The effects of subthreshold 1 Hz repetitive TMS on cortico-cortical and interhemispheric coherence.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) shows promise as a treatment for various movement and psychiatric disorders. Just how rTMS may have persistent effects on cortical function remains unclear. We hypothesised that it may act by modulating cortico-cortical and interhemispheric connectivity. To this end we assessed cortico-cortical and interhemispheric coherence before and after low frequency, subthreshold rTMS of the left motor cortex. METHODS: Fifteen healthy subjects received one train (1Hz, 90% of active motor threshold, 1500 stimuli) of rTMS to the left motor hand area. Spectral power and coherence estimates were calculated between different electroencephalogram (EEG) signals at rest and while muscles of the distal upper limb were tonically contracted. RESULTS: rTMS over the left motor hand area caused a significant increase in ipsilateral EEG-EEG coherence and in the interhemispheric coherence between motor areas in the alpha band. The effects of rTMS lasted up to 25 min post-stimulation. There was no significant change in EEG-EEG coherence over the hemisphere contralateral to stimulation. CONCLUSIONS: Low frequency, subthreshold rTMS of the motor cortex increases ipsilateral cortico-cortical and interhemispheric coherence in the alpha band. This may, in part, mediate the inhibitory effects of low frequency rTMS.     

Handedness effects on interhemispheric transfer time: a TMS study

The crossed-uncrossed difference (CUD) estimates the interhemispheric transfer time (ITT) through the corpus callosum. Previous research has shown that transcranial magnetic stimulation (TMS) to the occipital cortex determines an increased CUD during cognitive tasks. The aim of the present study was to investigate whether TMS stimulation applied at a motor stage can interfere with the ITT, comparing the performance of left- and right-handed people. Results showed a significant TMS effect, i.e. increasing reaction times were reported when stimulation was delivered on the left primary motor area. Effects were more evident when information was primarily perceived through the dominant hemisphere. Both left and right stimulations increased CUD times in right-handed subjects; however, left-handed subjects showed significant effects associated with left stimulation only. Furthermore, in both groups, TMS produced larger effects in the crossed than in the uncrossed condition. TMS stimulation increased reaction times, thus supporting the idea that the interhemispheric transfer of visuo-motor information occurs at a motor processing stage. The dominant hemisphere seems to play a major role within this process: our data indicates that left- and right-handed people have different ITT latencies associated with the transfer of information to the contralateral hemisphere.     

Pharmacologic treatment of schizophrenia.

The pharmacologic treatment of schizophrenia remains a critical component in the short- and long-term management of this disease. Considerable progress has been made in delineating different domains of this illness, ranging from positive and negative symptoms to cognitive dysfunction and psychosocial vulnerabilities. Increasingly, treatments are being studied in relation to a variety of different outcome measures with functional ability and quality of life achieving appropriate emphasis. The introduction of a new generation of antipsychotic drugs has helped to raise optimism and expectations. Overall, second-generation drugs do provide clear advantages in terms of reducing adverse effects (particularly drug-induced Parkinsonism, anesthesia, and, hopefully, tardive dyskinesia). Advantages in alleviating refractory symptoms, negative symptoms, depression, and suicidal behavior are found in some reports; however, much remains to be done methodologically in establishing the relative merits of specific drugs in the multiple domains of interest.     

Pharmacologic treatment of autism.

Autism is a chronic and lifelong pervasive developmental disorder for which there is yet no effective cure, and medical management remains a major challenge for clinicians. In spite of the possible similarities with conditions that have an established pharmacotherapy, and despite improvements in some associated "problematic behaviors" following the use of available medications, effective medical treatment for the core symptoms involving language and social cognition remains elusive. The purpose of the present article is to review current biologic knowledge about autism in an attempt to correlate clinical trials with known mechanisms of disease. In addition, the need for controlled studies and for the creation of homogeneous subgroups of patients based on clinical and genetic characteristics is emphasized. The application of molecular genetic investigations and pharmacogenetics in the diagnostic work-up of autistic patients can lead to more effective individualized medical care.     

Tranquilizers. Pharmacologic aspects]

An inventory was made of the various substances utilized as minor tranquillizers in man. Throughout the various methods of study of these drugs in animals the main pharmacological properties of tranquillizing drugs were considered. Attention is drawn on the various secondary or adverse effects of minor tranquillizers.     

