The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation.

BACKGROUND: The use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC). HYPOTHESIS: It was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity. METHODS: 29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis. RESULTS: In females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males. CONCLUSIONS: These preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.

Screening for depression with the Edinburgh Postnatal Depression Scale and finding borderline personality disorder.

OBJECTIVE: The aim of the study was to explore the range of psychiatric diagnoses seen in pregnant women who score above the 'cut-off' on the Edinburgh Postnatal Depression Scale when this is used as a routine screening instrument in the antenatal period. METHOD: Subjects were all pregnant women referred to and seen by the Perinatal Consultation-Liaison Psychiatry Team of a tertiary public hospital over a 14-month period. Edinburgh Postnatal Depression Scale score at maternity 'booking-in' visit, demographic and clinical data were recorded and diagnoses were made according to Diagnostic and Statistical Manual of Mental Disorders (5th ed.) criteria following clinical interview(s) and review of documented past history. Data were analysed using descriptive statistics. RESULTS: A total of 200 patients who had completed the Edinburgh Postnatal Depression Scale were seen for assessment; 86 (43%) scored ⩾13 on Edinburgh Postnatal Depression Scale. Of those scoring 13 or more on Edinburgh Postnatal Depression Scale, 22 (25.6%) had a depressive disorder. In total, 12 patients (14%) had an anxiety disorder, 14 (16.3%) had borderline personality disorder and 13 (15.1%) had a substance use disorder. An additional 23 women (26.7%) had two or more borderline personality traits. CONCLUSION: Psychiatric assessment of women who scored 13 or more on the Edinburgh Postnatal Depression Scale at routine antenatal screening identified a significant number with borderline personality disorder or borderline personality traits rather than depressive or anxiety disorders. Clinical Practice Guidelines note the importance of further assessment for all women who score 13 or more on the Edinburgh Postnatal Depression Scale. The findings here suggest that this assessment should be made by a clinician able to identify personality pathology and organise appropriate and timely interventions.

The influence of endogenous estrogen on transcranial direct current stimulation: A preliminary study.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique. Responses to tDCS differ substantially between individuals. Sex hormones that modulate cortical excitability, such as estrogen, may contribute to this inter-individual variability. The influence of estrogen on tDCS after-effects has not yet been researched. This study aimed to investigate whether endogenous estrogen levels influence cortical response to tDCS. Data from 15 male and 14 female healthy adults were analyzed. Males completed one experimental session. Females completed two, one during the early follicular phase of the menstrual cycle when estrogen was low, one during the mid-luteal phase when estrogen was high. Each session comprised 15-min of anodal tDCS delivered to the left dorsolateral prefrontal cortex (DLPFC). Response to stimulation was assessed using electroencephalography with DLPFC transcranial magnetic stimulation (TMS) administered before, immediately after, and 20-min after tDCS. Changes in amplitudes of N120 and P200 components of TMS-evoked potentials over time were compared between males, women with low estrogen and women with high estrogen. Blood assays verified estrogen levels. Women with high estrogen demonstrated a significant increase in P200 amplitude at both time points and change over time was greater for the high estrogen group compared with males. No significant differences were observed between males and women with low estrogen, or between women with low and high estrogen. These preliminary results indicate that greater neuroplastic response to DLPFC tDCS is seen in highest compared with lowest estrogen states, suggesting that endogenous estrogen levels contribute to inter-individual variability of tDCS outcomes.

Electroconvulsive therapy (ECT) during pregnancy: quantifying and assessing the electric field strength inside the foetal brain.

Electroconvulsive therapy (ECT) is an effective treatment option for severe mental illness during pregnancy. However, there is little knowledge about the amount of electric field produced inside the foetus, which is important to understand the effects of ECT on the foetal excitable tissues. Thus, in this paper, the electric field strength inside the foetus was computed and compared to the basic restriction of the International Commission for Non-Ionizing Radiation Protection (ICNIRP). A computational human phantom representing a 30-weeks pregnant female, four types of electrode placements and a range of stimulus pulse width (0.25 ms-2 ms) and frequency (10 Hz-140 Hz) were used to compute the electric field inside the foetus. A linear relationship between the maximum electric field inside the foetal brain and the electrode current was derived. The results suggest that, considering the maximum current output, pulse width, and frequency range of constant-current ECT devices, the electric field produced inside the foetal brain is most likely below the ICNIRP basic restriction. This is based on the practical scenario of a 30-weeks foetus with a bottom-up and head-down foetal position and the mother taller than 1.62 m.

Demonstration of short-term plasticity in the dorsolateral prefrontal cortex with theta burst stimulation: A TMS-EEG study.

