The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Repetitive transcranial magnetic stimulation treatment of major depressive disorder and comorbid chronic pain: response rates and neurophysiologic biomarkers.

BACKGROUND: Major depressive disorder (MDD) and chronic pain are highly comorbid, and pain symptoms are associated with a poorer response to antidepressant medication treatment. It is unclear whether comorbid pain also is associated with a poorer response to treatment with repetitive transcranial magnetic stimulation (rTMS). METHODS: 162 MDD subjects received 30 sessions of 10 Hz rTMS treatment administered to the left dorsolateral prefrontal cortex (DLPFC) with depression and pain symptoms measured before and after treatment. For a subset of 96 patients, a resting-state electroencephalogram (EEG) was recorded at baseline. Clinical outcome was compared between subjects with and without comorbid pain, and the relationships among outcome, pain severity, individual peak alpha frequency (PAF), and PAF phase-coherence in the EEG were examined. RESULTS: 64.8% of all subjects reported pain, and both depressive and pain symptoms were significantly reduced after rTMS treatment, irrespective of age or gender. Patients with severe pain were 27% less likely to respond to MDD treatment than pain-free individuals. PAF was positively associated with pain severity. PAF phase-coherence in the somatosensory and default mode networks was significantly lower for MDD subjects with pain who failed to respond to MDD treatment. CONCLUSIONS: Pain symptoms improved after rTMS to left DLPFC in MDD irrespective of age or gender, although the presence of chronic pain symptoms reduced the likelihood of treatment response. Individual PAF and baseline phase-coherence in the sensorimotor and midline regions may represent predictors of rTMS treatment outcome in comorbid pain and MDD.

White matter microstructure in habit and reward circuits in anorexia nervosa: Insights from a neurite orientation dispersion and density imaging study.

BACKGROUND: Behavioral features of anorexia nervosa (AN) suggest abnormalities in reward and habit. Neuroimaging evidence suggests morphometric and functional perturbations within these circuits, although fewer studies have assessed white matter characteristics in AN, and no studies to date have assessed white matter microstructure in AN. METHODS: In this brain imaging study, 29 female adolescents with partially or fully weight-restored AN and 27 healthy controls, all between 10 and 19 years, underwent whole-brain multi-shell diffusion tensor imaging. Utilizing neurite orientation dispersion and density imaging methods, we investigated group differences in white matter neurite density, orientation dispersion, and myelin density in tracts between prominent nodes of the reward circuit (ventral tegmental area (VTA) to nucleus accumbens (NAcc)) and the habit circuit (sensory motor area [SMA] to putamen). RESULTS: Findings revealed reduced neurite (F = 5.20, p = 0.027) and myelin density (F = 5.39, p = 0.025) in the left VTA-NAcc tract, and reduced orientation dispersion in the left (F = 7.00, p = 0.011) and right (F = 6.77, p = 0.012) VTA-NAcc tract. There were no significant group differences in the SMA-putamen tract. Significant relationships, after corrections, were not evident between tract microstructure and reward responsiveness, compulsive behaviors, illness duration, or BMI. CONCLUSIONS: Adolescents with AN exhibit less dense, undermyelinated, and less dispersed white matter tracts connecting prominent reward system nodes, which could potentially signify underutilization of this part of the reward circuit. These results provide a detailed examination of white matter microstructure in tracts underlying instrumental behavioral phenotypes contributing to illness in AN.

Absence of early mood improvement as a robust predictor of rTMS nonresponse in major depressive disorder.

BACKGROUND: Symptoms of major depressive disorder (MDD) are reported to change early in treatment with repetitive transcranial magnetic stimulation (rTMS). We evaluated early changes in sleep, anxiety, and mood as predictors of nonresponse to rTMS treatment. METHODS: Three hundred twenty-nine subjects with nonpsychotic MDD completed a 6-week course of rTMS treatment. Subjects were stratified by the severity of their baseline depression, and had their overall depressive symptoms recorded every week of treatment. We evaluated lack of improvement in sleep, anxiety, and mood symptoms after 1 and 2 weeks as potential predictors of eventual nonresponse, defined as <50% improvement in compositive depressive symptoms after 6 weeks. This was measured as negative predictive value (NPV; the likelihood that lack of early symptom improvement accurately predicted eventual treatment nonresponse). RESULTS: Subjects with severe or very severe baseline depression achieving <20% improvement in mood at 1 week were correctly predicted as nonresponders with NPVs largely >90%. At 2 weeks, subjects with very severe baseline depression who failed to demonstrate any improvement in mood were all nonresponders. Lack of improvement in sleep at 2 weeks was also a significant predictor. CONCLUSIONS: Identifying a lack of early mood improvement is a practical and robust method to predict rTMS nonresponse. This suggests a treatment protocol change may be indicated in patients with more severe baseline depression showing minimal early mood improvement.

