Noam Barnea-Ygael

Repeated Electrical Stimulation of Reward-Related Brain Regions Affects Cocaine But Not “Natural” Reinforcement

Drug addiction is associated with long-lasting neuronal adaptations including alterations in dopamine and glutamate receptors in the brain reward system. Treatment strategies for cocaine addiction and especially the prevention of craving and relapse are limited, and their effectiveness is still questionable. We hypothesized that repeated stimulation of the brain reward system can induce localized neuronal adaptations that may either potentiate or reduce addictive behaviors. The present study was designed to test how repeated interference with the brain reward system using localized electrical stimulation of the medial forebrain bundle at the lateral hypothalamus (LH) or the prefrontal cortex (PFC) affects cocaine addiction-associated behaviors and some of the neuronal adaptations induced by repeated exposure to cocaine. Repeated high-frequency stimulation in either site influenced cocaine, but not sucrose reward-related behaviors. Stimulation of the LH reduced cue-induced seeking behavior, whereas stimulation of the PFC reduced both cocaine-seeking behavior and the motivation for its consumption. The behavioral findings were accompanied by glutamate receptor subtype alterations in the nucleus accumbens and the ventral tegmental area, both key structures of the reward system. It is therefore suggested that repeated electrical stimulation of the PFC can become a novel strategy for treating addiction.

Induction of depressive‐like effects by subchronic exposure to cocaine or heroin in laboratory rats

The effect of psychoactive drugs on depression has usually been studied in cases of prolonged drug addiction and/or withdrawal, without much emphasis on the effects of subchronic or recreational drug use. To address this issue, we exposed laboratory rats to subchronic regimens of heroin or cocaine and tested long‐term effects on (i) depressive‐like behaviors, (ii) brain‐derived neurotrophic factor (BDNF) levels in reward‐related brain regions, and (iii) depressive‐like behavior following an additional chronic mild stress procedure. The long‐term effect of subchronic cocaine exposure was a general reduction in locomotor activity whereas heroin exposure induced a more specific increase in immobility during the forced swim test. Both cocaine and heroin exposure induced alterations in BDNF levels that are similar to those observed in several animal models of depression. Finally, both cocaine and heroin exposure significantly enhanced the anhedonic effect of chronic mild stress. These results suggest that subchronic drug exposure induces depressive‐like behavior which is accompanied by modifications in BDNF expression and increases the vulnerability to develop depressive‐like behavior following chronic stress. Implications for recreational and small‐scale drug users are discussed.

Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression.

BACKGROUND Approximately one third of all major depression patients fail to respond to conventional pharmacological antidepressants, and brain stimulation methods pose a promising alternative for this population. Recently, based on repeated multifactorial selective inbreeding of rats for depressive-like behaviors, we introduced a novel animal model for MDD. Rats from this Depressive Rat Line (DRL) exhibit inherent depressive-like behaviors, which are correlated with lower levels of brain-derived neurotrophic factor (BDNF) in specific brain regions. In addition, DRL rats do not respond to antidepressant medication but respond to electroconvulsive treatment, and they can thus be utilized to test the effectiveness of brain stimulation on hereditary, medication-resistant depressive-like behaviors. OBJECTIVE To test the effect of sub-convulsive electrical stimulation (SCES) of the prelimbic cortex, using TMS-like temporal pattern of stimulation, on depressive-like behaviors and regional BDNF levels in DRL rats. METHODS SCES sessions were administered daily for 10 days through chronically implanted electrodes. Temporal stimulation parameters were similar to those used in TMS for major depression in human patients. Depressive-like behaviors were assayed after treatment, followed by brain extraction and regional BDNF measurements. RESULTS SCES normalized both the depressive-like behaviors and the reduced BDNF levels observed in DRL rats. Correlation analyses suggest that changes in specific behaviors are mediated, at least in part, by BDNF expression in reward-related brain regions. CONCLUSIONS Brain stimulation is effective in a drug-resistant, inherited animal model for depression. BDNF alterations in specific regions may mediate different antidepressant effects.

Chronic cocaine administration induces long-term impairment in the drive to obtain natural reinforcers in high- but not low-demanding tasks

Repeated drug exposure induces short‐ and long‐term neuroadaptations in brain reward circuitries that are normally involved in the regulation of motivation. Hence, repeated drug exposure has been suggested to also affect the drive to acquire natural reinforcers. Here, we tested how chronic exposure of rats to cocaine, as well as a subsequent withdrawal period, affects acquisition of natural reinforcers in high‐ and low‐demanding tasks (HD and LD tasks, respectively). We chronically administered cocaine (i.p., 15 mg/kg once daily, or saline in control) for 30 days, followed by a 30‐day withdrawal period. We tested the effect of this treatment on the acquisition of two natural appetitive reinforcers, namely self‐administering a 10% sucrose solution and mounting a receptive female, under LD and HD conditions. During the cocaine exposure period, behavioral testing took place 18 hours after cocaine injection, namely after the acute pharmacologic effect of the drug dissipated. We show that chronic i.p. cocaine exposure decreased procurement of both reinforcers in HD but not in LD tasks. The effect was observed throughout the administration period with partial recovery after withdrawal. Taken together, we present empirical evidence that chronic exposure to a constant dose of cocaine is sufficient to reduce natural reinforcement, and that this decrease can outlast drug exposure. Importantly, such effects are observed only when high demands are opposing the consumption of the natural reinforcer.

