Lior Carmi

New treatment models for compulsive disorders

Obsessive compulsive disorder (OCD) as well as related disorders such as body dysmorphic disorder, tic disorder, and trichotillomania are all common and often debilitating. Although treatments are available, more effective approaches to these problems are needed. Thus this review article presents what is currently known about OCD and related disorders and suggests that understanding OCD more broadly as a compulsive disorder may allow for more effective treatment options. Toward that goal, the review presents new models of psychopharmacology and psychotherapy, as well as new brain stimulation strategies. Treatment advances, grounded in the neuroscience, have promise in advancing treatment response for OCD as well as other disorders of compulsivity.

Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients

BACKGROUNDnObsessive Compulsive Disorder (OCD) is a chronic and disabling disorder with poor response to pharmacological treatments. Converging evidences suggest that OCD patients suffer from dysfunction of the cortico-striato-thalamo-cortical (CSTC) circuit, including in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC).nnnOBJECTIVEnTo examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms.nnnMETHODSnTreatment resistant OCD participants were treated with either high-frequency (HF; 20xa0Hz), low-frequency (LF; 1xa0Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS).nnnRESULTSnInterim analysis revealed that YBOCS scores were significantly improved following HF (nxa0=xa07), but not LF stimulation (nxa0=xa08), compared to sham (nxa0=xa08), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (nxa0=xa018) was significantly higher than that of the sham group (nxa0=xa015) for at least one month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that is attributed to ACC activity.nnnCONCLUSIONnHF DTMS over the mPFC-ACC alleviates OCD symptoms and may be used as a novel therapeutic intervention. Notwithstanding alternative explanations, this may stem from DTMS ability to directly modify ACC activity.

Deep Transcranial Magnetic Stimulation (Tms) in Obsessive Compulsive Disorder (Ocd) Patients

Abstract Characterized by compulsive rituals and Obsessive thoughts, OCD is a chronic and disabling disorder. Despite converging evidence pointing towards the involvement of dysfunctional cortico-striato-thalamo-cortical circuit in OCD, the neurophysiological pathology of OCD is still not well characterized. Indeed, 40%-60% of patients do not respond adequately to standard treatments. TMS is a noninvasive therapeutic technique, recently applied to treat and investigate OCD. However, lacking the ability to target the CSTC circuit directly, standard TMS treatment protocols for OCD showed diversified results. The use of special deep TMS (dTMS) coils allows direct stimulation of deeper neuronal pathways relative to those affected by standard TMS coils. Here we evaluated whether dTMS targeting the medial prefrontal and the anterior cingulate cortices may influence symptom severity. Method 40 patients were treated with either dTMS or a sham coil for five weeks in a double-blind controlled study. The patients were divided into groups receiving either high (20Hz) or low (1Hz) stimulation frequencies, and were simultaneously administrated with symptom provocation. EEG measurements were taken at baseline and at the end of treatment. Results The active 20Hz dTMS group improved significantly in YBOCS score compared to the 1Hz and placebo groups (28% vs. 6% reduction), {t (93) = -2.29 (p=0.0243)}. Moreover, follow-up assessments revealed 3 months stability in improvements as measured by YBOCS scores. EEG evoked responses measured over the ACC correlated with clinical response. Conclusions High frequency dTMS treatment, targeting the medial prefrontal and the anterior cingulate cortices is a promising therapeutic intervention in OCD.

PTSD treatment in light of DSM-5 and the “golden hours” concept

One of the main changes in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was the separation of Stress Related Disorders from the Anxiety chapter. This separation paves the way to examine the unique characteristics of posttraumatic stress disorder (PTSD) (ie, identifiable onset, memory processes, etc) and related neural mechanisms. The time that elapses between the traumatic event and the manifestation of the disorder may also be addressed as the golden hours, or the window of opportunity in which critical processes take place and relevant interventions may be administrated.

A comparison between print vs. internet methods for a clinical trial recruitment—A pan European OCD study

Recruitment for clinical studies presents a serious challenge in terms of meeting both time and budget constraints. The internet offers a potentially powerful means for quick and effective recruitment-either as an add-on or as alternative to traditional methods. We developed a Google search based solution which enhances patient recruitment. Recruitment via internet was associated with greater exposure to relevant applicants and better response to treatment as compared to traditional printed ads.

Effects of Agomelatine on behavior, circadian expression of Period 1 and Period 2 clock genes and neuroplastic markers in the predator scent stress rat model of PTSD

Abstract Objectives: The therapeutic value of the antidepressant agomelatine in the aftermath of traumatic experience and early post-reminder has been questioned. Herein, agomelatine, its vehicle or melatonin agonist were administered either acutely 1u2009h post-stressor or repeatedly (7u2009days) after early post-reminder in a post-traumatic stress rat model (PSS) using the scent of predator urine. Methods: Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats. Results: When administered immediately after PSS, agomelatine induced a significant reduction of anxiety-like behaviour as assessed in the elevated-plus-maze and acoustic startle response at 8u2009days post-administration. Concomitantly, agomelatine significantly decreased Per1/Per2 expression in the CA1/CA3 areas, suprachiasmatic nucleus and basolateral amygdala, thereby partially restoring genes expression overregulated by PSS. Agomelatine further significantly increased cell growth and facilitated dendritic growth and arbour in dentate gyrus (DG) granule and apical CA1 cells and upregulated brain-derived neurotrophic factor protein in the DG and cortex III versus vehicle. When administered early post-reminder over 7u2009days before testing, agomelatine was ineffective on behavioural responses pattern, molecular and morphological changes induced by PSS. Conclusions: These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure.

