Abnormal functional asymmetry and its behavioural correlates in adults with ADHD: A TMS-EEG study.

OBJECTIVES: Abnormal functional brain asymmetry and deficient response inhibition are two core symptoms of attention deficit hyperactivity disorder (ADHD). We investigated whether these symptoms are inter-related and whether they are underlined by altered frontal excitability and by compromised interhemispheric connectivity. METHODS: We studied these issues in 52 ADHD and 43 non-clinical adults by comparing: (1) stop-signal reaction time (SSRT); (2) frontal asymmetry of the N200 event-related potential component, which is evoked during response inhibition and is lateralised to the right hemisphere; (3) TMS-evoked potential (TEP) in the right frontal hemisphere, which is indicative of local cortical excitability; and (4) frontal right-to-left interhemispheric TMS signal propagation (ISP), which is reversely indicative of interhemispheric connectivity. RESULTS: Compared to controls, the ADHD group demonstrated elongated SSRT, reduced N200 right-frontal-asymmetry, weaker TEP, and stronger ISP. Moreover, in the ADHD group, N200 right-frontal-asymmetry correlated with SSRT, with TEP, and with symptoms severity. Conversely, no relationship was observed between ISP and N200 right-frontal-asymmetry, and both TEP and ISP were found to be unrelated to SSRT. CONCLUSIONS: Our results indicate that abnormal frontal asymmetry is related to a key cognitive symptom in ADHD and suggest that it is underlined by reduced right-frontal excitability.

Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices.

BACKGROUND: Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS: This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS: Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS: We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.

Repetitive Transcranial Magnetic Stimulation With H-Coil Coupled With Cycling for Improving Lower Limb Motor Function After Stroke: An Exploratory Study.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke. MATERIALS AND METHODS: Twelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study. Eleven sessions of HF-rTMS (40 2s-trains of 20 Hz at 90% resting leg motor threshold) were delivered over the LE motor areas using the H-coil during active cycling for three weeks. Each subject underwent both real and sham rTMS treatments separated by a four-week washout period, in a random sequence. Vital signs were recorded before and after each rTMS session. Any discomfort related to stimulation and side effects were recorded. LE function was also evaluated with Fugl-Meyer assessment (FMA-LE), spasticity was assessed with modified-Ashworth scale and measures of gait speed and endurance (10-meter and 6-min walk tests, respectively) were recorded. RESULTS: No participant reported serious adverse effects. During real rTMS, 4 of 12 subjects reported mild side effects including transitory dizziness and muscle twitches on shoulder, so that intensity of stimulation initially set at 90% of RMT was reduced to 80% of RMT on average in these four subjects. Only real treatment was associated with a significant and sustained improvement in FMA-LL (67% responders vs. 9% of the sham). Spasticity significantly ameliorated only after the real rTMS. Real treatment did not offer advantages on walking timed measures when compared with sham. CONCLUSIONS: This exploratory study suggests that bilateral HF-rTMS combined with cycling is safe and potentially effective in ameliorating paretic LE motor function and spasticity, rather than gait speed or endurance, in chronic stroke.

Prisoners of Addictive Cues: Biobehavioral Markers of Overweight and Obese Adults with Food Addiction.

Obesity is associated with food and eating addiction (FA), but the biobehavioral markers of this condition are poorly understood. To characterize FA, we recruited 18 healthy controls and overweight/obese adults with (n = 31) and without (n = 17) FA (H-C, FAOB, NFAOB, respectively) to assess alpha brain asymmetry at rest using electroencephalogram; event-related potentials following exposure to high-calorie food (HCF), low-calorie food (LCF), and nonfood (NF) images in a Stroop paradigm; reaction time reflective of the Stroop bias; and symptoms of depression and disordered eating behavior. The FAOB group had the greatest emotional and uncontrollable eating, depressive, and binge-eating symptoms. The FAOB group displayed lower resting left alpha brain asymmetry than that of the NFAOB group. Differently from the other groups, the FAOB group presented attenuated Stroop bias following exposure to HCF relative to NF images, as well as a lower late positive potential component (LPPb; 450-495 ms) in both frontal and occipital regions. In the total cohort, a correlation was found between the Stroop bias and the LPPb amplitude. These results point to biobehavioral hypervigilance in response to addictive food triggers in overweight/obese adults with FA. This resembles other addictive disorders but is absent in overweight/obesity without FA.

