A Blind Module Identification Approach for Predicting Effective Connectivity Within Brain Dynamical Subnetworks.

Model-based network discovery measures, such as the brain effective connectivity, require fitting of generative process models to measurements obtained from key areas across the network. For distributed dynamic phenomena, such as generalized seizures and slow-wave sleep, studying effective connectivity from real-time recordings is significantly complicated since (i) outputs from only a subnetwork can be practically measured, and (ii) exogenous subnetwork inputs are unobservable. Model fitting, therefore, constitutes a challenging blind module identification or model inversion problem for finding both the parameters and the many unknown inputs of the subnetwork. We herein propose a novel estimation framework for identifying nonlinear dynamic subnetworks in the case of slowly-varying, otherwise unknown local inputs. Starting with approximate predictions obtained using Cubature Kalman filtering, residuals of local output predictions are utilized to improve upon local input estimates. The algorithm performance is tested on both simulated and clinical EEG of induced seizures under electroconvulsive therapy (ECT). For the simulated network, the algorithm significantly boosted the estimation accuracy for inputs and connections from noisy EEG. For the clinical data, the algorithm predicted increased subnetwork inputs during the pre-stimulus anesthesia condition. Importantly, it predicted an increased frontocentral connectivity during the generalized seizure that is commensurate with electrode placement and that corroborates the clinical hypothesis of increased frontal focality of therapeutic ECT seizures. The proposed framework can be extended to account for several input configurations and can in principle be applied to study effective connectivity within brain subnetworks defined at the microscale (cortical lamina interaction) or at the macroscale (sensory integration).

Association between substance use disorders and self- and other-directed aggression: An integrated model approach.

Our study's objective is to determine whether substance use disorders' association with aggression differs according to the type of substance and/or the form of aggression, within the same population. We used data from the National Survey on Drug Use and Health across 2008-2014, with a pooled sample of 270,227 adult respondents. We used regression models to estimate the odds ratios for those having alcohol and/or drug use disorder(s) perpetrating (a) each form of aggression compared with no aggression and (b) other-directed compared with self-directed aggression. Alcohol use disorder alone and drug use disorder(s) alone were both associated with significantly increased odds of committing self-directed, other-directed, and combined aggression. Individuals with drug use disorder(s) alone were more likely to commit other-directed than self-directed aggression (adjusted odds ratio = 1.46, 95% CI = 1.04-2.05). Individuals with alcohol use disorder alone were not likely to commit one over the other (adjusted odds ratio = 1.20, 95% CI = 0.90-1.61). In conclusion, the integrated model of aggression based on the stress-diathesis model is a relevant framework to study risk factors for aggression. Further research is needed to identify longitudinal predictors of directionality of aggression.

Expanded Safety and Efficacy Data for a New Method of Performing Electroconvulsive Therapy: Focal Electrically Administered Seizure Therapy.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most rapid and effective antidepressant treatment but with concerns about cognitive adverse effects. A new form of ECT, focal electrically administered seizure therapy (FEAST), was designed to increase the focality of stimulation and better match stimulus parameters with neurophysiology. We recently reported on the safety and feasibility of FEAST in a cohort (n = 17) of depressed patients. We now report on the safety, feasibility, preliminary efficacy, and cognitive effects of FEAST in a new cohort. METHODS: Open-label FEAST was administered to 20 depressed adults (6 men; 3 with bipolar disorder; age 49.1 ± 10.6 years). Clinical and cognitive assessments were obtained at baseline and end of course. Time to orientation recovery was assessed at each treatment. Nonresponders switched to conventional ECT. RESULTS: Participants tolerated the treatment well with no dropouts. Five patients (25%) transitioned from FEAST to conventional ECT due to inadequate response. After FEAST (mean, 9.3 ± 3.5 sessions; range, 4-14), there was a 58.1% ± 36.0% improvement in Hamilton Rating Scale for Depression scores compared with that in the baseline (P < 0.0001); 13 (65%) of 20 patients met response criteria, and 11 (55%) of 20 met remission criteria. Patients achieved reorientation (4 of 5 items) in 4.4 ± 3.0 minutes (median, 4.5 minutes), timed from eyes opening. There was no deterioration in neuropsychological measures. CONCLUSIONS: These findings provide further support for the safety and efficacy of FEAST. The remission and response rates were in the range found using conventional ECT, and the time to reorientation may be quicker. However, without a randomized comparison group, conclusions are tentative.