Neurosurgery and neuromodulation for anorexia nervosa in the 21st century: a systematic review of treatment outcomes.

As current psychosocial and pharmacological interventions show limited efficacy in the treatment of anorexia nervosa (AN), interest in the potential value of neurosurgical intervention and neuromodulation in managing severe and enduring illness has grown. We conducted a systematic review of 20 trials of neurosurgical and neuromodulatory treatments for AN, including neurosurgical ablation, deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Overall, there is evidence to support the role of stereotactic ablation and DBS in the treatment of AN. In contrast, results for rTMS and tDCS have been modest and generally more mixed. Neurosurgical treatment may offer important new avenues for the treatment of AN. Additional randomized clinical trials with comparable patient populations will be needed, in which change in affective, cognitive, and perceptual symptom phenomena, and interrogation of targeted circuits, pre- and post-intervention, are carefully documented.

Relationships between obsessive-compulsive disorder, depression and functioning before and after exposure and response prevention therapy.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is associated with impaired functioning and depression. Our aim was to examine relationships between OCD symptoms, depression and functioning before and after exposure and response prevention (ERP), a type of cognitive-behavioural therapy for OCD, specifically examining whether functioning, depression and other cognitive factors like rumination and worry acted as mediators. METHODS: Forty-four individuals with OCD were randomised to 4 weeks of intensive ERP treatment first (n = 23) or waitlist then treatment (n = 21). We used a bootstrapping method to examine mediation models. RESULTS: OCD symptoms, depression and functioning significantly improved from pre- to post-intervention. Functioning mediated the relationship between OCD symptoms and depression and the relationship between functioning and depression was stronger at post-treatment. Depression mediated the relationship between OCD symptoms and functioning, but only at post-intervention. Similarly, rumination mediated the relationship between OCD symptoms and depression at post-intervention. CONCLUSIONS: Our findings suggest that after ERP, relationships between depression and functioning become stronger. Following ERP, treatment that focuses on depression and functioning, including medication management for depression, cognitive approaches targeting rumination, and behavioural activation to boost functionality may be important clinical interventions for OCD patients.

Brain network dysfunction in late-life depression: a literature review.

As a common psychiatric disorder in the growing geriatric population, late-life depression (LLD) has a negative impact on the cognitive, affective, and somatic domains of the lives of the elderly individuals. Accumulating evidence from the structural and functional imaging studies on LLD supports a "network dysfunction model" rather than a "lesion pathology model" for understanding the underlying biological mechanism in this mental disorder. In this work, we used network dysfunction model as a conceptual framework for reviewing recent neuroimaging findings in LLD. Our focus was on 4 major neurocircuits that have been shown to be involved in LLD: default mood network, cognitive control network, affective/frontolimbic network, and corticostriatal circuits. Findings of LLD-related gray and white matter structural abnormalities and resting-state and task-based functional changes were discussed for each network separately. We extended our review by summarizing the latest works that apply graph theory-based network analysis techniques for testing alterations in whole-brain network properties associated with LLD.

Rumination symptoms in treatment-resistant major depressive disorder, and outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) treatment.

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.

Neural representations of anxiety in adolescents with anorexia nervosa: a multivariate approach.