TMS and drugs.

The application of a single dose of a CNS active drug with a well-defined mode of action on a neurotransmitter or neuromodulator system may be used for testing pharmaco-physiological properties of transcranial magnetic stimulation (TMS) measures of cortical excitability. Conversely, a physiologically well-defined single TMS measure of cortical excitability may be used as a biological marker of acute drug effects at the systems level of the cerebral cortex. An array of defined TMS measures may be used to study the pattern of effects of a drug with unknown or multiple modes of action. Acute drug effects may be rather different from chronic drug effects. These differences can also be studied by TMS measures. Finally, TMS or repetitive TMS by themselves may induce changes in endogenous neurotransmitters or neuromodulators. All these possible interactions are the focus of this in-depth review on TMS and drugs.     

Pharmacologic treatment of eating disorders.

OBJECTIVE: Eating disorders are a serious group of conditions that affect 3% of women in industrialized nations over their lifetimes. Recent years have seen considerable progress in the treatment of these disorders. This article reviews the current body of evidence for the pharmacologic treatment of eating disorders. METHODS: We undertook a literature review. RESULTS: For patients with anorexia nervosa (AN), drug trials have been disappointing. In contrast, numerous studies have demonstrated a clear role for antidepressants in the treatment of bulimia nervosa (BN). Pharmacologic investigations of binge eating disorder (BED), a more recently defined entity, have identified several promising drugs. There is also support for the utility of combined medication and psychotherapy. CONCLUSION: Continued research efforts are necessary, particularly regarding the long-term effects of therapy and the development of new pharmacologic strategies.     

Basic mechanisms of TMS.

Transcranial magnetic stimulation (TMS) is now established as an important noninvasive measure for neurophysiologic investigation of the central and peripheral nervous systems in humans. Magnetic stimulation can be used for stimulating peripheral nerves with a similar mechanism of activation as for electrical stimulation. When TMS is applied to the cerebral cortex, however, some features emerge that distinguish it from transcranial electrical stimulation. One of the most important features is designated the D and I wave hypothesis, which is now widely accepted as a mechanism of TMS of the motor cortex. Transcranial electrical stimulation excites the pyramidal tract axons directly, either at the initial segment of the neuron or at proximal internodes in the subcortical white matter, giving rise to D (direct) waves, whereas TMS excites the pyramidal neurons transsynaptically, giving rise to I (indirect) waves. There are still other phenomena with mechanisms that remain to be elucidated. First, not only excitatory effects but also inhibitory effects can be elicited by TMS of the cerebral cortex (e.g., the silent period and intracortical inhibition). The inhibitory effect may also be used to investigate cerebral functions other than the motor cortex, such as the visual, sensory cortices, and the frontal eye field, from which no overt response like the motor evoked potential can be elicited. Second, there is an abundance of intraregional functional connectivities among different cortical areas that can also be revealed by TMS, or TMS in combination with neuroimaging techniques. Last, repetitive transcranial stimulation exerts a lasting effect on brain function even after the stimulation has ceased. With further investigation of the neural mechanisms of TMS, these techniques will open up new possibilities for investigating the physiologic function of the brain as well as opportunities for clinical application.     

Social structure influences effects of pair-housing on wound healing

Chronic stress or noxious stimuli delay wound healing in humans and rodents. The effects of stress on wound healing appear to be mediated by the hypothalamic-pituitary-adrenal (HPA) axis and, in particular, increases in corticosteroids. As previously shown, positive social interaction faciltiates wound healing through suppression of corticosteroids. In the present study, we investigated the effects of pair-housing on wound healing and corticosteroid concentrations in three mouse species, the monogamous Peromyscus californicus, the facultative-monogamous Peromyscus eremicus, and the polygynous Peromyscus leucopus. Pair-housed P. californicus and P. eremicus had significantly smaller wounds than socially isolated cohorts. However, wound healing in P. leucopus was not affected by housing condition. P. californicus and P. eremicus mice that were pair-housed for 2 weeks, then separated from their partners 48h prior to wounding also had wounds comparable to socially isolated mice. The benefits of social housing diminished when P. californicus and P. eremicus pairs were prevented from interacting physically via a double screen barrier. Two hours of daily restraint did not affect basal corticosterone concentrations or wound healing in either P. californicus or P. eremicus. In contrast, restraint facilitated wound healing in P. leucopus. Taken together, these data suggest that social contact facilitates wound healing in two monogamous, but not a polygynous, mouse species.     

