Disrupted hemodynamic response within dorsolateral prefrontal cortex during cognitive tasks among people with multiple sclerosis-related fatigue.

INTRODUCTION: Mental fatigue is an early and enduring symptom in persons with autoimmune disease particularly multiple sclerosis (MS). Neuromodulation has emerged as a potential treatment although optimal cortical targets have yet to be determined. We aimed to examine cortical hemodynamic responses within bilateral dorsolateral prefrontal cortex (dlPFC) and frontopolar areas during single and dual cognitive tasks in persons with MS-related fatigue compared to matched controls. METHODS: We recruited persons (15 MS and 12 age- and sex-matched controls) who did not have physical or cognitive impairment and were free from depressive symptoms. Functional near infrared spectroscopy (fNIRS) registered hemodynamic responses during the tasks. We calculated oxyhemoglobin peak, time-to-peak, coherence between channels (a potential marker of neurovascular coupling) and functional connectivity (z-score). RESULTS: In MS, dlPFC demonstrated disrupted hemodynamic coherence during both single and dual tasks, as evidenced by non-significant and negative correlations between fNIRS channels. In MS, reduced coherence occurred in left dorsolateral PFC during the single task but occurred bilaterally as the task became more challenging. Functional connectivity was lower during dual compared to single tasks in the right dorsolateral PFC in both groups. Lower z-score was related to greater feelings of fatigue. Peak and time-to-peak hemodynamic response did not differ between groups or tasks. CONCLUSIONS: Hemodynamic responses were inconsistent and disrupted in people with MS experiencing mental fatigue, which worsened as the task became more challenging. Our findings point to dlPFC, but not frontopolar areas, as a potential target for neuromodulation to treat cognitive fatigue.

Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

Characteristics of oxyhemoglobin during the verbal fluency task in subthreshold depression: A multi-channel near-infrared spectroscopy study.

OBJECTIVE: Subthreshold depression is an essential precursor and risk factor for major depressive disorder, and its accurate identification and timely intervention are important for reducing the prevalence of major depressive disorder. Therefore, we used functional near-infrared spectroscopic imaging (fNIRS) to explore the characteristics of the brain neural activity of college students with subthreshold depression in the verbal fluency task. METHODS: A total of 72 subthreshold depressed college students (SDs) and 67 healthy college students (HCs) were recruited, and all subjects were subjected to a verbal fluency task (VFT) while a 53-channel fNIRS device was used to collect the subjects' cerebral blood oxygenation signals. RESULTS: The results of the independent samples t-test showed that the mean oxyhemoglobin in the right dorsolateral prefrontal (ch34, ch42, ch45) and Broca's area (ch51, ch53) of SDs was lower than that of HCs. The peak oxygenated hemoglobin of SDs was lower in the right dorsolateral prefrontal (ch34) and Broca's area (ch51, ch53).The brain functional connectivity strength was lower than that of HCs. Correlation analysis showed that the left DLPFC and Broca's area were significantly negatively correlated with the depression level. CONCLUSION: SDs showed abnormally low, inadequate levels of brain activation and weak frontotemporal brain functional connectivity. The right DLPFC has a higher sensitivity for the differentiation of depressive symptoms and is suitable as a biomarker for the presence of depressive symptoms. Dysfunction in Broca's area can be used both as a marker of depressive symptoms and as a biomarker, indicating the severity of depressive symptoms.

Relation between task-related activity modulation and cortical inhibitory function in schizophrenia and healthy controls: a TMS-EEG study.