Anorexia nervosa (AN) is characterized by low body weight, fear of gaining weight, and distorted body image. Anxiety may play a role in the formation and course of the illness, especially related to situations involving food, eating, weight, and body image. To understand distributed patterns and consistency of neural responses related to anxiety, we enrolled 25 female adolescents with AN and 22 non-clinical female adolescents with mild anxiety who underwent two fMRI sessions in which they saw personalized anxiety-provoking word stimuli and neutral words. Consistency in brain response patterns across trials was determined using a multivariate representational similarity analysis (RSA) approach within anxiety circuits and in a whole-brain voxel-wise searchlight analysis. In the AN group there was higher representational similarity for anxiety-provoking compared with neutral stimuli predominantly in prefrontal regions including the frontal pole, medial prefrontal cortex, dorsolateral prefrontal cortex, and medial orbitofrontal cortex, although no significant group differences. Severity of anxiety correlated with consistency of brain responses within anxiety circuits and in cortical and subcortical regions including the frontal pole, middle frontal gyrus, orbitofrontal cortex, thalamus, lateral occipital cortex, middle temporal gyrus, and cerebellum. Higher consistency of activation in those with more severe anxiety symptoms suggests the possibility of a greater degree of conditioned brain responses evoked by personally-relevant emotional stimuli. Anxiety elicited by disorder-related stimuli may activate stereotyped, previously-learned neural responses within- and outside of classical anxiety circuits. Results have implications for understanding consistent and automatic responding to environmental stimuli that may play a role in maintenance of AN.

Toward personalized circuit-based closed-loop brain-interventions in psychiatry: using symptom provocation to extract EEG-markers of brain circuit activity.

Symptom provocation is a well-established component of psychiatric research and therapy. It is hypothesized that specific activation of those brain circuits involved in the symptomatic expression of a brain pathology makes the relevant neural substrate accessible as a target for therapeutic interventions. For example, in the treatment of obsessive-compulsive disorder (OCD), symptom provocation is an important part of psychotherapy and is also performed prior to therapeutic brain stimulation with transcranial magnetic stimulation (TMS). Here, we discuss the potential of symptom provocation to isolate neurophysiological biomarkers reflecting the fluctuating activity of relevant brain networks with the goal of subsequently using these markers as targets to guide therapy. We put forward a general experimental framework based on the rapid switching between psychiatric symptom states. This enable neurophysiological measures to be derived from EEG and/or TMS-evoked EEG measures of brain activity during both states. By subtracting the data recorded during the baseline state from that recorded during the provoked state, the resulting contrast would ideally isolate the specific neural circuits differentially activated during the expression of symptoms. A similar approach enables the design of effective classifiers of brain activity from EEG data in Brain-Computer Interfaces (BCI). To obtain reliable contrast data, psychiatric state switching needs to be achieved multiple times during a continuous recording so that slow changes of brain activity affect both conditions equally. This is achieved easily for conditions that can be controlled intentionally, such as motor imagery, attention, or memory retention. With regard to psychiatric symptoms, an increase can often be provoked effectively relatively easily, however, it can be difficult to reliably and rapidly return to a baseline state. Here, we review different approaches to return from a provoked state to a baseline state and how these may be applied to different symptoms occurring in different psychiatric disorders.

Pretreatment pupillary reactivity is associated with outcome of Repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD).

BACKGROUND: Pre-treatment biomarkers for outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD) have proven elusive. One promising family of biomarkers involves the autonomic nervous system (ANS), which is dysregulated in individuals with MDD. METHODS: We examined the relationship between the pre-treatment pupillary light reflex (PLR) and rTMS outcome in 51 MDD patients. Outcome was measured as the percent change in the 30-item Inventory of Depressive Symptomatology Self Rated (IDS-SR) score from baseline to treatment 30. RESULTS: Patients showed significant improvement with rTMS treatment. There was a significant correlation between baseline pupillary Constriction Amplitude (CA) and clinical improvement over the treatment course (R = 0.41, p = 0.003). LIMITATIONS: We examined a limited number of subjects who received heterogeneous treatment protocols. Almost all patients in the study received psychotropic medications concomitant with rTMS treatment. CONCLUSION: PLR measured before treatment may be a predictive biomarker for clinical improvement from rTMS in subjects with MDD.

Pretreatment pupillary reactivity is associated with differential early response to 10 Hz and intermittent theta-burst repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD).

