The effects of TENS, interferential stimulation, and combined interferential stimulation and pulsed ultrasound on patients with disc herniation-induced radicular pain.

BACKGROUND: Electrotherapy is part of a physician's toolbox for treating various musculoskeletal conditions, including radicular pain, but the preferred modality is yet unclear. OBJECTIVE: To compare the short-term efficacy of three electrotherapeutic modalities in relieving lumbar disc herniation (LDH)-induced radicular pain. METHODS: Fourteen patients with LDH-induced radicular pain attended a single session of electrotherapy, which included four 10-min consecutive treatments: transcutaneous electrical nerve stimulation (TENS), interferential (IF) stimulation, a combined treatment with pulsed ultrasound and IF current (CTPI), and a sham control. Treatments were randomized and the straight leg raise (SLR) degree was measured immediately before and after each treatment. RESULTS: Each of the three active modalities significantly improved the SLR score. The most prominent improvement was observed in the CTPI condition, followed by IF and, finally, TENS. The sham stimulation did not affect the SLR scores. CONCLUSIONS: A single session with either TENS, IF current or CTPI is sufficient to improve the range of motion and degree of radicular pain associated with LDH. CTPI appears to be the most effective modality of the three, possibly due to greater penetration efficiency of the induced current. The effects of a long-term treatment schedule are yet to be identified.

Methylphenidate reduces orienting bias in healthy individuals.

BACKGROUND: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. AIM: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. METHODS: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. RESULTS/OUTCOMES: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. CONCLUSIONS/INTERPRETATIONS: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

Reducing Stigma Toward Psychiatry Among Medical Students: A Multicenter Controlled Trial.

OBJECTIVE: To examine the effect of a novel antistigma intervention curriculum (ASIC) in reducing stigma toward psychiatry among medical students. METHODS: Medical students from 8 hospitals in central Israel were divided into intervention (n = 57) and control (n = 163) arms. The students completed the 30-item Attitudes Toward Psychiatry (ATP-30) and the Attitudes Toward Mental Illness (AMI) scales at psychiatry rotation onset and conclusion. The ASIC was designed to target prejudices and stigma through direct informal encounters with people with serious mental illness (SMI) during periods of remission and recovery. Supervised small-group discussions followed those encounters to facilitate processing of thoughts and emotions that ensued and to discuss salient topics in psychiatry. The study was conducted between November 2017 and July 2018. RESULTS: Significant between-group differences were found at endpoint for attitudes toward psychiatry and psychiatric patients (P < .001). Although changing attitudes toward psychiatry as a career choice was not part of the ASIC, a significant between-group difference emerged by endpoint (P < .001). CONCLUSIONS: Implementation of an ASIC that includes contact with individuals with lived SMI experience followed by supervised small-group discussions is effective in reducing stigma in medical students' perceptions of people with mental illness and psychiatry. Further evaluation is warranted with regard to the long-term destigmatizing effects of an ASIC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03907696.

Initial Evaluation of Pain Intensity Among Depressed Patients as a Possible Mediator Between Depression and Pain Complaints.

Pain complaints are frequently described by depressed patients, and are mostly attributed to abnormal pain perception and modulation. The present study aimed to assess whether a unique pain processing profile differentiates depressed patients from healthy controls. Participants were 25 patients suffering from a moderate-severe unipolar depressive episode and 25 age and sex-matched healthy controls. Thermal stimuli were used to assess sensory threshold and pain threshold. Pain-60 temperature (temperature that induces pain ratings of 60 out of 100) was the first noxious stimuli to be administered during the experimental session. Central pain inhibition was assessed via conditioned pain modulation (CPM) and the degree of central nervous system excitability was assessed via mechanical temporal summation. Depressed patients reported higher levels of pain compared with healthy controls, and a significantly higher perceived pain during the last month. Additionally, they displayed significantly lower pain-60 temperature values compared with healthy controls (p = 0.01). Otherwise, no significant group differences were found in measures of pain perception and modulation. Our results suggest that the initial evaluation of pain intensity among depressed patients, as validated by pain-60 temperature values, is increased compared with healthy controls, and might be the mediator between depression and pain complaints. Possibly, depressed patients' negative bias in the processing of pain is similar to their processing pattern of facial expression or future events. Further studies are necessary in order to establish the mechanisms underlying the excessive pain complaints reported by patients with unipolar depression.