Schizophrenia has been associated with a reduced task-related modulation of cortical activity assessed through electroencephalography (EEG). However, to the best of our knowledge, no study so far has assessed the underpinnings of this decreased EEG modulation in schizophrenia. A possible substrate of these findings could be a decreased inhibitory function, a replicated finding in the field. In this pilot study, our aim was to explore the association between EEG modulation during a cognitive task and the inhibitory system function in vivo in a sample including healthy controls and patients with schizophrenia. We hypothesized that the replicated decreased task-related activity modulation during a cognitive task in schizophrenia would be related to a hypofunction of the inhibitory system. For this purpose, 27 healthy controls and 22 patients with schizophrenia (including 13 first episodes) performed a 3-condition auditory oddball task from which the spectral entropy modulation was calculated. In addition, cortical reactivity-as an index of the inhibitory function-was assessed by the administration of 75 monophasic transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex. Our results replicated the task-related cortical activity modulation deficit in schizophrenia patients. Moreover, schizophrenia patients showed higher cortical reactivity following transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex compared to healthy controls. Cortical reactivity was inversely associated with EEG modulation, supporting the idea that a hypofunction of the inhibitory system could hamper the task-related modulation of EEG activity.

Brain responses to decision-making in easy and hard choices in internet gaming disorder: Implications for irrepressible gaming behaviours.

BACKGROUND: Impaired decision-making was observed in internet gaming disorder (IGD), however, these studies did not differentiate 'hard' to 'easy' decisions, and only the 'hard' decision-making could reveal the mechanism underlying this issue. METHODS: We recruited forty-eight individuals with IGD and forty-six recreational internet game users (RGUs) as a control group in this study. fMRI data were collected when they were finishing a value-matching delayed discount task (DDT), which included easy and hard decisions judging based on the indifference points of every participant. The correlations between brain responses during DDT and IGD severity and the effective connectivity between brain regions were calculated. RESULTS: Compared to RGUs, IGD subjects showed enhanced activation in the orbitofrontal cortex (OFC) when facing hard choices, and this feature was associated with IGD severity. In addition, individuals with IGD showed increased effective connectivity from the OFC to the dorsolateral prefrontal cortex and the OFC to the occipital lobe and decreased effective connectivity from the occipital lobe to the OFC. CONCLUSION: The current study showed that the abnormal activation in the OFC was associated with IGD severity and higher OFC-DLPFC/OFC-occipital lobe effective connectivity and lower occipital lobe-OFC effective connectivity when individuals with IGD faced different choices in the DDT. These findings suggest the neural mechanisms of impulsive decision-making in individuals with IGD due to dysfunction with subjective evaluation and dysfunction of the connection with the executive control system.

The effect of high-definition transcranial direct current stimulation on pain processing in a healthy population: A single-blinded crossover controlled study.

Transcranial direct current stimulation (tDCS) is increasingly used in pain treatment. tDCS targeting both primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) may modulate the descending pain inhibitory system, however, it remains controversial regarding the optimal stimulation region for pain modulation. Therefore, this study aimed to explore the effects of high-definition anodic stimulation of M1 and DLPFC on conditioned pain modulation (CPM) and pain thresholds and establish a preferred stimulation setting. Twenty-six healthy adults were randomly assigned to M1-tDCS, DLPFC-tDCS, or sham-tDCS groups. During the three sessions, each participant received an active or sham stimulation of 2 mA for 20 min, with at least 3 days' interval between sessions. Quantitative sensory tests were performed to obtain pressure pain threshold (PPT), cold pain threshold (CPT), and CPM before and after the tDCS intervention. Only M1-tDCS significantly increased CPM in healthy individuals compared with sham control (P = 0.004). No statistically significant difference was found in PPT and CPT between tDCS vs. sham control (P > 0.05). Our findings further support the important role of M1 as a target in pain regulation. Further large-scale, multicenter studies in chronic pain populations are needed to validate the alterations of distinct target brain regions related to pain and thus for an optimal target stimulation strategy in pain management.

An engram of intentionally forgotten information.

Successful forgetting of unwanted memories is crucial for goal-directed behavior and mental wellbeing. While memory retention strengthens memory traces, it is unclear what happens to memory traces of events that are actively forgotten. Using intracranial EEG recordings from lateral temporal cortex, we find that memory traces for actively forgotten information are partially preserved and exhibit unique neural signatures. Memory traces of successfully remembered items show stronger encoding-retrieval similarity in gamma frequency patterns. By contrast, encoding-retrieval similarity of item-specific memory traces of actively forgotten items depend on activity at alpha/beta frequencies commonly associated with functional inhibition. Additional analyses revealed selective modification of item-specific patterns of connectivity and top-down information flow from dorsolateral prefrontal cortex to lateral temporal cortex in memory traces of intentionally forgotten items. These results suggest that intentional forgetting relies more on inhibitory top-down connections than intentional remembering, resulting in inhibitory memory traces with unique neural signatures and representational formats.