OBJECTIVES: To examine the effects of intermittent TBS (iTBS) and continuous TBS (cTBS) on cortical reactivity in the dorsolateral prefrontal cortex. METHODS: 10 healthy participants were stimulated with either iTBS, cTBS or sham at F3 electrode. Single- and paired-pulse TMS and concurrent electroencephalography (EEG) were used to assess change in cortical reactivity and long-interval intracortical inhibition (LICI) via TMS-evoked potentials (TEPs) and TMS-evoked oscillations. RESULTS: Significant increases in N120 amplitudes (p<0.01) were observed following iTBS over prefrontal cortex. Changes in TMS-evoked theta oscillations and LICI of theta oscillations were also observed following iTBS (increase) and cTBS (decrease). Change in LICI of theta oscillations correlated with change in N120 amplitude following TBS (r=-0.670, p=0.001). CONCLUSIONS: This study provides preliminary evidence that TBS produces direct changes in cortical reactivity in the prefrontal cortex. Combining TBS with TMS-EEG may be a useful approach to optimise stimulation paradigms prior to the conduct of clinical trials. SIGNIFICANCE: TBS is able to modulate cortical reactivity and cortical inhibition in the prefrontal cortex.

Analysing concurrent transcranial magnetic stimulation and electroencephalographic data: A review and introduction to the open-source TESA software.

The concurrent use of transcranial magnetic stimulation with electroencephalography (TMS-EEG) is growing in popularity as a method for assessing various cortical properties such as excitability, oscillations and connectivity. However, this combination of methods is technically challenging, resulting in artifacts both during recording and following typical EEG analysis methods, which can distort the underlying neural signal. In this article, we review the causes of artifacts in EEG recordings resulting from TMS, as well as artifacts introduced during analysis (e.g. as the result of filtering over high-frequency, large amplitude artifacts). We then discuss methods for removing artifacts, and ways of designing pipelines to minimise analysis-related artifacts. Finally, we introduce the TMS-EEG signal analyser (TESA), an open-source extension for EEGLAB, which includes functions that are specific for TMS-EEG analysis, such as removing and interpolating the TMS pulse artifact, removing and minimising TMS-evoked muscle activity, and analysing TMS-evoked potentials. The aims of TESA are to provide users with easy access to current TMS-EEG analysis methods and to encourage direct comparisons of these methods and pipelines. It is hoped that providing open-source functions will aid in both improving and standardising analysis across the field of TMS-EEG research.

Occipital bending in schizophrenia.

OBJECTIVE: To investigate the prevalence of occipital bending (an occipital lobe crossing or twisting across the midline) in subjects with schizophrenia and matched healthy controls. METHOD: Occipital bending prevalence was investigated in 37 patients with schizophrenia and 44 healthy controls. RESULTS: Ratings showed that prevalence was nearly three times higher among schizophrenia patients (13/37 [35.1%]) than in control subjects (6/44 [13.6%]). Furthermore, those with schizophrenia had greater normalized gray matter volume but less white matter volume and had larger brain-to-cranial ratio. CONCLUSION: The results suggest that occipital bending is more prevalent among schizophrenia patients than healthy subjects and that schizophrenia patients have different gray matter-white matter proportions. Although the cause and clinical ramifications of occipital bending are unclear, the results infer that occipital bending may be a marker of psychiatric illness.

Does Exposure to Diagnostic Ultrasound Modulate Human Nerve Responses to Magnetic Stimulation?

Ultrasound (US) at diagnostic frequency and power is known to alter nerve potentials; however, the precise mechanism of action is unknown. We investigated whether US alters resting nerve potential to lower the threshold for magnetic nerve stimulation. Seventeen healthy subjects were recruited. For each subject, a 1.5 MHz US imaging probe was placed onto the elbow with the beam directed at the ulnar nerve. The probe was coupled to the skin using standard acoustic coupling gel as would be done for a routine clinical US scan. Ulnar nerve stimulation was performed simultaneously with magnetic stimulation (MS). Successful magnetic stimulation of the ulnar nerve was confirmed with nerve potentials measured by electromyography. There was no significant change in electromyography signal when MS was performed during US exposure. US at the diagnostic frequency and power tested does not alter nerve thresholds with MS. Testing at other frequencies is required, however, before US is negated as a technique to modify MS thresholds.

Brain morphometry in blind and sighted subjects.

Previous neuroimaging studies have demonstrated structural brain alterations in blind subjects, but most have focused on primary open angle glaucoma or retinopathy of prematurity, used low-field scanners, a limited number of receive channels, or have presented uncorrected results. We recruited 10 blind and 10 age and sex-matched controls to undergo high-resolution MRI using a 3T scanner and a 32-channel receive coil. We evaluated whole-brain morphological differences between the groups as well as manual segmentation of regional hippocampal volumes. There were no hippocampal volume differences between the groups. Whole-brain morphometry showed white matter volume differences between blind and sighted groups including localised larger regions in the visual cortex (occipital gyral volume and thickness) among those with blindness early in life compared to those with blindness later in life. Hence, in our patients, blindness resulted in brain volumetric differences that depend upon duration of blindness.

