Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.

BACKGROUND: High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L > R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.     

Clozapine enhances prepulse inhibition in healthy humans with low but not with high prepulse inhibition levels.

BACKGROUND: Atypical antipsychotics have been assessed for normalization effects on deficient sensory gating as indexed by prepulse inhibition (PPI) in schizophrenics with generally positive, although somewhat conflicting, results. METHODS: We tested the acute effect of clozapine on startle, PPI, and attention, working memory, and executive functioning in 28 healthy male volunteers with low versus high PPI levels using a placebo-controlled within-subject design. RESULTS: Clozapine significantly increased PPI levels obtained at short lead intervals of 60 and 120 msec in subjects with low PPI performance but showed no effect in subjects with high PPI. Clozapine also caused a mild cognitive impairment on attention and pattern recognition memory tests. No correlations between cognitive measures and PPI performance were found. Moreover, low and high PPI performers were shown to exhibit stable levels of PPI across three separate nondrug testing days. CONCLUSIONS: Clozapine increases sensorimotor gating in healthy subjects with low but not high PPI levels in a manner comparable to that seen in clozapine-treated schizophrenia patients. Healthy subjects with low PPI level in combination with genetic studies may provide a translational model to elucidate the neuronal basis of PPI deficits and to test the efficacy of novel antipsychotic medication.     

Short-lasting impairment of temperature perception by high frequency rTMS of the sensorimotor cortex.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has become a useful tool for investigating and even modulating human brain function. RTMS of the human motor cortex can produce changes in excitability that outlast the period of stimulation. To investigate the persistent effect of high-frequency rTMS of sensorimotor cortex (SM1) on somatosensory function. METHODS: We evaluated the thermal thresholds (cold and warm sensation) in 14 normal subjects before and after a short train of 5Hz rTMS over the SM1 or occipital cortex (OC). RESULTS: Threshold for cold perception was increased immediately after rTMS of the left SM1 and no effects at all were noticed after OC stimulation. There was a slight, not significant, increase of warm threshold immediately after the rTMS of the left SM1 and no effects at all were noticed after OC stimulation. CONCLUSIONS: High frequency rTMS over primary sensorimotor cortex seems to modulate sensory function related to thermal (cold) perception. SIGNIFICANCE: The method may be useful for both the study of normal human physiology of temperature perception and for rTMS based manipulation of brain plasticity in patients with sensory disturbances.     

The effects of high frequency rTMS on negative attentional bias are influenced by baseline state anxiety

High frequency (HF) repetitive Transcranial Magnetic Stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) has been shown to induce an attentional bias towards threatening information in healthy adults, associated with decreased activation in the right DLPFC and increased activation in the right amygdala. Additionally, it has been shown that healthy individuals with higher state anxiety portray similar negative attentional biases and cortico-subcortical activation patterns to those induced by HF-rTMS of the right DLPFC. Therefore, the aim of this study is to investigate whether inter-individual differences in state anxiety levels prior to the administration of HF-rTMS of the right DLPFC might be related to the degree to which rTMS induces such a negative attentional bias in healthy volunteers. We administered HF-rTMS of the right DLPFC to a group of 28 healthy female individuals. In line with previous research, a single session of HF-rTMS of the right DLPFC induced an attentional bias towards threatening information. Moreover, self-report measures of state anxiety (STAI-State) prior to stimulation correlated positively with the magnitude of the induced attentional bias. More specifically, we found that healthy individuals who scored higher on self-reports of state anxiety acquired more attentional bias towards negative information after HF-rTMS. Therefore, the effects of a single placebo-controlled rTMS session of the right DLPFC is consistent with the effects of a disrupted prefrontal-amygdala circuitry. The effects on attentional bias are largest in those participants reporting higher state anxiety scores, possibly because underlying amygdala activation is highest.     

Ovarian hormones and cortical excitability. An rTMS study in humans.