Enhanced Temporal Coupling between Thalamus and Dorsolateral Prefrontal Cortex Mediates Chronic Low Back Pain and Depression.

Numerous neuroimaging studies have demonstrated that the brain plasticity is associated with chronic low back pain (cLBP). However, there is a lack of knowledge regarding the underlying mechanisms of thalamic pathways for chronic pain and psychological effects in cLBP caused by lumbar disc herniation (LDH). Combining psychophysics and magnetic resonance imaging (MRI), we investigated the structural and functional brain plasticity in 36 patients with LDH compared with 38 age- and gender-matched healthy controls. We found that (1) LDH patients had increased psychophysical disturbs (i.e., depression and anxiety), and depression (Beck-Depression Inventory, BDI) was found to be an outstanding significant factor to predict chronic pain (short form of the McGill Pain Questionnaire, SF-MPQ); (2) the LDH group showed significantly smaller fractional anisotropy values in the region of posterior corona radiate while gray matter volumes were comparable in both groups; (3) resting state functional connectivity analysis revealed that LDH patients exhibited increased temporal coupling between the thalamus and dorsolateral prefrontal cortex (DLPFC), which further mediate the relationship from chronic pain to depression. Our results emphasized that thalamic pathways underlying prefrontal cortex might play a key role in regulating chronic pain and depression of the pathophysiology of LDH.

Magnetoencephalography reveals differences in brain activations for fast and slow responses to simple multiplications.

Despite decades of studies, it is still an open question on how and where simple multiplications are solved by the brain. This fragmented picture is mostly related to the different tasks employed. While in neuropsychological studies patients are asked to perform and report simple oral calculations, neuroimaging and neurophysiological studies often use verification tasks, in which the result is shown, and the participant must verify the correctness. This MEG study aims to unify the sources of evidence, investigating how brain activation unfolds in time using a single-digit multiplication production task. We compared the participants' brain activity-focusing on the parietal lobes-based on response efficiency, dividing their responses in fast and slow. Results showed higher activation for fast, as compared to slow, responses in the left angular gyrus starting after the first operand, and in the right supramarginal gyrus only after the second operand. A whole-brain analysis showed that fast responses had higher activation in the right dorsolateral prefrontal cortex. We show a timing difference of both hemispheres during simple multiplications. Results suggest that while the left parietal lobe may allow an initial retrieval of several possible solutions, the right one may be engaged later, helping to identify the solution based on magnitude checking.

Increased neural motor activation and functional reorganization in patients with idiopathic rapid eye movement sleep behavior disorder.

INTRODUCTION: Altered brain activity and functional reorganization patterns during self-initiated movements have been reported in early pre-motor and motor stages of Parkinson's disease. The aim of this study was to investigate whether similar alterations can be observed in patients with idiopathic REM-sleep behavior disorder (RBD). METHODS: 13 polysomnography-confirmed male and right-handed RBD patients and 13 healthy controls underwent a bilateral hand-movement fMRI task including internally selected (INT) and externally-guided (EXT) movement conditions for each hand. We examined functional activity and connectivity differences between groups and task-conditions, structural differences using voxel-based morphometry, as well as associations between functional activity and clinical variables. RESULTS: No group differences were observed in fMRI-task performance or in voxel-based morphometry. Both groups showed faster reaction times and exhibited greater neural activation when movements were internally selected compared to externally-guided tasks. Compared to controls, RBD patients displayed stronger activation in the dorsolateral prefrontal cortex and primary somatosensory cortex during INT-tasks, and in the right fronto-insular cortex during EXT-tasks performed with the non-dominant hand. Stronger activation in RBD patients was associated with cognitive and olfactory impairment. Connectivity analysis demonstrated overall less interregional coupling in patients compared to controls. In particular, patients showed reduced temporo-cerebellar, occipito-cerebellar and intra-cerebellar connectivity, but stronger connectivity in fronto-cerebellar and fronto-occipital pathways. CONCLUSION: The observed stronger activation during hand-movement tasks and connectivity changes in RBD may reflect early compensatory and reorganization patterns in order to preserve motor functioning. Our findings may contribute to a better understanding and prognosis of prodromal stages of α-synucleinopathies.