Levetiracetam influences human motor cortex excitability mainly by modulation of ion channel function--a TMS study

PURPOSE: Levetiracetam (LEV) is a new compound with anticonvulsive efficacy in focal and generalized epilepsies. Recent in vitro studies suggest LEV to act as a selective N-type-calcium-channel blocker. METHODS: We used transcranial magnetic stimulation (TMS) in order to investigate if ion-channel blockade is relevant to the inhibitory CNS effects of LEV in vivo and if motor thresholds (MTs) are a valid TMS parameter to detect this mode of action. In a double blind, placebo-controlled, crossover study, the effects of single oral doses of 500 and 2000 mg LEV on motor thresholds, recruitment curves (REC), cortical induced silent period (CSP) and on intracortical inhibition (ICI) and facilitation (ICF) were studied in 10 healthy subjects. RESULTS: A significant increase of motor thresholds was noticed after 2000 mg LEV as compared to placebo. The recruitment curve showed a trend towards motor evoked potential (MEP) amplitude reduction after LEV. LEV had no significant effect on CSP or on intracortical excitability as measured by inhibition and facilitation. CONCLUSIONS: We conclude that the modulation of ion-channel function, reflected by motor threshold elevation and a trend towards recruitment curve suppression, is relevant to the inhibitory CNS effects of LEV in vivo, and therefore, may contribute to the anticonvulsive efficacy of LEV. GABAergic or glutamatergic mechanisms seem to be less important in vivo as measured by TMS.     

The effects of high fat diets and environmental influences on cognitive performance in rats.

As part of a continuing investigation of the relationship between dietary factors and cognitive function, the present study examined the combined effects of environmental influences and high-fat diets on learning and memory. Following 3 months of dietary (20% by weight fat diets, composed primarily of either beef tallow or soybean oil versus standard laboratory chow) and environmental treatments (standard, enriched or impoverished), subjects were tested on a variable interval delayed alternation (VIDA) task which measures learning and memory functions that differentially involve specific brain regions. The results confirmed the negative effects of high fat diets, relative to chow, on all aspects of VIDA performance and showed that environmental enrichment overcame deficits associated with dietary fat. Housing rats fed high-fat diets in an impoverished environment did not further exacerbate cognitive deficits observed in such rats living under standard conditions. By comparison, chow-fed rats exhibited no benefit associated with the enriched environment on any aspect of task performance, and only a transitory learning impairment when housed in an impoverished environment. The results show that high fat diets and environmental conditions influence cognitive function and that these two factors interact with one another to produce different profiles of benefits and impairments.     

Pharmacologic treatment of generalized anxiety disorder.

GAD is a severe, chronic, and distressing illness that often requires long-term management. Considerable progress has been made in the ability to help these patients. New antidepressants, such as venlafaxine, and the SSRIs provide an important treatment alternative to "traditional" anxiollytic treatments, which include the benzodiazepines, buspirone, and the TCAs; however, comparative efficacy and the effects of psychiatric comorbidity, long-term treatment, and relapse prevention are areas requiring further investigation.     

Pharmacologic treatment of obsessive compulsive disorders.

Medications are currently available that have been well studied in adequately designed controlled trials that predictably help the majority of obsessive compulsive disorder (OCD) patients. This article reviews the considerable data on the use of these agents in patients with OCD. In addition, an approach to patients with resistant symptoms is presented.     

A combined TMS/fMRI study of intensity-dependent TMS over motor cortex.

BACKGROUND: Transcranial magnetic stimulation (TMS) allows noninvasive stimulation of neurons using time-varying magnetic fields. Researchers have begun combining TMS with functional imaging to simultaneously stimulate and image brain activity. Recently, the feasibility of interleaving TMS with functional magnetic resonance imaging (fMRI) was demonstrated. This study tests this new method to determine if TMS at different intensities shows different local and remote activation. METHODS: Within a 1.5 Tesla (T) MRI scanner, seven adults were stimulated with a figure-eight TMS coil over the left motor cortex for thumb, while continuously acquiring blood oxygen level dependent (BOLD) echoplanar images. TMS was applied at 1 Hz in 18-second long trains delivered alternately at 110% and 80% of motor threshold separated by rest periods. RESULTS: Though the TMS coil caused some artifacts and reduced the signal to noise ratio (SNR), higher intensity TMS caused greater activation than lower, both locally and remotely. The magnitude (approximately 3% increase) and temporal onset (2 to 5 sec) of TMS induced blood flow changes appear similar to those induced using other motor and cognitive tasks. CONCLUSIONS: Though work remains in refining this potentially powerful method, combined TMS/fMRI is both technically feasible and produces measurable dose-dependent changes in brain activity.     