Resting-state functional connectivity of antero-medial prefrontal cortex sub-regions in major depression and relationship to emotional intelligence.

BACKGROUND: Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals. METHODS: Twenty-one medication-free, non-treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10 m, 10r, and 10p were created and compared between the two groups. RESULTS: Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence. CONCLUSIONS: These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence.

Neutral face distractors differentiate performance between depressed and healthy adolescents during an emotional working memory task.

The aim of the present study is to examine the effect of neutral and emotional facial expressions on voluntary attentional control using a working memory (WM) task in adolescents with major depressive disorder (MDD). We administered the Emotional Face n-back (EFNBACK) task, a visual WM task with neutral, happy and angry faces as distractors to 22 adolescents with MDD (mean age 15.7 years) and 21 healthy controls (HC) (mean age 14.7 years). There was a significant group by distractor type interaction (p = 0.045) for mean percent accuracy rates. Group comparisons showed that MDD youth were less accurate on neutral trials than HC (p = 0.027). The two groups did not differ on angry, happy and blank trials (p > 0.05). Reaction time did not differ across groups. In addition, when comparing the differences between accuracies on neutral trials and each of the happy and angry trials, respectively [(HAP-NEUT) and (ANG-NEUT)], there was a group effect on (HAP-NEUT) where the difference was larger in MDD than HC (p = 0.009) but not on ANG-NEUT (p > 0.05). Findings were independent of memory load. Findings indicate that attentional control to neutral faces is impaired and negatively affected performance on a WM task in adolescents with MDD. Such an impact of neutral faces on attentional control in MDD may be at the core of the social-cognitive impairment observed in this population.

A roadmap to parity in mental health financing: the case of Lebanon.

BACKGROUND: Inadequate access to mental health (MH) services in Lebanon, where prevalence is noteworthy, is a concern. Although a multitude of factors affects access to services, lack of financial coverage of MH services is one that merits further investigation. AIM OF THE STUDY: This study aims at providing a systematic description of MH financing systems with a special focus on Lebanon, presenting stakeholder viewpoints on best MH financing alternatives/strategies and recommending options for enhancing financial coverage. METHODS: A comprehensive review of existing literature on MH financing systems was conducted, with a focus on the system in Lebanon. In addition, key stakeholders were interviewed to assess MH organizational and financing arrangements. Finally, a national round table was organized with the aim of discussing findings (from the review and interviews) and developing an action roadmap. RESULTS: Taxation and out-of-pocket payments are the most common MH financing sources worldwide and in the Eastern Mediterranean Region. In Lebanon, all funding entities, except private insurance and mutual funds, cover inpatient and outpatient MH services, albeit with inconsistencies in levels of coverage. The national roundtable recommended two main MH financing enhancements: (i) creating a knowledge-sharing committee between insurers and MH specialists, and (ii) convincing labor unions/representatives to lobby for MH coverage as part of the negotiated benefit package. DISCUSSION: There are concerns regarding the equity, effectiveness and efficiency of the MH financing system in Lebanon. The fragmented system in Lebanon leads to differences in MH coverage across different financing intermediaries, which is inequitable. The fact that one out of four Lebanese suffer a mental disorder throughout their lives and very low percentages of those obtain treatment signals a problem in effectiveness. As for efficiency, the inefficient fragmentation of MH financing among seven intermediaries is a problematic characteristic of the healthcare financing system as a whole. Moreover, the orientation of the general healthcare system towards curative rather than preventive care is reflected in MH financing as well. Limitations of the study include the lack of access to data about the MH expenditure of every financing intermediary in Lebanon; therefore it was not possible to calculate a total annual MH spending on a country level. Another limitation was the inability to map the sources of funding with the MH service provision sector, as more extensive data about the MH services provided by each of the public, private, voluntary and informal sectors is needed. IMPLICATIONS FOR HEALTH POLICIES: Providing a clear description of the current MH financing system helps policymakers recognize the disparities present in the coverage of MH, guiding them into making informed decisions on allocation of funds. This study therefore constitutes the first step towards achieving more equitable and socially just coverage, advances knowledge and provides well-needed locally relevant research. Findings are expected to inform policymaking and have already contributed to influencing a change in the policy of the Internal Security Forces Health Fund. As a result of the roundtable discussion and follow up that ensued, the fund has removed the suicide attempt exclusion from its insurance policy.

Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression.

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. OBJECTIVE/HYPOTHESIS: This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. METHODS: 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. LIMITATIONS: Main limitations include a small sample size and open-label design. CONCLUSIONS: These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

A pilot functional MRI study of the effects of prefrontal rTMS on pain perception.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively treat depression, and its potential value in pain management is emphasized by recent studies. Transcranial magnetic stimulation (TMS)-evoked activity in the prefrontal cortex may be associated with corticolimbic inhibitory circuits capable of decreasing pain perception. The present exploratory pilot study used functional magnetic resonance imaging (fMRI) to examine the effects of left prefrontal rTMS on brain activity and pain perception. DESIGN AND INTERVENTION: Twenty-three healthy adults with no history of depression or chronic pain underwent an 8-minute thermal pain protocol with fMRI before and after a single rTMS session. Participants received 15 minutes of either real (N = 12) or sham (N = 11) 10 Hz rTMS over the left prefrontal cortex (110% of resting motor threshold; 5 seconds on, 10 seconds off). RESULTS: TMS was associated with a 13.30% decrease in pain ratings, while sham was associated with an 8.61% decrease (P = 0.04). TMS was uniquely associated with increased activity in the posterior cingulate gyrus, precuneous, right superior frontal gyrus, right insula, and bilateral postcentral gyrus. Activity in the right superior prefrontal gyrus was negatively correlated with pain ratings (r = -0.65, P = 0.02) in the real TMS group. CONCLUSIONS: Findings suggest that prefrontal rTMS may be capable of activating inhibitory circuits involved with pain reduction.

Validation of an Arabic multi-informant psychiatric diagnostic interview for children and adolescents: development and Well Being Assessment-Arabic (DAWBA-Arabic).

BACKGROUND: Countries in the Arab region lack a valid Arabic psychiatric diagnostic interview for children and adolescents. We set out to establish the diagnostic validity of the Arabic version of the Development and Well Being Assessment (DAWBA-Arabic), a multi-informant structured interview for predicting DSM-IV-TR diagnoses. METHODS: The DAWBA was translated, updated, and administered to 45 participants (child and adolescent psychiatric outpatients and their parents) as part of a clinic registry. Two clinicians, blinded to their respective diagnoses, formulated the DAWBA diagnoses. Participants also underwent a clinical evaluation by a child and adolescent psychiatrist who generated clinical diagnoses according to the DSM-IV-TR. RESULTS: Inter-rater reliabilities were .93, .82, and .72 for disruptive disorders, mood disorders and anxiety disorders respectively. Agreement between DAWBA and clinical diagnoses was substantial for disruptive disorders (κ=.0.82) and mood disorders (κ=0.74), and moderate for anxiety disorders (κ=0.46). CONCLUSION: The DAWBA-Arabic could serve as a valid and reliable clinical tool for assessing psychiatric disorders among children and adolescents in the Arab region.

Causally mapping human threat extinction relevant circuits with depolarizing brain stimulation methods.

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.

Long-term efficacy of repeated daily prefrontal transcranial magnetic stimulation (TMS) in treatment-resistant depression.

BACKGROUND: A few studies have examined the durability of transcranial magnetic stimulation (TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up. METHODS: Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome. RESULTS: Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission (HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction <50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month. CONCLUSIONS: While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS.

Sustained Activation of the Anterior Thalamic Neurons with Low Doses of Kainic Acid Boosts Hippocampal Neurogenesis.