Polygenic risk for obsessive-compulsive disorder (OCD) predicts brain response during working memory task in OCD, unaffected relatives, and healthy controls.

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p < 0.05). A whole-brain analysis of the fMRI data indicated decreased neural activity in bilateral inferior parietal lobule and dorsolateral prefrontal cortex in both patients and relatives. Most importantly, OCD polygenic risk scores predicted neural activity in orbitofrontal cortex. Results indicate that genetic risk for OCD can partly explain alterations in brain response during working memory performance, supporting the notion of a neuro-functional endophenotype for OCD.

Contrasting dorsal caudate functional connectivity patterns between frontal and temporal cortex with BMI increase: link to cognitive flexibility.

BACKGROUND: Obesity is associated with brain intrinsic functional reorganization. However, little is known about the BMI-related interhemispheric functional connectivity (IHFC) alterations, and their link with executive function in young healthy adults. METHODS: We examined voxel-mirrored homotopic connectivity (VMHC) patterns in 417 young adults from the Human Connectome Project. Brain regions with significant association between BMI and VMHC were identified using multiple linear regression. Results from these analyses were then used to determine regions for seed-voxel FC analysis, and multiple linear regression was used to explore the brain regions showing significant association between BMI and FC. The correlations between BMI-related executive function measurements and VMHC, as well as seed-voxel FC, were further examined. RESULTS: BMI was negatively associated with scores of Dimensional Change Card Sort Test (DCST) assessing cognitive flexibility (r = -0.14, p = 0.006) and with VMHC of bilateral inferior parietal lobule, insula and dorsal caudate. The dorsal caudate emerged as a nexus for BMI-related findings: greater BMI was associated with greater FC between caudate and hippocampus and lower FC between caudate and several prefrontal nodes (right inferior frontal gyrus, anterior cingulate cortex, and middle frontal gyrus). The FC between right caudate and left hippocampus was negatively associated with scores of DCST (r = -0.15, p = 0.0018). CONCLUSIONS: Higher BMI is associated with poorer cognitive flexibility performance and IHFC in an extensive set of brain regions implicated in cognitive control. Larger BMI was associated with higher caudate-medial temporal lobe FC and lower caudate-dorsolateral prefrontal cortex FC. These findings may have relevance for executive function associated with weight gain among otherwise healthy young adults.

Ventrolateral prefrontal hemodynamic responses in autism spectrum disorder with and without depression.

In clinical settings, autism spectrum disorder (ASD) with comorbid depression is often difficult to diagnose, and should be considered in treatment. However, to our knowledge, no functional imaging study has examined the difference between ASD adolescents with and without comorbid depression. We aimed to compare the characteristics and prefrontal brain function of ASD with and without depression in order to identify a biological marker that can be used to detect the difference. Twenty-eight drug-naïve adolescents with ASD (14 ASD with and 14 ASD without depression) and 14 age- and gender-matched adolescents with typical development were evaluated using several variables. These included intelligence quotient, autism quotient, depression severity using the Beck Depression Inventory 2nd edition (BDI-II), and level of social functioning using the Social Adaptation Self-evaluation Scale (SASS). In addition, frontotemporal hemodynamic responses during a verbal fluency task (VFT) were measured using functional near-infrared spectroscopy (fNIRS). The ASD group, including both of the ASD with and ASD without depression groups, showed smaller hemodynamic responses than the typical development group in portions of the left dorsolateral prefrontal cortex (DLPFC), bilateral ventrolateral prefrontal cortex (VLPFC) and anterior part of the temporal cortex (aTC) during the VFT. Moreover, the smaller hemodynamic responses in the right VLPFC during the VFT in the ASD group were associated with the worse BDI-II and SASS scores. Furthermore, the ASD with depression group showed smaller hemodynamic responses in the right VLPFC during the VFT than the ASD without depression group in a direct comparison. Adolescents with ASD showed reduced activation in broad frontotemporal regions during a cognitive task compared with those with typical development. More specifically, the right VLPFC activation reflected the level of self-estimated depression and social functioning in the ASD subjects, and could be used to discriminate between ASD adolescents with and without depression.

