Dorsomedial prefrontal rTMS for depression in borderline personality disorder: A pilot randomized crossover trial.

BACKGROUND: Recently, a small literature has emerged suggesting that repetitive transcranial magnetic stimulation (rTMS) may offer benefit for MDD even in BPD patients, perhaps by enhancing cognitive control, and/or disrupting excessive 'non-reward' activity in right orbitofrontal regions. This study aimed primarily to assess the therapeutic effects of dorsomedial prefrontal cortex (DMPFC)-rTMS against MDD symptoms in BPD patients, and secondarily to assess whether the therapeutic effects ensued via mechanisms of reduced impulsivity and core BPD pathology on clinical scales (BIS-11, ZAN-BPD) or of reduced alpha- and theta-band activity on EEG recordings of right orbitofrontal cortex.. METHODS: In a crossover-design trial, 20 BPD patients with MDD underwent 2 × 30 session/15 day blocks of either active-then-sham or sham-then-active bilateral 20 Hz DMPFC-rTMS. RESULTS: Sixteen out of 20 patients completed treatment. A significant (p = 0.00764) crossover effect was detected, with overall reductions in HamD17 score from 23.1±SD3.1 to 10.75±SD5.8. Nine out of 16 (56.3%) treatment completers achieved response (>50% improvement) and 6/16 (37.5%) achieved remission (HamD≤7), maintained at 1 month followup. BIS-11 scores remained unchanged, and ZAN-BPD scores improved similarly in both groups with no significant crossover effect. Change in low-band power over right orbitofrontal regions correlated with clinical improvement. LIMITATIONS: This was a crossover study with a small sample size. A randomized controlled trial with larger sample size will be needed to establish the efficacy more definitively. CONCLUSIONS: The results suggest efficacy for DMPFC-rTMS in treating MDD in BPD, and provide a foundation for a larger future trial.

Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial.

BACKGROUND: Dorsomedial prefrontal cortex (DMPFC) repetitive transcranial magnetic stimulation (rTMS) is a novel intervention for treatment-refractory depression (TRD). To date, many open-label case series and one randomized controlled trial of modest sample size have provided preliminary evidence that DMPFC-rTMS is an effective treatment for TRD. Here, we report the results of a large, double-blinded, sham-controlled trial of DMPFC-rTMS for TRD. OBJECTIVE: The primary aim of this study was to determine the efficacy of DMPFC-rTMS for TRD under sham-controlled conditions. METHODS: 120 TRD patients were randomized to receive 30 twice-daily sessions of either active high-frequency, active low-frequency, or sham DMPFC-rTMS using a novel bent active/sham double-cone coil. Placebo stimulation also involved the use of surface electrodes placed above the eyebrows. The 17-item Hamilton Rating Scale for Depression served as the primary outcome measure. RESULTS: Although there was a significant main effect of treatment across all arms, active DMPFC-rTMS was not superior to sham. Both participants and assessors were unable to accuracy determine whether patients received active or placebo stimulation. However, technicians' treatment arm guesses were significantly above chance. CONCLUSION: DMPFC rTMS did not result in improvement of depressive symptoms greater than sham stimulation. We cannot rule out that the sham apparatus may also have elicited an antidepressant effect via electrical trigeminal stimulation; future DMPFC-rTMS trials are therefore warranted.

Effect of Theta Transcranial Alternating Current Stimulation and Phase-Locked Transcranial Pulsed Current Stimulation on Learning and Cognitive Control.

Non-invasive brain stimulation (NIBS) is emerging as a robust treatment alternative for major depressive disorder, with a potential for achieving higher remission rates by providing targeted stimulation to underlying brain networks, such as the salience network (SN). Growing evidence suggests that these therapeutic effects are dependent on the frequency and phase synchrony between SN oscillations and stimulation as well as the task-specific state of the SN during stimulation. However, the development of phase-synchronized non-invasive stimulation has proved challenging until recently. Here, we use a phase-locked pulsed brain stimulation approach to study the effects of two NIBS methods: transcranial alternating current stimulation (tACS) versus phase-locked transcranial pulsed current stimulation (tPCS), on the SN during an SN activating task. 20 healthy volunteers participated in the study. Each volunteer partook in four sessions, receiving one stimulation type at random (theta-tACS, peak tPCS, trough tPCS or sham) while undergoing a learning game, followed by an unstimulated test based on learned material. Each session lasted approximately 1.5 h, with an interval of at least 2 days to allow for washout and to avoid cross-over effects. Our results showed no statistically significant effect of stimulation on the event related potential (ERP) recordings, resting electroencephalogram (EEG), and the performance of the volunteers. While stimulation effects were not apparent in this study, the nominal performance of the phase-locking algorithm offers a technical foundation for further research in determining effective stimulation paradigms and conditions. Specifically, future work should investigate stronger stimulation and true task-specific stimulation of SN nodes responsible for the task as well as their recording. If refined, NIBS could offer an effective, homebased treatment option.