Manifesto for a European research network into Problematic Usage of the Internet

The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.

HIGH FREQUENCY DEEP REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (dTMS) OF MEDIAL PREFRONTAL AND ANTERIOR CINGULATE CORTICES IN PATIENTS WITH OCD: A DOUBLE-BLIND, PLACEBO CONTROLLED, PERSPECTIVE MULTI-CENTER STUDY

Introduction Obsessive compulsive disorder (OCD) is a disabling disease with an annual prevalence of 1.2%. Currently approved medications only result in a reduction of symptoms for 40-60% of patients leaving most patients significantly affected. Symptom severity is correlated to the degree of hyperconnectivity in the cortico-stiriato-thalamic circuit and increased glucose metabolism in the anterior cingulate cortex during symptom provocation and at rest. Methods Ninety-four OCD patients who met inclusion/exclusion criteria (age 22-68, YBOCS≥20 despite SSRI treatment and/or CBT, stable on medications or therapy for at least two months) were randomized to receive active or sham treatment for twenty-nine sessions over six weeks. Deep transcranial magnetic stimulation(dTMS) was applied over the medial prefrontal(mPFC) and anterior cingulate cortices(ACC) using the H7 dTMS coil. Once the coil was in the treatment position, the patient’s symptoms were provoked using an individualized script tailored to the patient’s obsessions and compulsions. Subsequently, dTMS was administered for eighteen minutes at 100% resting motor threshold of the foot, 20HZ pulse frequency, in 2 second trains, with a 20 second inter-train interval totaling 2000 pulses. The sham coil was designed to have the same sound, scalp and facial sensation of the real coil without stimulating the brain directly. Results The mean age of the subjects was 38.7 (±11.75), 58.7%male, 78.8% Caucasian, mean age of onset was 13, 98% had failed medications approved for OCD and 68.7% had failed CBT. At the end of week 6 (the primary endpoint) the YBOCS decreased by 5.7 points (95% CI: [3.3;8.2]) in the dTMS arm and by 3.0 points (95% CI: [0.7;5.4]) in the control arm (p-value: 0.0157). Response (≥30% decrease/20% decrease in the YBOCS) rates were dTMS 38.10% in the dTMS arm and 11.11% in the sham arm (p-value:0.0033). Partial response rates were (≥20% decrease in the YBOCS) 54.76 in the dTMS arm and 26.67% in the sham arm (p-value: 0.0076). At week 10 (follow up) the YBOCS decreased by 6.2 points (95% CI: [3.6;8.7]) in the dTMS arm and by 3.8 points (95% CI: [1.4;6.2]) in the control arm (p-value: 0.0459). There were no serious adverse events related to the treatment. The most frequent adverse event, headache, did not differ in frequency between the two arms. Conclusions High frequency dTMS of the ACC was found to be an effective treatment for OCD. This approach is an additional intervention in the toolbox for treating OCD.

Deep transcranial magnetic stimulation of the anterior cingulate cortex in obsessive compulsive disorder patients

Objective: Evaluate whether dTMS targeting the medial prefrontal and the anterior cingulate cortices influences symptom severity in obsessive compulsive disorder (OCD). Background: Converging evidence points toward the involvement of a dysfunctional cortico-striato-thalamo-cortical (CSTC) circuit in OCD. Transcranial magnetic stimulation (TMS) has been applied to treat and investigate OCD. However, conventional TMS coils lack the ability to target the CSTC circuits directly and treatment protocols for OCD showed diversified results. The use of dTMS coils allows direct stimulation of deeper neuronal pathways relative to those affected by conventional TMS coils. We evaluated whether dTMS targeting the medial prefrontal and the anterior cingulate cortices may influence symptom severity. Methods: Forty OCD patients were treated with either dTMS H7/ HAC high (20 Hz) or low (1 Hz) stimulation frequencies or sham coil daily for five weeks in a double blind controlled study. OCD symptoms were provoked in each patient in order to activate the OCD circuitry before treatment. EEG measurements were taken at baseline and at the end of treatment. Results: The active 20 Hz dTMS group improved significantly in YBOCS score compared to the 1 Hz and sham groups (26 vs. 6% reduction), {t (93) = -2.29 (p = 0.0243)} with three month durability. EEG evoked responses over the anterior cingulate cortex correlated with clinical response, providing an objective measure, or biomarker of dTMS efficacy. Conclusions: High frequency dTMS treatment with the H7 coil, targeting the medial prefrontal and anterior cingulate cortices, is a promising therapeutic intervention in OCD. Disclosure: Drs. Zangen, Alyagon and Tendler have a financial interest in Brainsway.