Brain Neuromodulation Techniques: A Review.

The modulation of brain function via the application of weak direct current was first observed directly in the early 19th century. In the past 3 decades, transcranial magnetic stimulation and deep brain stimulation have undergone clinical translation, offering alternatives to pharmacological treatment of neurological and neuropsychiatric disorders. Further development of novel neuromodulation techniques employing ultrasound, micro-scale magnetic fields and optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications of artificially stimulating or depressing brain activity in human health and disease. With the current rapid growth in neuromodulation technologies and applications, it is timely to review the genesis of the field and the current state of the art in this area.

Factors to consider when applying transcranial magnetic stimulation of dorsolateral prefrontal cortex when resting motor threshold is asymmetric: A case study.

Transcranial magnetic stimulation (TMS) is an increasingly popular tool in treating psychiatric conditions. The dorsal lateral prefrontal cortex (DLPFC) is typically targeted for stimulation, with magnetic field intensity being calibrated by establishing resting motor threshold (RMT) at hand region of primary motor cortex (M1 hand). This presumes that scalp-to-cortex distance (SCD) and cortical thickness is similar at both sites. We present data from a patient who had very asymmetrical RMTs (47 and 78). We investigated SCDs in this patient at the M1 hand and DLPFC, and the M1 hand cortical thickness. We also investigated TMS electric field distribution. The M1 hand SCD and cortical thickness of the M1 hand was larger on the side with higher RMT. Electric field finite element modelling demonstrated the focal point did not effectively reach the M1 hand with higher RMT as the postcentral gyrus was shunting it. Hence, successful DLPFC treatment was based upon the side with lower RMT. This study highlights the importance of tailoring DLPFC treatment intensity not only based on RMT at the M1 hand, and upon the degree to which SCD distance differs between sites, but also based upon size, shape, and density of M1 hand, as well as electric field distribution.

Reduced mu suppression and altered motor resonance in euthymic bipolar disorder: Evidence for a dysfunctional mirror system?

Social cognitive difficulties are common in the acute phase of bipolar disorder and, to a lesser extent, during the euthymic stage, and imaging studies of social cognition in euthymic bipolar disorder have implicated mirror system brain regions. This study aimed to use a novel multimodal approach (i.e., including both transcranial magnetic stimulation (TMS) and electroencephalogram (EEG)) to investigate mirror systems in bipolar disorder. Fifteen individuals with euthymic bipolar disorder and 16 healthy controls participated in this study. Single-pulse TMS was applied to the optimal site in the primary motor cortex (M1), which stimulates the muscle of interest during the observation of hand movements (goal-directed or interacting) designed to elicit mirror system activity. Single EEG electrodes (C3, CZ, C4) recorded mu rhythm modulation concurrently. Results revealed that the patient group showed significantly less mu suppression compared to healthy controls. Surprisingly, motor resonance was not significantly different overall between groups; however, bipolar disorder participants showed a pattern of reduced reactivity on some conditions. Although preliminary, this study indicates a potential mirror system deficit in euthymic bipolar disorder, which may contribute to the pathophysiology of the disorder.

No evidence for mirror system dysfunction in schizophrenia from a multimodal TMS/EEG study.

Dysfunctional mirror neuron systems have been proposed to contribute to the social cognitive deficits observed in schizophrenia. A few studies have explored mirror systems in schizophrenia using various techniques such as TMS (levels of motor resonance) or EEG (levels of mu suppression), with mixed results. This study aimed to use a novel multimodal approach (i.e. concurrent TMS and EEG) to further investigate mirror systems and social cognition in schizophrenia. Nineteen individuals with schizophrenia or schizoaffective disorder and 19 healthy controls participated. Single-pulse TMS was applied to M1 during the observation of hand movements designed to elicit mirror system activity. Single EEG electrodes (C3, CZ, C4) recorded brain activity. Participants also completed facial affect recognition and theory of mind tasks. The schizophrenia group showed significant deficits in facial affect recognition and higher level theory of mind compared to healthy controls. A significant positive relationship was revealed between mu suppression and motor resonance for the overall sample, indicating concurrent validity of these measures. Levels of mu suppression and motor resonance were not significantly different between groups. These findings indicate that in stable outpatients with schizophrenia, mirror system functioning is intact, and therefore their social cognitive difficulties may be caused by alternative pathophysiology.