OBJECTIVE: Ovarian steroids influence neural excitability. Using repetitive transcranial magnetic stimulation (rTMS) we investigated changes in cortical excitability during the menstrual cycle. METHODS: Eight women underwent rTMS on Days 1 and 14 of the menstrual cycle. As a control group, 8 age-matched men were also tested twice, with a 14-day interval between the two experimental sessions. Repetitive magnetic pulses were delivered in trains of 10 stimuli (5 Hz frequency and 120% of the motor threshold calculated at rest) to the left motor area of the first dorsal interosseous muscle. RESULTS: In women, the motor evoked potential (MEP) size did not increase on Day 1, but it increased progressively during the train on Day 14. The duration of the silent period progressively lengthened during the train on both days. In men the MEP increased in size, and the silent period lengthened to a similar extent on both days. CONCLUSIONS: In women, hormone changes related to the menstrual cycle alter cortical excitability. SIGNIFICANCE: Low estrogen levels probably reduce cortical excitability because their diminished action on sodium channels reduces recruitment of excitatory interneurons during rTMS thus abolishing the MEP facilitation.     

Interhemispheric disconnection effects in multiple sclerosis.

Patients with multiple sclerosis reported less left ear numbers but more right ear numbers than controls in a dichotic listening test. The multiple sclerosis patients were also relatively impaired on three learning tasks; one of these, a test for paired-associate learning of names and faces, correlated with left ear findings; the results are interpreted as supporting a hypothesised disconnection mechanism.     

高频重复经颅磁刺激联合度洛西汀治疗抑郁症临床研究

目的 探讨高频重复经颅磁刺激（rTMS）联合度洛西汀治疗抑郁症的早期疗效与安全性。方法 将60例抑郁症患者随机分为研究组和对照组各30例。研究组给予r TMS联合度洛西汀治疗,对照组用度洛西汀联合模拟r TMS治疗。观察6周。两组分别于治疗前及治疗后第1、2、3、4、6周末进行汉密尔顿抑郁量表（HAMD）和治疗中需处理的不良反应症状量表（TESS）评定。结果 两组治疗后第2、3、4、6周末HAMD评分均较治疗前降低（P〈0.01）,研究组治疗后第1、2、3、4周末HAMD评分低于对照组（P﹤0.05）。治疗后第2周末,两组HAMD入睡困难、总睡眠分均较治疗前降低（P〈0.01）,研究组入睡困难、总睡眠分低于对照组（P﹤0.05）。治疗后第4周末,研究组治愈率和显效率显著高于对照组（P〈0.05）。治疗后第6周末,两组治愈率和显效率比较均无显著性差异（P〉0.05）。两组头晕或头皮痛不良反应发生率比较无显著性差异（P〉0.05）。结论 r TMS联合度洛西汀治疗抑郁症起效快,早期疗效优于单一用药。     

Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression?

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is proposed for the treatment of drug-resistant depression. Studies performed in accordance with evidence-based medicine (EBM) are scarce, particularly in seeking optimal treatment and evaluation parameters. We aimed to test various types of rTMS in a large sample of depressed patients following EBM rules and to investigate treatment-related changes in plasma levels of neurotransmitters involved in depression. METHODS: Seventy-one drug-resistant depressed patients were randomly assigned to low (1 Hz) or high (17 Hz) rate TMS, applied for 5 days over the left dorsolateral prefrontal cortex (L-DLPFC). Patients were separated into two study designs. One group (20 patients) received only active treatment, while the other entered a double-blind, placebo-controlled, crossover design. Pre- and post-treatment blood samples were taken for evaluation of plasma levels of dopamine and serotonin. RESULTS: After a week of treatment patients had a measurable benefit. However, overall the placebo stimulation did not differ significantly from real stimulation, nor were differences observed between the two rates of rTMS. The only difference emerged when the real stimulation was applied at 17 Hz following placebo treatment. Plasma levels of neurotransmitters between active and placebo rTMS were similar. CONCLUSIONS: Using the treatment schedule of 1 week, although a clinical improvement after active treatment was indeed observed, this was both clinically and biochemically indistinguishable from that seen in the placebo arm. SIGNIFICANCE: This suggests that most of the previous emphasis, for short period of treatment, should be tempered down and that further work is required in order to verify whether optimal stimulation and evaluation parameters for TMS-treatment of depression beyond the placebo effect may be found following EBM rules.     