Efficiency of Tissue Penetration by Currents Induced by 3 Electrotherapeutic Techniques: A Comparative Study Using a Novel Deep-Tissue Measuring Technique.

BACKGROUND: Electrotherapy provides a wide range of treatment alternatives for musculoskeletal pathologies. However, for the electrical stimulation to exert a significant therapeutic effect, the induced current must often penetrate deep inside the target tissue. OBJECTIVE: The objective was to systematically compare the penetration efficiency of 3 electrotherapeutic stimulation modalities: transcutaneous electrical nerve stimulation (TENS), interferential (IF) stimulation, and combined therapy with pulsed ultrasound and IF current (CTPI). DESIGN: This was a comparative, experimental laboratory study. METHODS: The penetration efficiency was evaluated as a voltage difference between 2 of an 8-contact spinal cord stimulation array. Each of 20 participants with a preimplanted spinal cord stimulation array was stimulated with TENS (3 different electrode configurations), IF current (3 configurations), and CTPI (1 configuration). RESULTS: Significant differences in penetration efficiency were found between the various stimulation conditions and electrode configurations. CTPI showed the highest penetration efficiency, followed by IF, and finally TENS. Penetration efficiency was inversely and significantly correlated with skinfold thickness in all conditions, but this correlation was lowest for the CTPI stimulation. LIMITATIONS: Our study design did not include a condition of combined therapy with pulsed ultrasound and TENS, and it did not directly control for current or voltage density under the stimulating electrodes. In addition, further research is required to determine whether a higher stimulation intensity of the target tissue is advantageous clinically. CONCLUSIONS: Pending further testing, CTPI stimulation could prove more effective than IF and TENS in reaching deeper tissues, especially considering the variability in adipose tissue thickness in the population, for example, in cases of patients with obesity.

MEG resting-state oscillations and their relationship to clinical symptoms in schizophrenia.

Neuroimaging studies suggest that schizophrenia is characterized by disturbances in oscillatory activity, although at present it remains unclear whether these neural abnormalities are driven by dimensions of symptomatology. Examining different subgroups of patients based on their symptomatology is thus very informative in understanding the role of neural oscillation patterns in schizophrenia. In the present study we examined whether neural oscillations in the delta, theta, alpha, beta and gamma bands correlate with positive and negative symptoms in individuals with schizophrenia (SZ) during rest. Resting-state brain activity of 39 SZ and 25 neurotypical controls was recorded using magnetoencephalography. Patients were categorized based on the severity of their positive and negative symptoms. Spectral analyses of beamformer data revealed that patients high in positive symptoms showed widespread low alpha power, and alpha power was negatively correlated with positive symptoms. In contrast, patients high in negative symptoms showed greater beta power in left hemisphere regions than those low in negative symptoms, and beta power was positively correlated with negative symptoms. We further discuss these findings and suggest that different neural mechanisms may underlie positive and negative symptoms in schizophrenia.

Efficacy, tolerability, and cognitive effects of deep transcranial magnetic stimulation for late-life depression: a prospective randomized controlled trial.

Late-life depression (LLD) is a growing worldwide problem due to demographic changes, with limited treatment options due to high rates of pharmacotherapy adverse effects, accessibility of psychotherapy, and tolerability of electroconvulsive therapy. Novel neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), may overcome these limitations. The objective of this study is to determine the efficacy, tolerability, and cognitive effects of high-dose deep rTMS in LLD. In this study we randomized older adults between 60 and 85 years old with major depressive disorder (MDD) to sham or active deep rTMS (H1 coil, 6012 pulses, 18 Hz, 120% of resting motor threshold) delivered over the dorsolateral and ventrolateral prefrontal cortex 5 days per week over 4 weeks. Our primary outcome was remission of depression in an intention-to-treat analysis. We also assessed change in cognitive functioning with rTMS treatment and tolerability based on adverse effects. Fifty-two participants were randomized to active (n = 25) or sham H1 coil (n = 27). Remission rate was significantly higher with active than sham rTMS (40.0% vs 14.8%) with a number needed to treat of 4.0 (95% CI: 2.1-56.5). There was no change on any measure of executive function and no serious adverse events. Adverse effect profiles were similar between active and sham rTMS, except for reports of pain being significantly more common in the active condition (16.0% vs 0%). High-dose deep rTMS appears to be safe, well tolerated, and efficacious in the treatment of LLD.