Alleviation of ADHD symptoms by non-invasive right prefrontal stimulation is correlated with EEG activity.

Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder with effective pharmacological treatment that benefits most patients. However, about one-third fail to benefit while others search non-pharmacological alternatives, and for those options are scarce. One alternative treatment option is to alter abnormal right prefrontal cortex (rPFC) activity, given that rPFC abnormality has been repeatedly implicated in ADHD neurophathology. Here, we evaluated whether targeting the rPFC with multiple sessions of repetitive transcranial magnetic stimulation (rTMS), which can modulate neuronal excitability, activity, and plasticity in a non-invasive manner, will affect clinical symptoms in adults suffering from ADHD. Concomitantly, we used EEG to characterize electrophysiological alterations induced by treatment and to search for correlation between baseline neuronal activity and clinical response. Forty-three drug free adults with ADHD were randomized to receive either Real, Active Control, or Sham treatment (13 females, age ranging 21-46; n = 15, 14, 14, respectively), and underwent three weeks of daily high-frequency (18 Hz) stimulation sessions. We found that Real treatment was safe and resulted in significant improvement of symptoms (η2p = 0.34; Cohen's d(against Sham) = 0.96; Cohen's d(against AC) = 0.68; p = 0.00085). Furthermore, based on EEG recorded within the first treatment session we established a novel biomarker, composed of the Alpha and Low-gamma power, which highly correlated the magnitude of the clinical outcome (r = 0.92, p = 0.0001). Taken together, the results of this pilot study indicate safety and effectiveness of rTMS directed to the rPFC for treatment of adult ADHD patients. The biomarker is suggested to reflect the responsiveness of the cortex to this rTMS intervention. Following validation of the results in larger samples, this study may represent a step towards a non-pharmacological treatment for adults with ADHD using EEG-based selection of optimal candidates for treatment.

Interhemispheric cortico-cortical paired associative stimulation of the prefrontal cortex jointly modulates frontal asymmetry and emotional reactivity.

BACKGROUND: As advances in neuroimaging further our understanding of the brain's functional connectivity, neuropsychology has moved away from a regional approach of attributing behavior to a specific region towards a network approach, attributing behavior to interconnected regions. A prime example of this is the suggested relevance of frontal asymmetry of the lateral prefrontal cortex (LPFC) in emotional processing. Yet, while neuroimaging defines relevant networks, it can only establish correlations and not causality. OBJECTIVE: We address this deficiency by applying cortico-cortical paired associative stimulation (ccPAS) to twenty-seven healthy, human participants (both genders represented equally). ccPAS involves TMS applied to two brain regions contemporaneously, changing the connectivity via Hebbian mechanisms. METHODS: We evaluate modifications in connectivity following ccPAS between the right and left LPFC that are dependent on the direction of ccPAS, i.e., which hemisphere is stimulated first. Participants performed an emotional reactivity task, assessed by measuring attentional bias, and brain activity was recorded with electroencephalogram (EEG) both at rest and in response to TMS pulses. RESULTS: We find that ccPAS modulates attentional bias bidirectionally depending on the order of stimulation. Furthermore, this modulation is accompanied by a change in frontal asymmetry. Measuring the direction of the information flow using TMS evoked potentials provides evidence that ccPAS strengthens inhibition from the hemisphere stimulated first to the hemisphere stimulated second. CONCLUSIONS: Our findings provide causal evidence for the role of frontal asymmetry in emotional processing and establish ccPAS combined with the EEG measures as a tool to causally characterize functionality of neuronal circuits.

Randomised sham-controlled study of high-frequency bilateral deep transcranial magnetic stimulation (dTMS) to treat adult attention hyperactive disorder (ADHD): Negative results.