Cardiovascular effects of gastric intubation and distension in healthy humans

Abstract  Few data exist on the effect of upper gut stimuli on the cardiovascular system. Aim of our study was to evaluate the cardiovascular effects of gastric intubation and distension. Eleven healthy subjects (eight men, aged 21–30 years) were studied and a non-invasive beat-to-beat cardiovascular monitoring system was used. After 15-min basal recording, a bag catheter was positioned in the proximal stomach and connected to a barostat. Recordings were first performed for 15 min with the bag deflated, then during inflation of air using a 100 mL per 2 min stepwise protocol until epigastric discomfort was reported, and finally for 15 min with the bag inflated at 75% of discomfort volume separed from the preceding period by 10 min with the bag deflated. Presence of the deflated bag catheter significantly increased mean arterial pressure. Stepwise distension progressively increased heart rate and cardiac index, while mean arterial pressure was affected only at discomfort volume. Peripheral resistances and systemic plasma catecholamines were unaffected. During prolonged distension, the effect on heart rate and cardiac index was transient. In conclusion, both gastric intubation and distension alter cardiovascular parameters, but the effect of distension undergoes rapid adaptation. Experimentally induced gastric distension is a valuable stimulus to study viscero-cardiovascular reflexes and their mechanisms using beat-to-beat measurements.     

How to improve reading skills in dyslexics: The effect of high frequency rTMS

The latest progress in understanding remediation of dyslexia underlines how some changes in brain are a necessary mechanism of improvement. We wanted to determine whether high frequency repetitive transcranial magnetic stimulation (hf-rTMS) over areas that are underactive during reading in dyslexics, would improve reading of dyslexic adults. We applied 5Hz-TMS over both left and right inferior parietal lobule (IPL) and superior temporal gyrus (STG) prior to word, non-word and text reading aloud.     

Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising relatively non-invasive alternative for the treatment of depression. The purpose of this study was to compare the apparent effectiveness of high frequency (20 Hertz) rTMS applied over the left dorsolateral prefrontal cortex (DLPFC) with that of low frequency (1 Hz) rTMS applied over the right DLPFC METHODS: Twenty-eight antidepressant-free adults with major depressive (n = 25) or bipolar (n = 3) disorder (not on mood stabilizers) in a current major depression (Hamilton Rating Scale for Depression [HAM-D-21] > or = 18; Mean = 24.5, SD = 5.51) were treated (14 right, 14 left) for 4 weeks. RESULTS: Overall paired t-tests revealed a significant reduction in mean HAM-D-21, Beck Depression Inventory (BDI-II), and Clinical Global Impression of Change (CGIC) scores at the end of treatment for both groups (high frequency left DLPFC and low frequency right DLPFC). The treatment response rate found (32%) was typical of other response rates reported in the literature (6,30). One-month follow-up data was obtained from 50% of participants. At 1-month follow-up no significant differences were noted as compared to patients' performance at last treatment visit, indicating moderate robustness of rTMS treatment over time. Furthermore, magnetic stimulation did not substantially alter patient memory over the course of treatment. CONCLUSION: rTMS given at low frequency over the right frontal cortex appears to be as effective treatment of refractory depression as high frequency treatment over the left frontal cortex.     

Safety of rTMS to non-motor cortical areas in healthy participants and patients.

OBJECTIVE: rTMS is increasingly being used for stimulation to non-motor areas, but available safety guidelines are derived from experience with motor cortex rTMS. We reviewed the literature and our own data to assess the safety of rTMS to non-motor areas. METHODS: We reviewed for adverse effects all articles published from January 1998 to December 2003 that applied rTMS to non-motor areas, and analyzed data from our own studies from January 1997 to December 2003. RESULTS: Adverse effects were infrequent and generally mild. Headache was the most common, occurring in 23% of the subjects and more frequent with frontal rTMS. More serious adverse effects were rare and consisted of two seizures and four instances of psychotic symptoms induced by rTMS to the dorsolateral prefrontal cortex in patients with depression. CONCLUSIONS: Overall, as currently applied rTMS to non-motor areas appears to be safe with few, generally mild adverse effects. In future studies, we recommend systematic reporting of adverse effects and careful documentation of machine type, coils used, and actual intensity as a function of maximum stimulator output. Phosphene threshold might be used to index stimulation intensity when rTMS is applied to the visual cortex, and research should be directed to identifying other indexes of intensity for TMS to other non-motor areas. SIGNIFICANCE: rTMS under the present guidelines is safe, with minimal adverse effects, when applied to non-motor areas.     

Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation

We determined the numbers, cellular origin and thrombin-generating properties of microparticles in healthy individuals (n = 15). Microparticles, isolated from fresh blood samples and identified by flow cytometry, originated from platelets [237 x 10(6)/L (median; range 116-565)], erythrocytes (28 x 10(6)/L; 13-46), granulocytes (46 x 10(6)/L; 16-94) and endothelial cells (64 x 10(6)/L; 16-136). They bound annexin V, indicating surface exposure of phosphatidylserine, and supported coagulation in vitro. Interestingly, coagulation occurred via tissue factor (TF)-independent pathways, because antibodies against TF or factor (F)VII were ineffective. In contrast, in our in vitro experiments coagulation was partially inhibited by antibodies against FXII (12%, p = 0.006), FXI (36%, p <0.001), FIX (28%, p <0.001) or FVIII (32%, p <0.001). Both the number of annexin V-positive microparticles present in plasma and the thrombin-generating capacity inversely correlated to the plasma concentrations of thrombin-antithrombin complex (r = -0.49, p = 0.072 and r = -0.77, p = 0.001, respectively), but did not correlate to prothrombin fragment F1+2 (r = -0.002, p = 0.99). The inverse correlations between the number of microparticles and their thrombin-forming capacity and the levels of thrombin-antithrombin complex in plasma may indicate that microparticles present in the circulation of healthy individuals have an anticoagulant function by promoting the generation of low amounts of thrombin that activate protein C. We conclude that microparticles in blood from healthy individuals support thrombin generation via TF- and FVII-independent pathways, and which may have an anticoagulant function.     

Differential effects of noradrenergic drugs on anxiety and arousal in healthy volunteers with high and low anxiety

1. 1. The appearance of frontal midline theta activity (Fmθ), the distinct EEG theta rhythm in the frontal midline area during performance of a mental task, indicates relief from anxiety in humans.

2. 2. The authors investigated the effects of clonidine and yohimbine on anxiety and arousal in 24 male university students with (Fmθ group, n = 12) and without (non-Fmθ group, n = 12) Fmθ. Subjects received placebo, 0.15 mg clonidine and 15 mg yohimbine in a double-blind crossover design.

3. 3. Blood samples were obtained, state-trait anxiety inventory (STAI) scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated twice: before and 1 hr after drug administration.

4. 4. Clonidine reduced the 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration in both groups; yohimbine caused an increase in both groups. In the Fmθ group, clonidine reduced the appearance time of Fmθ and the number of task performance but did not alter the state anxiety scores; yohimbine had no effects on Fmθ or the state anxiety but increased the task performance. In the non-Fmθ group, clonidine increased the Fmθ amount and reduced the state anxiety score but did not affect task performance, while yohimbine reduced Fmθ but increased the state anxiety, the task performance and the number of errors.

5. 5. These results suggest that changes in noradrenaline (NA) activity affect both anxiety and arousal levels in high-anxiety humans, but predominantly affect only the arousal level in low-anxiety humans.

     

Hormonal effects of high dose naloxone in humans

Utilizing a double-blind crossover design, the hormonal effects of high dose, 2 mg/kg, were compared to low dose, 0.4 mg (approx. 5 micrograms/kg), naloxone administration in physically healthy humans. A significant naloxone dose effect on plasma cortisol levels was found (p less than 0.001), but no significant effect on plasma or serum levels of prolactin, follicle stimulating hormone, luteinizing hormone, norepinephrine or epinephrine. These results confirm involvement of the endogenous opioid system (EOS) in the tonic regulation of the hypothalamicpituitary-adrenal axis, but fail to find evidence of EOS involvement in the regulation of adrenal medullary function or the gonadotrophic axis in man. The results are however consistent with a continuing action of naloxone as an EOS antagonist even at high doses in man.