The effect of methylphenidate on decision making in patients with borderline personality disorder and attention-deficit/hyperactivity disorder.

Impaired decision making in patients with borderline personality disorder (BPD) has been reported in several studies. Although methylphenidate (MPH) is known to ameliorate impaired decision making in patients with attention-deficit/hyperactivity disorder (ADHD), it has not yet been examined in patients with BPD. We therefore assessed the efficacy of a single dose of MPH on cognitive functions and decision making in patients with BPD. Twenty-two patients diagnosed with BPD participated in the study. The study was a randomized, double-blind placebo-controlled, random block order cross-over trial. Patients participated in two sessions and performed the Test of Variables of Attention, a digit-span test, and the computerized Iowa Gambling Task, after they had been administered either the MPH or a placebo. ADHD symptoms were assessed using the Adult ADHD Self-Report Scale-18. Lower scores on the inattention symptoms scale were associated with a greater improvement in decision making following the administration of MPH when compared with improvements in patients with higher ADHD scores [F(1,17)=5.63, P=0.030]. We conclude that MPH may improve decision making in patients with BPD, although this effect is mediated by the level of ADHD symptoms. Further studies are needed to assess whether a prolonged beneficial effect of MPH on decision making in patients with BPD might also be present in 'real life'.

[BIPOLAR DISORDER AS A MULTI-SYSTEM ILLNESS].

INTRODUCTION: Bipolar disorder is a chronic condition, characterized by high distress in patients and high suicide rates (30%). Most patients suffer from medical and other psychiatric comorbidities, which worsen the psychiatric symptoms and decrease the likelihood of remission. More than 70% of bipolar patients have cardio-metabolic symptoms, with higher rates compared to other psychiatric disorders. Cardiovascular disease is the major cause of high mortality rates in these patients, with 1.5-2 fold increased risk of mortality, compared to the general population without psychiatric symptoms. The rates of cardiovascular risk factors and their resulting increased mortality rates are similar to those found in schizophrenia. In addition to cardio-metabolic conditions, 50% of patients with bipolar disorder suffer from other medical symptoms, which are also associated with worse outcomes. Therefore, the current perspective is that bipolar disorder is not only a psychiatric disorder, but rather a multi-system illness, affecting the entire body. The optimal treatment for these patients should include diagnosis, monitoring and treatment of both psychiatric and physical symptoms, which would improve their prognosis.

Methylphenidate Reduces State Anxiety During a Continuous Performance Test That Distinguishes Adult ADHD Patients From Controls.

OBJECTIVE: We hypothesized that patients with ADHD were typified by distress more than by functional difficulties. Thus, a decline in state anxiety while performing a cognitive task when taking methylphenidate would discriminate between ADHD patients and controls. METHOD: State anxiety and cognitive performance on a continuous performance test were assessed in ADHD patients and controls with and without taking methylphenidate. RESULTS: State anxiety and cognitive performance improved from baseline in 36 ADHD adults after taking methylphenidate. In 25 controls, cognitive performance improved, but state anxiety did not abate after a recess. In two additional studies, 5 controls were evaluated at baseline and after receiving methylphenidate, and showed improvement in cognitive assessment but not in state anxiety. Five ADHD adults were assessed at baseline and after a recess, and showed no improvement. CONCLUSION: Our results support the hypothesis that adult ADHD patients are characterized by distress and the relief of this distress under effective therapy as expressed by a decline in state anxiety while they perform a cognitive task.