A multimodal approach using TMS and EEG reveals neurophysiological changes in Parkinson's disease.

INTRODUCTION: Alterations in large scale neural networks leading to neurophysiological changes have been described in Parkinson's disease (PD). The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been suggested as a promising tool to identify and quantify neurophysiological mechanisms. The aim of this study was to investigate specific changes in electrical brain activity in response to stimulation of four brain areas in patients with PD. METHODS: 21 healthy controls and 32 patients with PD underwent a combined TMS-EEG assessment that included stimulation of four brain areas: left M1, right M1, left dorso-lateral prefrontal cortex (DLPFC), and right DLPFC. Six measures were calculated to characterize the TMS evoked potentials (TEP) using EEG: (1) wave form adherence (WFA), (2) late phase deflection (LPD), (3) early phase deflection (EPD), (4) short-term plasticity (STP), (5) inter-trial adherence, and (6) connectivity between right and left M1 and DLPFC. A Linear mixed-model was used to compare these measures between groups and areas stimulated. RESULTS: Patients with PD showed lower WFA (p = 0.052), lower EPD (p = 0.009), lower inter-trial adherence (p < 0.001), and lower connectivity between homologs areas (p = 0.050), compared to healthy controls. LPD and STP measures were not different between the groups. In addition, lower inter-trial adherence correlated with longer disease duration (r = -0.355, p = 0.050). CONCLUSIONS: Our findings provide evidence to various alterations in neurophysiological measures in patients with PD. The higher cortical excitability along with increased variability and lower widespread of the evoked potentials in PD can elucidate different aspects related to the pathophysiology of the disease.

Executive function in obesity and anorexia nervosa: Opposite ends of a spectrum of disordered feeding behaviour?

Higher-order executive functions such as decision-making, cognitive flexibility and behavioural control are critical to adaptive success in all aspects of life, including the maintenance of a healthy body weight by regulating food intake. Performance on tasks designed to assess these aspects of cognition is impaired in individuals with obesity and anorexia nervosa (AN); conditions at either end of a spectrum of body weight disturbance. While the conceptualisation of obesity and AN as mirror images of each other makes some sense from a metabolic point of view, whether or not these conditions also reflect opposing states of executive function is less clear. Here, we review evidence from neurocognitive and neuroimaging studies to compare the direction and extent of executive dysfunction in subjects with obesity and AN and how these are underpinned by changes in structure and function of subregions of the prefrontal cortex (PFC). Both conditions of extreme body weight disturbance are associated with impaired decision-making and cognitive inflexibility, however, impulsive behaviour presents in opposing directions; obesity being associated with reduced behavioural control and AN being associated with elevated control over behaviour with respect to food and feeding. Accordingly, the subregions of the PFC that guide inhibitory control and valuation of action outcomes (dorsolateral prefrontal cortex and orbitofrontal cortex) show opposite patterns of activation in subjects with obesity compared to those with AN, whereas the subregions implicated in cognitive and behavioural flexibility (ventromedial prefrontal cortex and anterior cingulate cortex) show alterations in the same direction in both conditions but with differential extent of dysfunction. We synthesise these findings in the context of the utility of animal models of obesity and AN to interrogate the detail of the neurobiological contributions to cognition in patient populations and the utility of such detail to inform future treatment strategies that specifically target executive dysfunction.

Increased functional interaction within frontoparietal network during working memory task in major depressive disorder.