OBJECTIVES: Recent studies support the possible effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a treatment for attention deficit hyperactivity disorder (ADHD). The objective of this study was to evaluate the safety and possible efficacy of bilateral prefrontal deep rTMS for the treatment of adult ADHD. METHODS: Twenty-six adult ADHD patients were randomised blindly to sham or actual deep TMS (dTMS). Twenty daily sessions were conducted using the bilateral H5 dTMS coil (Brainsway, IL) in order to stimulate the prefrontal cortex at 120% of the motor threshold at high frequency. For assessment, Conners' Adult ADHD Rating Scale questionnaire and a computerised continuous performance test, Test of Variables of Attention, were used. RESULTS: No differences in clinical outcomes were detected between the actual dTMS and sham groups. CONCLUSIONS: The presented evidence does not support the utility of bilateral prefrontal stimulation to treat adult ADHD. Due to the small sample size, caution must be exercised in interpreting our preliminary findings.

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

BACKGROUND: Obsessive 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). OBJECTIVE: To examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms. METHODS: Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), 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). RESULTS: Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) 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. CONCLUSION: HF 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.

Answering the missed call: Initial exploration of cognitive and electrophysiological changes associated with smartphone use and abuse.

BACKGROUND: Smartphone usage is now integral to human behavior. Recent studies associate extensive usage with a range of debilitating effects. We sought to determine whether excessive usage is accompanied by measurable neural, cognitive and behavioral changes. METHOD: Subjects lacking previous experience with smartphones (n = 35) were compared to a matched group of heavy smartphone users (n = 16) on numerous behavioral and electrophysiological measures recorded using electroencephalogram (EEG) combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex (rPFC). In a second longitudinal intervention, a randomly selected sample of the original non-users received smartphones for 3 months while the others served as controls. All measurements were repeated following this intervention. RESULTS: Heavy users showed increased impulsivity, hyperactivity and negative social concern. We also found reduced early TMS evoked potentials in the rPFC of this group, which correlated with severity of self-reported inattention problems. Heavy users also obtained lower accuracy rates than nonusers in a numerical processing. Critically, the second part of the experiment revealed that both the numerical processing and social cognition domains are causally linked to smartphone usage. CONCLUSION: Heavy usage was found to be associated with impaired attention, reduced numerical processing capacity, changes in social cognition, and reduced right prefrontal cortex (rPFC) excitability. Memory impairments were not detected. Novel usage over short period induced a significant reduction in numerical processing capacity and changes in social cognition.

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.

Response inhibition in preschoolers at familial risk for attention deficit hyperactivity disorder: a behavioral and electrophysiological stop-signal study.

Children participating in the Ben-Gurion Infant Development Study were assessed with a dynamic-tracking version of the stop-signal task at the age of 5 years. The sample consisted of 60 males. Stop-signal reaction time (SSRT) was correlated with concurrent ratings of the child's attention deficit hyperactivity disorder (ADHD) symptoms. Paternal symptoms measured in the child's early infancy predicted the child's performance in the stop-signal task: Paternal inattentiveness predicted SSRT, whereas hyperactivity predicted error proportion. Maternal symptoms were not correlated with the performance of the child in the task. A subsample of children, who were tested while electrophysiological brain activity was measured, showed that having higher ADHD symptomatology, especially hyperactivity, correlated with less activity in the brain areas that are usually recruited by children for successful inhibition.

Fear-related pictures deteriorate the performance of university students with high fear of snakes or spiders.

Despite research regarding emotional processing, it is still unclear whether fear-evoking stimuli are processed when they are irrelevant and when attention is oriented elsewhere. In this study, 63 healthy university students with high fear from snakes or spiders participated in two different experiments. In an emotional modification of the spatial cueing task, 31 subjects (5 males) were asked to detect a target letter while ignoring a neutral or fear-related distracting picture. The distribution of attention was independently manipulated by a spatial cue that preceded the appearance of the picture and the target letter. In an emotional modification of the cognitive load paradigm, 32 subjects (4 males) were asked to discriminate between two target letters, while ignoring a central neutral or fear-related picture, and additional 1, 3, or 5 distracting letters that created a varied attentional load. Fear-related pictures interfered with the performance of highly fearful participants, even when the pictures were presented outside the focus of attention and when the task taxed attentional resources. We suggest that highly fearful individuals process fear-related information automatically, either inattentively or with prioritized attention capture over competing items, leading to deteriorated cognitive performance. Different results were shown in healthy individuals while processing negative--but not phobic--pictures, suggesting that emotional processing depends on the fear value of the stimulus for a specific observer.