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD). Two common rTMS protocols, 10 Hz and intermittent theta burst stimulation (iTBS), have comparable rates of efficacy in groups of patients. Recent evidence suggests that some individuals may be more likely to benefit from one form of stimulation than the other. The pretreatment pupillary light reflex (PLR) is significantly associated with response to a full course of rTMS using heterogeneous stimulation protocols. OBJECTIVE: To test whether the relationship between pretreatment PLR and early symptom improvement differed between subjects treated with iTBS or 10 Hz stimulation. METHODS: PLR was measured in 52 subjects who received solely 10 Hz (n = 35) or iTBS (n = 17) to left dorsolateral prefrontal cortex (DLPFC) for the first ten sessions of their treatment course. Primary outcome measure was the percent change of Inventory of Depressive Symptomatology - Self Report (IDS-SR) from session 1 to session 10. RESULTS: There was a positive association between normalized maximum constriction velocity (nMCV) and early improvement in subjects receiving 10 Hz stimulation (R = 0.48, p = 0.004) and a negative association in subjects receiving iTBS (R = -0.52, p = 0.03). ANOVA revealed a significant interaction between nMCV and the type of initial stimulation (p = 0.001). Among subjects with low nMCV, those initially treated with iTBS showed 2.6 times greater improvement after 10 sessions (p = 0.01) than subjects initially receiving 10 Hz stimulation. CONCLUSION: nMCV may detect physiologic differences between those likely to benefit from 10 Hz or iTBS treatment. Future studies should examine whether PLR could guide prospective treatment selection.

A comparison of self- and observer-rated scales for detecting clinical improvement during repetitive transcranial stimulation (rTMS) treatment of depression.

Clinical outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of Major Depressive Disorder (MDD) vary widely, and no single mood rating scale is standard for assessing rTMS outcomes. This study of 708 subjects undergoing clinical rTMS compared the performance of four scales in measuring symptom change during rTMS treatment. Self-report and observer ratings were examined weekly with the Inventory of Depressive Symptomatology 30-item (IDS), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item (POMS), and Hamilton Depression Rating Scale 17-item (HDRS). While all scales were correlated and detected significant improvement, the degree of improvement over time as well as response (33-50%) and remission (20-24%) rates varied significantly. Higher baseline severity was associated with lower likelihood of remission, and greater improvement by sessions 5 and 10 predicted response across all scales. Use of only a single scale to assess outcome conferred 14-36% risk of failing to detect response/remission indicated by another scale. The PHQ was most likely to indicate improvement and least likely to miss response or remission. These findings indicate that assessment of symptom burden during rTMS treatment may be most accurately assessed through use of multiple instruments.

Neurocircuit dynamics of arbitration between decision-making strategies across obsessive-compulsive and related disorders.

Obsessions and compulsions are central components of obsessive-compulsive disorder (OCD) and obsessive-compulsive related disorders such as body dysmorphic disorder (BDD). Compulsive behaviours may result from an imbalance of habitual and goal-directed decision-making strategies. The relationship between these symptoms and the neural circuitry underlying habitual and goal-directed decision-making, and the arbitration between these strategies, remains unknown. This study examined resting state effective connectivity between nodes of these systems in two cohorts with obsessions and compulsions, each compared with their own corresponding healthy controls: OCD (nOCD = 43; nhealthy = 24) and BDD (nBDD = 21; nhealthy = 16). In individuals with OCD, the left ventrolateral prefrontal cortex, a node of the arbitration system, exhibited more inhibitory causal influence over the left posterolateral putamen, a node of the habitual system, compared with controls. Inhibitory causal influence in this connection showed a trend for a similar pattern in individuals with BDD compared with controls. Those with stronger negative connectivity had lower obsession and compulsion severity in both those with OCD and those with BDD. These relationships were not evident within the habitual or goal-directed circuits, nor were they associated with depressive or anxious symptomatology. These results suggest that abnormalities in the arbitration system may represent a shared neural phenotype across these two related disorders that is specific to obsessive-compulsive symptoms. In addition to nosological implications, these results identify potential targets for novel, circuit-specific treatments.

Neural, physiological, and psychological markers of appetitive conditioning in anorexia nervosa: a study protocol.