Abnormal fronto-parietal activation has been suggested as a neural underpinning of the working memory (WM) deficits in major depressive disorder (MDD). However, the potential interaction within the frontoparietal network during WM processing in MDD remains unclear. This study aimed to examine the role of abnormal functional interactions within frontoparietal network in the neuropathological mechanisms of WM deficits in MDD. A total of 40 MDD patients and 47 demographic matched healthy controls (HCs) were included. Functional magnetic resonance imaging and behavioral data were collected during numeric n-back tasks. The psychophysiological interaction and dynamic causal modelling methods were applied to investigate the connectivity within the frontoparietal network in MDD during n-back tasks. The psychophysiological interaction analysis revealed that MDD patients showed increased functional connectivity between the right inferior parietal lobule (IPL) and the right dorsolateral prefrontal cortex (dlPFC) compared with HCs during the 2-back task. The dynamic causal modelling analysis revealed that MDD patients had significantly increased forward modulation connectivity from the right IPL to the right dlPFC than HCs during the 2-back task. Partial correlation was used to calculate the relationship between connective parameters and psychological variables in the MDD group, which showed that the effective connectivity from right IPL to right dlPFC was correlated negatively with the sensitivity index d' of WM performances and positively with the depressive severity in MDD group. In conclusion, the abnormal functional and effective connectivity between frontal and parietal regions might contribute to explain the neuropathological mechanism of working memory deficits in major depressive disorder.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Childhood trauma mediates repetitive transcranial magnetic stimulation efficacy in major depressive disorder.

Childhood trauma is one of the most prominent risk factors in developing major depressive disorder (MDD) and may lead to unfavorable outcomes of pharmacotherapy and psychotherapy in MDD. While how it modulates the treatment outcome of the repetitive transcranial magnetic stimulation (rTMS) and how sex difference may play a role in mediating this relationship remain unknown. To evaluate this question, 51 (37 women) MDD patients were treated with 10 Hz rTMS to the left dorsolateral prefrontal cortex (lDLPFC). The experience of childhood trauma was quantified by the Childhood Traumatic Questionnaire (CTQ). The depressive severity was assessed by Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) as the primary and secondary assessments. Beck Hopelessness Scale (BHS) and Hamilton Anxiety Scale (HAMA) were also assessed for further confirmation. Thirty-six (70.6%) participants showed a response including 17 (33.3%) achieving remission to the rTMS treatment. The alleviation of depressive symptoms was negatively correlated with the CTQ scores, specifically in women but not men, in subjective BDI and BHS, but not objective HAMD or HAMA. We demonstrate that childhood trauma negatively affects the subjective perception of rTMS-lDLPFC treatment outcomes in female MDD patients. This highlights the importance of measuring childhood trauma-related symptoms in routine clinical rTMS treatment, as they may impact perceived efficacy.

Functional impairment-based segmentation of anterior cingulate cortex in depression and its relationship with treatment effects.

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) is widely related to depression impairment and antidepressant treatment response. The multiplicity of ACC subdivisions calls for a fine-grained investigation of their functional impairment and recovery profiles. We recorded resting state fMRI signals from 59 MDD patients twice before and after 12-week antidepressant treatment, as well as 59 healthy controls (HCs). With functional connectivity (FC) between each ACC voxel and four regions of interests (bilateral dorsolateral prefrontal cortex [DLPFC] and amygdalae), subdivisions with variable impairment were identified based on groups' dissimilarity values between MDD patients before treatment and HC. The ACC was subdivided into three impairment subdivisions named as MedialACC, DistalACC, and LateralACC according to their dominant locations. Furthermore, the impairment pattern and the recovery pattern were measured based on group statistical analyses. DistalACC impaired more on its FC with left DLPFC, whereas LateralACC showed more serious impairment on its FC with bilateral amygdalae. After treatment, FCs between DistalACC and left DLPFC, and between LateralACC and right amygdala were normalized while impaired FC between LateralACC and left amygdala kept dysfunctional. Subsequently, FC between DistalACC and left DLPFC might contribute to clinical outcome prediction. Our approach could provide an insight into how the ACC was impaired in depression and partly restored after antidepressant treatment, from the perspective of the interaction between ACC subregions and critical frontal and subcortical regions.