A Real-Time Phase-Locking System for Non-invasive Brain Stimulation.

Non-invasive brain stimulation techniques are entering widespread use for the investigation and treatment of a range of neurological and neuropsychiatric disorders. However, most current techniques are 'open-loop', without feedback from target brain region activity; this limitation could contribute to heterogeneous effects seen for nominally 'inhibitory' and 'excitatory' protocols across individuals. More potent and consistent effects may ensue from closed-loop and, in particular, phase-locked brain stimulation. In this work, a closed-loop brain stimulation system is introduced that can analyze EEG data in real-time, provide a forecast of the phase of an underlying brain rhythm of interest, and control pulsed transcranial electromagnetic stimulation to deliver pulses at a specific phase of the target frequency band. The technique was implemented using readily available equipment such as a basic EEG system, a low-cost Arduino board and MATLAB scripts. The phase-locked brain stimulation method was tested in 5 healthy volunteers and its phase-locking performance evaluated at 0, 90, 180, and 270 degree phases in theta and alpha frequency bands. On average phase locking values of 0.55° ± 0.11° and 0.52° ± 0.14° and error angles of 11° ± 11° and 3.3° ± 18° were achieved for theta and alpha stimulation, respectively. Despite the low-cost hardware implementation, signal processing time generated a phase delay of only 3.8° for theta and 57° for alpha stimulation, both readily accommodated in the pulse trigger algorithm. This work lays the methodological steps for achieving phase-locked brain stimulation for brief-pulse transcranial electrical stimulation (tES) and repetitive transcranial magnetic stimulation (rTMS), facilitating further research on the effect of stimulation phase for these techniques.

Abnormal Functional Connectivity of Frontopolar Subregions in Treatment-Nonresponsive Major Depressive Disorder.

BACKGROUND: Approximately 30% of patients with major depressive disorder develop treatment-nonresponsive depression (TNRD); novel interventions targeting the substrates of this illness population are desperately needed. Convergent evidence from lesion, stimulation, connectivity, and functional neuroimaging studies implicates the frontopolar cortex (FPC) as a particularly important region in TNRD pathophysiology; regions functionally connected to the FPC, once identified, could present favorable targets for novel brain stimulation treatments. METHODS: We recently published a parcellation of the FPC based on diffusion tensor imaging data, identifying distinct medial and lateral subregions. Here, we applied this parcellation to resting-state functional magnetic resonance imaging scans obtained in 56 patients with TNRD and 56 matched healthy control subjects. RESULTS: In patients, the medial FPC showed reduced connectivity to the anterior midcingulate cortex and insula. The left lateral FPC showed reduced connectivity to the right lateral orbitofrontal cortex and increased connectivity to the fusiform gyri. In addition, TNRD symptom severity correlated significantly with connectivity of the left lateral FPC subregion to a medial orbitofrontal cortex region of the classical reward network. CONCLUSIONS: Taken together, these findings suggest that changes in FPC subregion connectivity may underlie several dimensions of TNRD pathology, including changes in reward/positive valence, nonreward/negative valence, and cognitive control domains. Nodes of functional networks showing abnormal connectivity to the FPC could be useful in generating novel candidates for therapeutic brain stimulation in TNRD.

Chronic cannabis use and attentional bias: Extended attentional capture to cannabis cues.

INTRODUCTION: A significant proportion of chronic cannabis users experience occupational, social, and psychological problems thought to reflect, in part, cannabis-related cognitive and emotional attentional biases. The emotional attentional blink (EAB) is a unique test of attentional bias that assesses automatic responses, cue-detection failures, and rapid and temporally extended biases. Using the EAB, we tested users' and non-users' attentional biases and how cannabis exposure correlates with these attentional biases. METHODS: Forty-eight regular cannabis users and 51 non-users completed demographic, psychological, and cannabis-use reports and two EAB target-detection experiments. Each experiment comprised 160 trials. Each trial included a rapid serial visual presentation of images with one of four types of distractor images (cannabis, generically positive, neutral, or scrambled) preceding the target image. Distractor images were presented 200ms (Lag 2) or 800ms (Lag 8) before the target in Experiment 1 and 200ms (Lag 2) or 500ms (Lag 5) before the target in Experiment 2. RESULTS: Chronic cannabis users exhibited exaggerated, immediate attentional bias (Lag 2) and exaggerated, extended attentional bias (Lag 5) compared to non-users. The intensity of cannabis-use (grams per week) correlated with more errors at the extended attentional bias durations (Lags 5 and 8). CONCLUSIONS: Our results represent novel evidence of automatic attentional capture consistent with an exaggerated "wanting" motive in models of addiction. Our unique evidence of temporally extended attentional biases is consistent with attentional disengagement deficits associated with chronic cannabis use.

1Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes.