Diminished Auditory Responses during NREM Sleep Correlate with the Hierarchy of Language Processing.

Natural sleep provides a powerful model system for studying the neuronal correlates of awareness and state changes in the human brain. To quantitatively map the nature of sleep-induced modulations in sensory responses we presented participants with auditory stimuli possessing different levels of linguistic complexity. Ten participants were scanned using functional magnetic resonance imaging (fMRI) during the waking state and after falling asleep. Sleep staging was based on heart rate measures validated independently on 20 participants using concurrent EEG and heart rate measurements and the results were confirmed using permutation analysis. Participants were exposed to three types of auditory stimuli: scrambled sounds, meaningless word sentences and comprehensible sentences. During non-rapid eye movement (NREM) sleep, we found diminishing brain activation along the hierarchy of language processing, more pronounced in higher processing regions. Specifically, the auditory thalamus showed similar activation levels during sleep and waking states, primary auditory cortex remained activated but showed a significant reduction in auditory responses during sleep, and the high order language-related representation in inferior frontal gyrus (IFG) cortex showed a complete abolishment of responses during NREM sleep. In addition to an overall activation decrease in language processing regions in superior temporal gyrus and IFG, those areas manifested a loss of semantic selectivity during NREM sleep. Our results suggest that the decreased awareness to linguistic auditory stimuli during NREM sleep is linked to diminished activity in high order processing stations.

Neuromodulation of Attentional Control in Major Depression: A Pilot DeepTMS Study.

While Major Depressive Disorder (MDD) is primarily characterized by mood disturbances, impaired attentional control is increasingly identified as a critical feature of depression. Deep transcranial magnetic stimulation (deepTMS), a noninvasive neuromodulatory technique, can modulate neural activity and induce neuroplasticity changes in brain regions recruited by attentional processes. This study examined whether acute and long-term high-frequency repetitive deepTMS to the dorsolateral prefrontal cortex (DLPFC) can attenuate attentional deficits associated with MDD. Twenty-one MDD patients and 26 matched control subjects (CS) were administered the Beck Depression Inventory and the Sustained Attention to Response Task (SART) at baseline. MDD patients were readministered the SART and depressive assessments following a single session (n = 21) and after 4 weeks (n = 13) of high-frequency (20 Hz) repetitive deepTMS applied to the DLPFC. To control for the practice effect, CS (n = 26) were readministered the SART a further two times. The MDD group exhibited deficits in sustained attention and cognitive inhibition. Both acute and long-term high-frequency repetitive frontal deepTMS ameliorated sustained attention deficits in the MDD group. Improvement after acute deepTMS was related to attentional recovery after long-term deepTMS. Longer-term improvement in sustained attention was not related to antidepressant effects of deepTMS treatment.

Deep TMS add-on treatment for intractable Tourette syndrome: A feasibility study.

OBJECTIVES: In a considerable minority of patients who suffer from Tourette syndrome (TS) the disorder persists into adulthood and is associated with severe symptoms and limited therapeutic options. Repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) has shown promising therapeutic results. Deep rTMS is a novel technology that enables deeper non-invasive cortical stimulation. This open-label pilot study is the first to examine the possible role of deep rTMS as add-on treatment for intractable TS. METHODS: Twelve patients were recruited in order to examine bilateral SMA inhibition via deep TMS using the HBDL coil, as a possible treatment for adult TS treatment-resistant patients. Two patients did not complete the 20-day study protocol. RESULTS: There were no significant side effects. While tics did not improve among the group as a whole, the subgroup of six patients with combined TS and OCD (obsessive compulsive syndrome) showed significant improvement in tic severity (P = 0.037). CONCLUSIONS: These findings support the safety of deep rTMS for treating TS. The results also highlight the importance of studying the different TS syndromes separately (e.g., with or without OCD comorbidity) when evaluating deep rTMS protocols for TS patients.

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Impairments of event-related magnetic fields in schizophrenia patients with predominant negative symptoms.