Adult hippocampal neurogenesis is prone to modulation by several intrinsic and extrinsic factors. The anterior nucleus (AN) of the thalamus has extensive connections with the hippocampus, and stimulation of this region may play a role in altering neurogenesis. We have previously shown that electrical stimulation of the AN can substantially boost hippocampal neurogenesis in adult rats. Here, we performed selective unilateral chemical excitation of the cell bodies of the AN as it offers a more specific and sustained stimulation when compared to electrical stimulation. Our aim is to investigate the long-term effects of KA stimulation of the AN on baseline hippocampal proliferation of neural stem cells and neurogenesis. Continuous micro-perfusion of very low doses of kainic acid (KA) was administered into the right AN for seven days. Afterwards, adult male rats received 5'-bromo-2'-deoxyuridine (BrdU) injections (200 mg/kg, i.p) and were euthanized at either one week or four weeks post micro-perfusion. Open field and Y-maze tests were performed before euthanasia. The KA stimulation of the AN evoked sustained hippocampal neurogenesis that was associated with improved spatial memory in the Y-maze test. Administering dexamethasone prior to and simultaneously with the KA stimulation decreased both the hippocampal neurogenesis and the improved spatial recognition memory previously seen in the Y-maze test. These results suggest that hippocampal neurogenesis may be a downstream effect of stimulation in general, and of excitation of the cell bodies of the AN in particular, and that stimulation of that area improves spatial memory in rats.

DLPFC stimulation alters working memory related activations and performance: An interleaved TMS-fMRI study.

BACKGROUND: Findings from correlative neuroimaging studies link increased frontoparietal network (FPN) activation and default mode network (DMN) deactivation to enhanced high cognitive demand processing. To causally investigate FPN-DMN contributions to high cognitive demand processing, the current interleaved TMS-fMRI study simultaneously manipulated and indexed neural activity while tracking cognitive performance during high and low cognitive load conditions. METHODS: Twenty participants completed an n-back task consisting of four conditions (0-back, 0-backTMS, 2-back, 2-backTMS) while undergoing interleaved TMS-fMRI. During TMS concurrent with n-back blocks, TMS single pulses were delivered to the left DLPFC at 100% motor-threshold every 2.4s. RESULTS: TMS delivered during high cognitive load strengthened cognitive processing. FPN node activations and DMN node deactivations were increased in the high versus low cognitive load TMS condition. Contrary to our hypothesis, TMS did not increase high load related activation in FPN nodes. However, as hypothesized, increased DMN node deactivations emerged as a function of TMS during high load (right angular gyrus) and from interactions between cognitive load and TMS (right middle temporal gyrus). Load and TMS combined to dampen activation within the DMN at trend level (p = .058). Deactivation in a dorsomedial DMN node was associated with TMS driven improvements in high load cognitive processing. CONCLUSIONS: Exogenous perturbation of the DLPFC via single pulse TMS amplified DMN node deactivations and enhanced high cognitive demand processing. Neurobehavioral findings linking these effects hint at a promising, albeit preliminary, cognitive control substrate requiring replication in higher-powered studies that use control stimulation.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Improving the antidepressant efficacy of transcranial magnetic stimulation: maximizing the number of stimulations and treatment location in treatment-resistant depression.

OBJECTIVE: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). METHOD: Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. RESULTS: Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. CONCLUSION: The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations.

Using interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (fMRI) and dynamic causal modeling to understand the discrete circuit specific changes of medications: lamotrigine and valproic acid changes in motor or prefrontal effective connectivity.

The purpose of this study was to use interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (TMS/fMRI) to investigate the effects of lamotrigine (LTG) and valproic acid (VPA) on effective connectivity within motor and corticolimbic circuits. In this randomized, double-blind, crossover trial, 30 healthy volunteers received either drug or placebo 3.5 h prior to interleaved TMS/fMRI. We utilized dynamic causal modeling (DCM) to assess changes in the endogenous effective connectivity of bidirectional networks in the motor-sensory system and corticolimbic circuit. Results indicate that both LTG and VPA have network-specific effects. When TMS was applied over the motor cortex, both LTG and VPA reduced TMS-specific effective connectivity between primary motor (M1) and pre-motor cortex (PMd), and between M1 and the supplementary area motor (SMA). When TMS was applied over prefrontal cortex, however, LTG alone increased TMS-specific effective connectivity between the left dorsolateral prefrontal cortex(DLPFC) and the anterior cingulate cortex (ACC). In summary, LTG and VPA inhibited effective connectivity in motor circuits, but LTG alone increased effective connectivity in prefrontal circuits. These results suggest that interleaved TMS/fMRI can assess region- and circuit-specific effects of medications or interventions.