Alternative antidepressant deep transcranial magnetic stimulation protocols

Overview: The clinical outcomes in a multisite clinical TMS practice were analyzed and profiled. A series 109 patients with Major Depression were treated in 2015 with an iron core figure eight TMS coil. Outcomes were assessed by PHQ-9 and BDI-II at onset of treatment and weekly thereafter. Patients included 56 females and 53 males with an average age of 45. The population overall had severe symptoms of depression with an average PHQ-9 of 19.7 and BDI-II of 38.6 at baseline. Results: Patients received an average of 41 TMS treatments. When measured by at least one of the two measures, there was an overall response rate in 76% (80% in female and 72% in males) and a remission rate of 56% with average decreases of 12.4 in the PHQ-9 and 23.9 in the BDI-II. Overall there were few differentiating characteristics between remitters, responders, and non-responders, including no correlation with age or handedness. Factors corresponding with improved response were female sex, increased number of treatments, and lower baseline score on the baseline BDI-II. Remitters presented with lower average baseline BDI-II scores than responders and non-responders (36.0 versus 40.5 and 37.6) and underwent higher average number of treatments (42.2 sessions versus 31.3 and 37.3, respectively). Response as measured by PHQ-9 was statistically significantly correlated to sex (p1⁄40.01) and number of treatments (p1⁄40.005). BDI-II response rate also correlated with number of treatments (p1⁄40.04). Chi-square analysis demonstrated a statistically significant difference between males and females in response measured with PHQ-9 (p1⁄40.04). 11 LOW FREQUENCY RTMS AMELIORATES AKATHISIA: CASE REPORT Jos e Luis Guerrero Solano , Elena Molina Pacheco , Julio I. Prieto Montalvo , Alejandro Marfil Rivera . 1 Department of Clinical Neurophysiology, Hospital Angeles Valle Oriente, Mexico; 2 Department of Internal Medicine, University General Hospital of Albacete, Spain; 3 Department of Clinical Neurophysiology, Gregorio Mara~ n on University General Hospital, Spain; 4 Department of Clinical Neurology, “Dr. Jos e Eleuterio Gonzalez” University General Hospital, Mexico Introduction: Akathisia is a common side effect of psychotropic medications, including selective serotonin reuptake inhibitors (SSRI). Recently, a mechanism in which compensatory increased noradrenergic activity is triggered by dopamine reduction has been proposed1. We report the use of rTMS in a 34 year old, 20 weeks gestation patient, with chronic akathisia after taking fluoxetine (SSRI) that worsened with pregnancy. The patient referred mild to moderate akathisia from head to toes, but being severe and presenting most of the times just over left extremities 1,2. Methods: We applied a single session of 1200 pulses of low frequency rTMS over right M1, at 90% of the resting motor threshold (RMT), since low frequency stimulation over M1 has shown to reduce dopaminergic activity and cortical excitability3,4. RMT and cortical silent period (CSP) were measured on both sides before the rTMS session, and after 600 and 1200 pulses; finding a RMT 7% difference, being lower on the right cortex, and no differences on the CSP.

How to Use the H1 Deep Transcranial Magnetic Stimulation Coil for Conditions Other than Depression

Deep transcranial magnetic stimulation (dTMS) is a relatively new technique that uses different coils for the treatment of different neuropathologies. The coils are made of soft copper windings in multiple planes that lie adjacent to the skull. They are located within a special helmet so that their magnetic fields combine and improve depth penetration. The H1 dTMS coil is designed to stimulate bilateral prefrontal cortices with greater effective stimulation over the left than the right. By positioning the left side of the coil close to the left dorsolateral prefrontal cortex (DLPFC), the H1 coil was used in a multisite study, leading to FDA approval for treatment-resistant depression. In this same position, the H1 coil was also explored as a possible treatment for negative symptoms of schizophrenia, bipolar depression, and migraine. When moved to different positions over the subjects skull, the H1 coil was also explored as a possible treatment for other conditions. Such manipulation of the H1 coil was demonstrated for PTSD and alcohol dependence by positioning it over the medial prefrontal cortex (mPFC), for anxiety by positioning it over the right prefrontal cortex (rPFC), for auditory hallucinations and tinnitus by positioning it over the temporoparietal junction (TPJ), and for Parkinsons and fatigue from multiple sclerosis (MS) by positioning it over the motor cortex (MC) and PFC. Corresponding electrical field diagrams measured with an oscilloscope through a saline-filled head are included.

Antidepressant remission to dTMS of the dmPFC and ACC in lateral PFC dTMS nonresponders: Case series

• Patients who failed H1 dTMS to the L DLPFC were administered H7 dTMS to the dmPFC and ACC resulting in 56% remission.