Recently there is a growing understanding that patients suffering from negative symptoms of schizophrenia represent a distinct patient population. However, despite the abundance of EEG studies characterizing schizophrenia patients in general, only a handful of studies have focused on the electrophysiological correlates of negative symptoms. The current study examined whether the impairments in event-related magnetic fields (ERFs) commonly reported in heterogeneous groups of patients with mixed positive and negative symptoms also occur in patients with predominantly negative symptoms, and investigated their correlation to clinical symptoms and cognitive deficits. Twenty schizophrenia patients suffering from predominant negative symptoms and 25 healthy subjects underwent neuropsychological and electromagnetic assessments. ERFs were recorded during a three-stimuli novelty oddball and a sensory gating paradigm, and M50, P300m and Novelty-P3m components were investigated. Patients displayed impaired M50 ratios, reduced left P300m and frontal Novelty-P3m amplitudes. These electromagnetic measures correlated significantly with the severity of negative symptoms (SANS scale). The electrophysiological abnormalities which have been proposed as candidate biomarkers for schizophrenia are also manifested in patients with predominantly negative symptoms.

Magnetoencephalographic evidence of early right hemisphere overactivation during metaphor comprehension in schizophrenia.

Whereas language processing in neurotypical brains is left lateralized, individuals with schizophrenia (SZ) display a bilateral or reversed pattern of lateralization. We used MEG to investigate the implications of this atypicality on fine (left hemisphere) versus coarse (right hemisphere) semantic processing. Ten SZ and 14 controls were presented with fine (conventional metaphor, literal, and unrelated expressions) and coarse (novel metaphor) linguistic stimuli. Results showed greater activation of the right hemisphere for novel metaphors and greater bilateral activation for unrelated expressions at the M170 window in SZ. Moreover, at the M350, SZ showed reduced bilateral activation. We conclude that SZ are overreliant on early-stage coarse semantic processing. As a result, they jump too quickly to remote conclusions, with limited control over the meanings they form. This may explain one of the core symptoms of the disorder-loose associations.

Early post-stressor intervention with minocycline, a second-generation tetracycline, attenuates post-traumatic stress response in an animal model of PTSD.

We assessed the effects of minocycline, a tetracycline with anti-inflammatory, anti-apoptotic and neuroprotective capacities, in an animal model of post-traumatic stress disorder (PTSD). Rats were exposed to psychogenic stress and treated 1h later with minocycline or saline. Behavioral measures included the elevated plus-maze (EPM) and acoustic startle response (ASR) 7 days post stress-exposure. One day after behavioral testing, animals were exposed to a trauma cue and freezing response was assessed. Local levels of cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the hippocampus, frontal cortex (FC) and hypothalamus were then examined. Minocycline attenuated anxious-like behaviors in stress-exposed rats. In addition, decreased levels of cytokines were measured in exposed rats treated with minocycline compared to their counterparts treated with saline. This study suggests a potential use of minocycline in preventing physiological and behavioral alternations resulting from acute exposure to psychological stress. As this is the first study to report beneficial outcomes for minocycline treatment in an animal model of PTSD, further investigations of the use of minocycline in stress-related conditions with emphasis on PTSD is needed.

Double-blind, randomized sham controlled study of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia.

Negative symptoms and cognitive deficits are considered core symptoms of schizophrenia, yet treatment for them remains inadequate. Deep-transcranial magnetic stimulation (TMS) is a novel technology that enables non-invasive stimulation of deep layers of the prefrontal cortex. Preliminary evidence suggests that deep-TMS could be effective in the treatment of negative symptoms and cognitive deficits. The current study is the first double-blind, randomized sham-controlled study to examine the feasibility of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia. Twenty daily H1 deep-TMS treatments (20Hz, 120% MT) were delivered, in a double-blind, randomized sham-controlled design (n=30). Extensive clinical and cognitive assessments were carried out throughout the study and for an additional one month follow-up period. The results indicate that at the end of the treatment period, negative symptoms (as indicated by the Scale for the Assessment of Negative Symptoms (SANS)) significantly reduced in the TMS group (-7.7), but not in the sham group (-1.9). Differences between the groups were not statistically significant.