BACKGROUND: Anorexia nervosa (AN) is a chronic and disabling psychiatric condition characterized by low hedonic drive towards food, and is thought to be inclusive of altered dimensions of reward processing. Whether there exists a fundamental aberrancy in the capacity to acquire and maintain de novo hedonic associations-a critical component of hedonic responding-has never been studied in AN. METHODS: This multi-modal study will employ a 2-day Pavlovian appetitive conditioning paradigm to interrogate the (1) acquisition, (2) extinction, (3) spontaneous recovery and (4) reinstatement of appetitive learning in adolescents and young adults with AN. Participants will be 30 currently ill, underweight individuals with AN; 30 weight-restored individuals with AN; and 30 age-matched healthy controls, all aged 12-22 years. All subjects will undergo clinical assessment, followed by the 2-day appetitive conditioning task during which fMRI, pupillometry, heart rate deceleration, and subjective ratings will be acquired. DISCUSSION: This study will be the first to interrogate appetitive conditioning in AN-a disorder characterized by altered hedonic responding to food. Results will help establish objective biomarkers of appetitive conditioning in AN and lay the groundwork for developing novel lines of treatment for AN and other psychiatric disorders involving diminished ability to experience pleasure and reward. TRIAL REGISTRATION: Pending. INTENDED REGISTRY: Clinicaltrials.gov.

Sequential Prefrontal and Temporoparietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment of Tinnitus With and Without Comorbid Depression: A Case Series and Systematic Review.

Background: Tinnitus distress is related to both the loudness and intrusiveness of the tinnitus percept. Treatment approaches targeting both attentional/limbic and auditory systems may better alleviate tinnitus distress than approaches targeting the auditory system alone. Materials and Methods: Ten subjects with chronic tinnitus received sequential rTMS treatment involving: 1) excitatory stimulation administered to the left dorsolateral prefrontal cortex (DLPFC) or inhibitory stimulation administered to the right DLPFC, followed by 2) inhibitory stimulation administered to primary auditory cortex (Heschel's gyrus or HG). A systematic literature review was performed to evaluate the existing literature on sequential repetitive Transcranial Magnetic Stimulation (rTMS) treatment approaches for tinnitus. Results of the case series are interpreted in the context of tinnitus neurobiology and the extant literature. Results: Subjects experienced a significant decrease (average 21.7%) in symptoms on the Tinnitus Functional Index (TFI). Those with tinnitus alone experienced a greater mean symptom reduction than those with comorbid MDD (27.7 vs. 17.0%, respectively). Adverse effects were transient and minor. Literature review confirmed that sequential approaches had some advantages compared to single site rTMS; in general, the addition of 1 Hz treatment at DLPFC was superior to single site rTMS in the short term (1-12 weeks), while the addition of 20 Hz treatment at DLPFC appeared superior in the long term (90-180 days). Conclusions: Sequential rTMS approaches for the treatment of tinnitus-particularly those administering low-frequency treatment at left DLPFC-merit further investigation.

Mesolimbic Neurobehavioral Mechanisms of Reward Motivation in Anorexia Nervosa: A Multimodal Imaging Study.

Diminished motivation to pursue and obtain primary and secondary rewards has been demonstrated in anorexia nervosa (AN). However, the neurobehavioral mechanisms underlying the behavioral activation component of aberrant reward motivation remains incompletely understood. This work aims to explore this underexplored facet of reward motivation in AN. We recruited female adolescents with AN, restricting type (n = 32) and a healthy control group (n = 28). All participants underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. Diffusion MRI data was also collected to examine the reward motivation circuit's structural connectivity. Behavioral results demonstrated slower speed of reward-seeking behavior in those with AN compared with controls. Accompanying this was lower functional connectivity and reduced white matter structural integrity of the connection between the ventral tegmental area/substantia nigra pars compacta and the nucleus accumbens within the mesolimbic circuit. Further, there was evidence of neurobehavioral decoupling in AN between reward-seeking behavior and mesolimbic regional activation and functional connectivity. Aberrant activity of the bed nucleus of the stria terminalis (BNST) and its connectivity with the mesolimbic system was also evident in AN during the reward motivation period. Our findings suggest functional and structural dysconnectivity within a mesolimbic reward circuit, neurofunctional decoupling from reward-seeking behavior, and abnormal BNST function and circuit interaction with the mesolimbic system. These results show behavioral indicators of aberrant reward motivation in AN, particularly in its activational component. This is mediated neuronally by mesolimbic reward circuit functional and structural dysconnectivity as well as neurobehavioral decoupling. Based on these findings, we suggest a novel circuit-based mechanism of impaired reward processing in AN, with the potential for translation to developing more targeted and effective treatments in this difficult-to-treat psychiatric condition.