Occipital bending (Yakovlevian torque) in bipolar depression.

Differing levels of occipital lobe asymmetry and enlarged lateral ventricles have been reported within patients with bipolar disorder (BD) compared with healthy controls, suggesting different rates of occipital bending (OB). This may exert pressure on subcortical structures, such as the hippocampus, reduced among psychiatric patients. We investigated OB prevalence in 35 patients with BD and 36 healthy controls, and ventricular and occipital volumes. Prevalence was four times higher among BD patients (12/35 [34.3%]) than in control subjects (3/36 [8.3%]), as well as larger lateral ventricular volumes (LVVs). Furthermore, we found OB to relate to left-to-right ventricular and occipital lobe volume (OLV) ratios. Those with OB also had reduced left-to-right hippocampal volume ratios. The results suggest that OB is more common among BD patients than healthy subjects, and prevalent in both BD Type I and Type II patients. We posit that anomalies in neural pruning or ventricular enlargement may precipitate OB, consequently resulting in one occipital lobe twisting around the other. Although the clinical implications of these results are unclear, the study suggests that asymmetrical ventricular volume matched with a pattern of oppositely asymmetrical occipital volume is related to OB and may be a marker of psychiatric illness.

Volumetric, cortical thickness and white matter integrity alterations in bipolar disorder type I and II.

BACKGROUND: Bipolar disorder (BD) is a debilitating psychiatric disorder affecting millions of people worldwide with mean time to diagnosis estimated to be at least 10 years. Whilst many brain imaging studies have compared those with BD to controls, few have attempted to investigate differences between BD Type I and II and matched controls. METHODS: Thirty-one patients with BD (16 Type I and 15 Type II) and 31 matched healthy controls were MRI brain scanned with conventional T1-weighted and diffusion tensor imaging methods. RESULTS: There was significantly reduced regional brain volume and thickness among the BD subjects, but also between BD Type I when compared to Type II. White matter integrity also differed between the groups and BD severity correlated significantly with regional brain volume and thickness. LIMITATIONS: Future investigations will consider length of time each BD patient had been diagnosed with BD, as well as assessing controls for family history of psychiatric illness, specifically BD. Similarly, genetic assessment will be conducted as well. CONCLUSIONS: These findings suggest that there are not only regional brain volumetric, thickness and white matter integrity differences between BD and matched controls, but also between those with BD Type I and Type II, such that reduced regional brain volume may underlie BD Type I whereas white matter integrity is more altered in BD Type II.

Removing artefacts from TMS-EEG recordings using independent component analysis: importance for assessing prefrontal and motor cortex network properties.

INTRODUCTION: The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful tool for causally investigating cortical mechanisms and networks. However, various artefacts contaminate TMS-EEG recordings, particularly over regions such as the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to substantiate removal of artefacts from TMS-EEG recordings following stimulation of the DLPFC and motor cortex using independent component analysis (ICA). METHODS: 36 healthy volunteers (30.8 ± 9 years, 9 female) received 75 single TMS pulses to the left DLPFC or left motor cortex while EEG was recorded from 57 electrodes. A subset of 9 volunteers also received 50 sham pulses. The large TMS artefact and early muscle activity (-2 to ~15 ms) were removed using interpolation and the remaining EEG signal was processed in two separate ICA runs using the FastICA algorithm. Five sub-types of TMS-related artefacts were manually identified: remaining muscle artefacts, decay artefacts, blink artefacts, auditory-evoked potentials and other noise-related artefacts. The cause of proposed blink and auditory-evoked potentials was assessed by concatenating known artefacts (i.e. voluntary blinks or auditory-evoked potentials resulting from sham TMS) to the TMS trials before ICA and evaluating grouping of resultant independent components (ICs). Finally, we assessed the effect of removing specific artefact types on TMS-evoked potentials (TEPs) and TMS-evoked oscillations. RESULTS: Over DLPFC, ICs from proposed muscle and decay artefacts correlated with TMS-evoked muscle activity size, whereas proposed TMS-evoked blink ICs combined with voluntary blinks and auditory ICs with auditory-evoked potentials from sham TMS. Individual artefact sub-types characteristically distorted each measure of DLPFC function across the scalp. When free of artefact, TEPs and TMS-evoked oscillations could be measured following DLPFC stimulation. Importantly, characteristic TEPs following motor cortex stimulation (N15, P30, N45, P60, N100) could be recovered from artefactual data, corroborating the reliability of ICA-based artefact correction. CONCLUSIONS: Various different artefacts contaminate TMS-EEG recordings over the DLPFC and motor cortex. However, these artefacts can be removed with apparent minimal impact on neural activity using ICA, allowing the study of TMS-evoked cortical network properties.