Tianeptine: potential influences on neuroplasticity and novel pharmacological effects

Tianeptine is an atypical antidepressant drug. In contrast to tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), it has been suggested that tianeptine decreases serotonin's activity and amount in serotonergic synapses of the central nervous system by increasing serotonin reuptake. Tianeptine, which has a mechanism of action opposite to that of SSRIs, necessitated a re-evaluation of the biochemical basis of depression and revealed that it cannot be explained by the monoamine hypothesis only. Recent studies by tianeptine have been focused on neuroplasticity. Neuroplasticity hypothesis of depression has the potential to make important contributions to the diagnosis, as well as it may be helpful in the explanation of the drug effects, which cannot be explained by neurochemical mechanisms. In addition, recent interesting results indicating anticonvulsant and analgesic activity of tianeptine and its possible interaction with adenosine A₁ receptors were obtained. In this review, novel central actions of tianeptine and the relationship between stress, neuroplasticity and drug effects were evaluated in the light of the current literature.     

Transcranial magnetic stimulation (TMS) effects on testosterone, prolactin, and corticosterone in adult male rats.

BACKGROUND: Transcranial magnetic stimulation is a relatively new technique for inducing small, localized, and reversible changes in living brain tissue. Although transcranial magnetic stimulation generally results in no immediate changes in plasma corticosterone, prolactin, and testosterone, it normalizes the dexamethasone suppression test in some depressed subjects and has been shown to attenuate stress-induced increases in adrenocorticotropic hormone in rats. METHODS: In this study, serum corticosterone and testosterone concentrations were assayed in male rats immediately and 3, 6, 9, 12, 24, and 48 hours following a single transcranial magnetic stimulation or sham application. Serum prolactin concentrations were determined immediately and 2 hours following a one-time application of either transcranial magnetic stimulation or sham. RESULTS: Transcranial magnetic stimulation animals displayed significantly lower corticosterone concentrations at 6 and 24 hours following a single application compared with sham-control values. Transcranial magnetic stimulation also resulted in lower corticosterone concentrations numerically but not statistically in transcranial magnetic stimulation animals immediately after application (p =.089). No significant differences were found between groups for serum prolactin or testosterone levels at any given collection time point. CONCLUSIONS: These findings 1) suggest that transcranial magnetic stimulation alters the hypothalamic-pituitary-adrenal stress axis and 2) provide time-course data for the implications of the hormonal mechanism that may be involved in the actions of transcranial magnetic stimulation.     

Cortical and subcortical brain effects of transcranial magnetic stimulation (TMS)-induced movement: an interleaved TMS/functional magnetic resonance imaging study.

BACKGROUND: To date, interleaved transcranial magnetic stimulation and functional magnetic resonance imaging (TMS/fMRI) studies of motor activation have not recorded whole brain patterns. We hypothesized that TMS would activate known motor circuitry with some additional regions plus some areas dropping out. METHODS: We used interleaved TMS/fMRI (11 subjects, three scans each) to elucidate whole brain activation patterns from 1-Hz TMS over left primary motor cortex. RESULTS: Both TMS (110% motor threshold) and volitional movement of the same muscles excited by TMS caused blood oxygen level-dependent (BOLD) patterns encompassing known motor circuitry. Additional activation was observed bilaterally in superior temporal auditory areas. Decreases in BOLD signal with unexpected post-task "rebounds" were observed for both tasks in the right motor area, right superior parietal lobe, and in occipital regions. Paired t test of parametric contrast maps failed to detect significant differences between TMS- and volition-induced effects. Differences were detectable, however, in primary data time-intensity profiles. CONCLUSIONS: Using this interleaved TMS/fMRI technique, TMS over primary motor cortex produces a whole brain pattern of BOLD activation similar to known motor circuitry, without detectable differences from mimicked volitional movement. Some differences may exist between time courses of BOLD intensity during TMS circuit activation and volitional circuit activation.