Use of right orbitofrontal repetitive transcranial magnetic stimulation (rTMS) augmentation for treatment-refractory obsessive-compulsive disorder with comorbid major depressive disorder.

We examined the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) of the right orbitofrontal cortex (OFC) in patients with refractory obsessive-compulsive disorder (OCD) and comorbid Major Depressive Disorder. All participants (n = 26) received excitatory stimulation of the left dorsolateral prefrontal cortex followed by inhibitory stimulation of bilateral supplementary motor area for 10 sessions. In 18 patients with poor early OCD response, treatment was augmented with OFC inhibitory stimulation after the tenth treatment session. Augmentation with OFC stimulation was well-tolerated, and associated with further alleviation of both OCD and depression symptoms, particularly in individuals with more severe illnesses.

Treatment of Spider Phobia Using Repeated Exposures and Adjunctive Repetitive Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

Background: Specific phobias represent the largest category of anxiety disorders. Previous work demonstrated that stimulating the ventromedial prefrontal cortex (vmPFC) with repetitive Transcranial Magnetic Stimulation (rTMS) may improve response to exposure therapy for acrophobia. Objective: To examine feasibility of accelerating extinction learning in subjects with spider phobia using intermittent Theta Burst Stimulation (iTBS) rTMS of vmPFC. Methods: In total, 17 subjects with spider phobia determined by spider phobia questionnaires [Spider Phobia Questionnaire (SPQ) and Fear of Spiders questionnaire (FSQ)] underwent ratings of fear of spiders as well as behavioral and skin conductance data during a behavioral avoidance test (BAT). Subjects then received a sequential protocol of in vivo spider exposure followed by iTBS for three sessions administered to either active or control treatment sites (vmPFC [n = 8] or vertex [n = 9], respectively), followed 1 week later by repetition of questionnaires and BAT. Results: All subjects improved significantly regardless of group across both questionnaires (FSQ η2 = 0.43, p = 0.004; SPQ η2 = 0.39, p = 0.008) and skin conductance levels during BAT (Wald χ2 = 30.9, p < 0.001). Subjects in the vmPFC group tolerated lower treatment intensity than in the control group, and there was a significant correlation between treatment intensity, BAT subjective distress improvement, and physiologic measures (all ρ > 0.5). Conclusion: This proof-of-concept study provides preliminary evidence that a sequential exposure and iTBS over vmPFC is feasible and may have rTMS intensity-dependent effects on treatment outcomes, providing evidence for future areas of study in the use of rTMS for phobias.

Distinct roles for I(T) and I(H) in controlling the frequency and timing of rebound spike responses.

The ability for neurons to generate rebound bursts following inhibitory synaptic input relies on ion channels that respond in a unique fashion to hyperpolarization. Inward currents provided by T-type calcium channels (I(T)) and hyperpolarization-activated HCN channels (I(H)) increase in availability upon hyperpolarization, allowing for a rebound depolarization after a period of inhibition. Although rebound responses have long been recognized in deep cerebellar nuclear (DCN) neurons, the actual extent to which I(T) and I(H) contribute to rebound spike output following physiological levels of membrane hyperpolarization has not been clearly established. The current study used recordings and simulations of large diameter cells of the in vitro rat DCN slice preparation to define the roles for I(T) and I(H) in a rebound response. We find that physiological levels of hyperpolarization make only small proportions of the total I(T) and I(H) available, but that these are sufficient to make substantial contributions to a rebound response. At least 50% of the early phase of the rebound spike frequency increase is generated by an I(T)-mediated depolarization. An additional frequency increase is provided by I(H) in reducing the time constant and thus the extent of I(T) inactivation as the membrane returns from a hyperpolarized state to the resting level. An I(H)-mediated depolarization creates an inverse voltage-first spike latency relationship and produces a 35% increase in the precision of the first spike latency of a rebound. I(T) and I(H) can thus be activated by physiologically relevant stimuli and have distinct roles in the frequency, timing and precision of rebound responses.