1.34). (2) The meta-analysis of the remission rate was based on 5 studies, including 131 MDD patients (64 for HF over the L-DLPFC and 67 for LF over the R-DLPFC; odds ratio = 1.29; 95% confidence interval = 0.54–3.10).Conclusion: Both HF rTMS over the L-DLPFC and LF over the R-DLPFC demonstrated similar therapeutic efficacy for the treatment of patients with MDD. The results suggested that further investigation on treatment efficacy indicators before/during treatment is necessary and helpful for optimizing a personalized protocol for patients

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson’s disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders

Enhancing cognitive training effects in Alzheimer's disease: rTMS as an add-on treatment.

The treatment of Alzheimer's disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning. The present study provides important hints on the promising therapeutic use of rTMS in AD

Effects of High-Frequency Transcranial Magnetic Stimulation for Cognitive Deficit in Schizophrenia: A Meta-Analysis

Objective: Repetitive transcranial magnetic stimulation (rTMS) has been applied to dorsolateral prefrontal cortex (DLPFC) to improve cognitive function of patients with schizophrenia (SZs). The aim of this meta-analysis was to evaluate whether a high-frequency rTMS course could enhance cognitive function in SZs.Methods: Studies published in PubMed, Cochrane Library, Embase, ScienceDirect, and Web of science were searched until April 2018. The search terms included: “repetitive transcranial magnetic stimulation” or “Rtms,” “SZ,” or “schizophrenia,” and “neuro-cognition” or “neurocognitive performance” or “cognitive effects” or “cognitive” or “cognition” or “working memory” or “executive function” or “language function” or “processing speed,” After screening the literatures according to inclusion and exclusion criteria, extracting data, and evaluating the methodological quality of the included studies, a meta-analysis was performed using RevMan 5.3 software (The Cochrane Collaboration, USA).Results: A total of 9 studies on cognitive dysfunction of SZs were included and involved 351 patients. A significant efficacy of high-frequency rTMS on working memory in SZs was found compared to sham stimulation [p = 0.009, standardized mean difference (SMD) = 0.34]. Specifically, rTMS treatment positioned on the left DLPFC, with a total pluses &lt;30,000 was more significantly more effective in improving the working memory (SMD = 0.33, p = 0.03). No improvement was found in other cognitive domains such as executive function, attention, processing speed, and language function. For the follow-up observations, high-frequency rTMS had long-lasting sustained effects on working memory (SMD = 0.45, p = 0.01) and language function (SMD = 0.77, p = 0.02) in SZs.Conclusions: High-frequency rTMS over the left DLPFC with a total pulses &lt;30,000 stimulation could significantly improve working memory in SZs for an extended period of time

Impact of non-brain anatomy and coil orientation on inter- and intra-subject variability in TMS at midline

Objective: To investigate inter-subject variability with respect to cerebrospinal fluid thickness and brain-scalp distance, and to investigate intra-subject variability with different coil orientations. Methods: Simulations of the induced electric field (E-Field) using a figure-8 coil over the vertex were conducted on 50 unique head models, and varying orientations on 25 models. Metrics exploring stimulation intensity, spread, and localization were used to describe inter-subject variability and effects of non-brain anatomy. Results: Both brain-scalp distance and CSF thickness were correlated with weaker stimulation intensity, and greater spread. Coil rotations show that for the dorsal portion of the stimulated brain, E-Field intensities are highest when the anterior-posterior axis of the coil is perpendicular to the longitudinal fissure, but highest for the medial portion of the stimulated brain when the coil is oriented parallel to the longitudinal fissure. Conclusions: Normal anatomical variation in healthy individuals leads to significant differences in the site of TMS, the intensity and the spread. These variables are generally neglected but could explain significant variability in basic and clinical studies. Significance: This is the first work to show how brain-scalp distance and cerebrospinal fluid thickness influence focality, and to show the disassociation between dorsal and medial TMS

Concurrent neuroimaging and neurostimulation reveals a causal role for dlPFC in coding of task-relevant information.

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA

Novel coil designs for different neurological disorders in transcranial magnetic stimulation

Transcranial magnetic stimulation is a non-invasive, safe, painless out-patient treatment for major depressive disorder. In TMS, time varying magnetic field is used to induce electric field, in the region of interest, to stimulate the neurons. Coil design is an important aspect of TMS, as coils are used to navigate the magnetic field in the desired location. The work presented in this dissertation is regarding the use of the coil design development for the application of transcranial magnetic simulation. Two TMS coils namely the Triple Halo Coil and the Quadruple Butterfly Coil were presented, with one aiming for deep brain stimulation and other one for precise stimulation. The magnetic field due to the Triple Halo Coil is 7 times more than circular coil at 10 cm below the head. It can stimulate deep brain regions which are affected in disorders such as Parkinson’s disease and PTSD. The Quadruple Butterfly Coil has reduced volume of stimulation by around 10% at the vertex and dorsolateral prefrontal cortex when compared with the Figure-8 coil. Fifty heterogeneous MRI derived head models were used for the analysis of the induced electric field due to the Quadruple Butterfly Coil and the results were compared with the Figure-8 coil. For both the coils, first computer modelling was done on heterogeneous head models, using a finite element tool and testing using a prototype built by Jali Medicals with the help of an axial Hall probe and a gaussmeter. Furthermore, seven different coils for small animals were presented in this dissertation. These coils had varying electric field with the Slinky coil having the minimum area of stimulation and lowest electric field below 10 mm of the head, while the Animal Halo Coil had maximum area of stimulation and highest electric field at 1 mm below the head. Animal coils are important as animal testing reduces the cost and expedites the research time