Conventional rTMS in major depressive disorder (MDD) targets the dorsolateral prefrontal cortex (DLPFC). However, many patients do not respond to DLPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in 'non-reward' functions and shows hyperconnectivity in MDD. OFC-rTMS has been used successfully in obsessive-compulsive disorder, and achieved remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. Here, we assess the safety and tolerability of right OFC-rTMS, and examine the effectiveness of inhibitory right OFC-rTMS in MDD, particularly among patients with previous nonresponse to DMPFC-rTMS. We performed a chart review to retrieve data on clinical characteristics, stimulation parameters, adverse events, and clinical symptom outcomes for a series of 42 patients with medication-resistant and/or DMPFC-rTMS-nonresponsive MDD, who underwent 20-30 sessions of 1Hz right OFC-rTMS at a single Canadian clinic from 2015 to 2017. Over 882 sessions of treatment, there were no seizures, visual/ocular complications, or other serious or treatment-limiting adverse events. Pain ratings averaged 6-7/10 (10=maximum tolerable); no patient discontinued treatment prematurely due to pain. 15/42 patients (35.7%) achieved response (≥50% symptom reduction) and 10/42 (23.8%) achieved remission. Among the 30/42 patients who were previous nonresponders to DMPFC-rTMS, 9/30 (30.0%) achieved response and 7/30 (23.8%) achieved remission. Response distribution was sharply bimodal. 1Hz right OFC-rTMS appears safe and tolerable, and may achieve remission in MDD patients even when conventional rTMS has failed. Sham-controlled follow-up studies may be warranted.

Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness.

Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.

Influence of inter-train interval on the plastic effects of rTMS.

BACKGROUND: High frequency repetitive transcranial magnetic stimulation (rTMS) elicits plastic effects in excitatory and inhibitory circuits. Inter-train intervals (ITI) were initially incorporated into rTMS paradigms to avoid overheating and for safety considerations. Recent studies have shown that inclusion of ITI, as opposed to continuous stimulation, is essential for eliciting excitatory effects, but the optimal ITI remains unknown. Moreover, if ITI duration has no effect, it may be possible to substantially reduce treatment time for rTMS. HYPOTHESIS: ITI duration modulates the excitatory and disinhibitory effects of rTMS. METHODS: rTMS (20 Hz, 2 s trains, 1200 pulses, 100% RMT) was applied in 14 healthy individuals with ITI of 4s (duration: ∼3 min), 8s (∼5 min), 16s (∼9 min) or 32s (16.5 min) in sessions separated by ≥5 days. Effects on cortical excitability and GABAA receptor mediated short interval intracortical inhibition (SICI) were measured for 75 min following rTMS. RESULTS: The time-course of increased cortical excitability following rTMS was independent of ITI duration. There was a striking influence of ITI on SICI, whereby disinhibition increased with shorter ITI duration. Changes in cortical excitability and SICI were independent of each other. CONCLUSION: These findings provide the first evidence to suggest that ITI may be substantially shortened without loss of rTMS effects, and warrant further investigation where rTMS is applied therapeutically. Furthermore, shorter ITIs result in greater disinhibitory effects which may be desirable in some clinical disorders and accelerated treatment paradigms. The tuning of the plasticity of cortical excitatory and inhibitory circuits to rTMS parameters in human cortex are independent.

Symptom Manifestation and Impairments in College Students With ADHD.

To better understand the nature of impairment resulting from attention-deficit/hyperactivity disorder (ADHD) for students in a post-secondary education (PSE) setting, the authors analyzed the symptoms and associated impairment of 135 students with a diagnosis of ADHD who were recruited via Student Disability Services in Canadian post-secondary institutions. The authors (a) developed a novel semistructured telephone interview based on the 6-item Adult ADHD Self-Report Scale Screener-Telephone Interview With Probes (ASRS-TIPS) to elicit students' descriptions of their behavior for each symptom they endorsed, (b) administered standardized tests of executive functioning (EF) and academic fluency, and (c) obtained self-reports of grade point averages (GPAs), EF, cognitive failures, psychopathology, distress, and resilience. Qualitative analysis of the ASRS-TIPS revealed significant impairment relating to symptoms of ADHD in the PSE setting. Students reported clinically significant symptoms of ADHD, psychological distress, and impairment in EF (67%, severe range) and cognitive failure (62%, atypical range) in everyday life. By contrast, their GPAs and standardized scores of EF and academic fluency were in the average range. Standardized scores and GPAs did not capture the impairment that participants experienced in their PSE settings. The ASRS-TIPS may provide a useful tool to help document how these students' symptoms impair functioning in the PSE setting.

Delayed administration of a bio-engineered zinc-finger VEGF-A gene therapy is neuroprotective and attenuates allodynia following traumatic spinal cord injury.

Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF--an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression--would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats--under cyclosporin immunosuppression--received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits.