Genetic risk for schizophrenia is associated with increased proportion of indirect connections in brain networks revealed by a semi-metric analysis: evidence from population sample stratified for polygenic risk.

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ.

Genetic risk for schizophrenia is associated with altered visually-induced gamma band activity: evidence from a population sample stratified polygenic risk.

Gamma oscillations (30-90 Hz) have been proposed as a signature of cortical visual information processing, particularly the balance between excitation and inhibition, and as a biomarker of neuropsychiatric diseases. Magnetoencephalography (MEG) provides highly reliable visual-induced gamma oscillation estimates, both at sensor and source level. Recent studies have reported a deficit of visual gamma activity in schizophrenia patients, in medication naive subjects, and high-risk clinical participants, but the genetic contribution to such a deficit has remained unresolved. Here, for the first time, we use a genetic risk score approach to assess the relationship between genetic risk for schizophrenia and visual gamma activity in a population-based sample drawn from a birth cohort. We compared visual gamma activity in a group (N = 104) with a high genetic risk profile score for schizophrenia (SCZ-PRS) to a group with low SCZ-PRS (N = 99). Source-reconstructed V1 activity was extracted using beamformer analysis applied to MEG recordings using individual MRI scans. No group differences were found in the induced gamma peak amplitude or peak frequency. However, a non-parametric statistical contrast of the response spectrum revealed more robust group differences in the amplitude of high-beta/gamma power across the frequency range, suggesting that overall spectral shape carries important biological information beyond the individual frequency peak. Our findings show that changes in gamma band activity correlate with liability to schizophrenia and suggest that the index changes to synaptic function and neuronal firing patterns that are of pathophysiological relevance rather than consequences of the disorder.

Evaluation and comparison of conjunctival swab polymerase chain reaction results in SARS-CoV-2 patients with and without ocular manifestations.

PURPOSE: The aim of this study was to evaluate and compare the presence of SARS-CoV-2 in tears of patients with and without ocular symptoms in SARS-CoV-2 positive patients. METHODS: The prospective observational study conducted on 60 consecutive SARS-CoV-2 positive patients with ocular complaints was compared with 60 controls who had no ocular manifestations. The tear samples were taken within 48 h of admission from both the eyes of the enrolled patients for evaluating the presence SARS-CoV-2 by reverse transcription-polymerase chain reaction. RESULTS: Eleven cases (18.33%) tested positive for SARS-CoV-2 in tears on RT-PCR from cojunctival swab compared to 10 (16.66%) controls. The difference was not statistical significant. The difference between mean age of patients who tested positive or negative was also without statistical significance (P = 0.652), but the difference between patients who tested positive or negative by conjunctival swab for SARS-CoV-2 was statistically significant in terms of severity of COVID-19 disease (P = 0.0011), presence of comorbidity (P = 0.0015), mean TLC (P = 0.00498), and mean d dimer (P = 0.00465). CONCLUSION: Though the percentage of patients with positive RT PCR from conjunctival secretions is significantly less than nasopharyngeal swabs, potential risk of transmission of SARS-Co-2 through tears cannot be ruled out. Moreover, SARS-CoV-2 can be present in tears irrespective of ocular involvement.

A rare case of bullhorn-injury associated traumatic hernia of anterior abdominal wall managed by laparoscopic sutured tissue-only repair.

Traumatic abdominal wall hernias (TAWHs) are relatively uncommon entities. Common mechanisms that predispose to such hernias include motor vehicle accidents, seat belt injuries, fall from height, handlebar injuries, and bullfighting. Bullhorn injury leading to TAWHs is an uncommon mechanism. We report here one such patient who was managed by laparoscopic transperitoneal anatomical repair of the defect using polypropylene suture. The patient recovered well without any complication and is being followed up. Such small defects can be managed laparoscopically and tissue-only repair using a nonabsorbable suture is a feasible option. Our case is the first reported case of bullhorn-injury associated traumatic hernia managed laparoscopically and first reported case of TAWH in an adult which was managed by laparoscopic sutured tissue-only repair.

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma.

The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function - and its response to pharmacological intervention - to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures.

Effect of different phases of menstrual cycle on brainstem auditory evoked response.

INTRODUCTION: The change in the hormonal levels during the three phases of menstrual cycle, namely, menstrual phase (hormonal withdrawal), proliferative phase (estrogen peak), and secretory phase (progesterone peak), influences the conduction velocities in the central auditory pathways. Variable findings of brainstem auditory evoked response (BAER) have been reported during different phases of menstrual cycle by different researchers. AIM: To study the effect of different phases of menstrual cycle on BAER. METHODOLOGY: A prospective observational study on 80 audiometrically normal, healthy, eumenorrheic female students in age group of 18-24 years was done at a medical college of northern India. BAER was recorded across the three phases of the menstrual cycle, i.e., menstrual phase (day 1-3), proliferative phase (day 10-12), and secretory phase (day 20-22). Recordings of peak latencies, interpeak latencies, and amplitude of waves of BAER were taken and statistically analyzed. RESULTS: In this study, significant decrease in the latencies of wave III, wave V, and interpeak latency I-III and a trend of decrease in latencies of wave I and interpeak latency I-V (which was statistically insignificant) were observed in proliferative (estrogen peak) phase as compared to menstrual and secretory phase. However, there was no statistically significant difference found in the amplitude of waves of BAER during all the three phases of menstrual cycle. CONCLUSION: The hormonal changes during different phases of menstrual cycle do seem to influence BAER.

Effect of Different Phases of Menstrual Cycle on Heart Rate Variability (HRV).

BACKGROUND: Heart Rate Variability (HRV), which is a measure of the cardiac autonomic tone, displays physiological changes throughout the menstrual cycle. The functions of the ANS in various phases of the menstrual cycle were examined in some studies. AIMS AND OBJECTIVES: The aim of our study was to observe the effect of menstrual cycle on cardiac autonomic function parameters in healthy females. MATERIALS AND METHODS: A cross-sectional (observational) study was conducted on 50 healthy females, in the age group of 18-25 years. Heart Rate Variability (HRV) was recorded by Physio Pac (PC-2004). The data consisted of Time Domain Analysis and Frequency Domain Analysis in menstrual, proliferative and secretory phase of menstrual cycle. Data collected was analysed statistically using student's pair t-test. RESULTS: The difference in mean heart rate, LF power%, LFnu and HFnu in menstrual and proliferative phase was found to be statistically significant. The difference in mean RR, Mean HR, RMSSD (the square root of the mean of the squares of the successive differences between adjacent NNs.), NN50 (the number of pairs of successive NNs that differ by more than 50 ms), pNN50 (the proportion of NN50 divided by total number of NNs.), VLF (very low frequency) power, LF (low frequency) power, LF power%, HF power %, LF/HF ratio, LFnu and HFnu was found to be statistically significant in proliferative and secretory phase. The difference in Mean RR, Mean HR, LFnu and HFnu was found to be statistically significant in secretory and menstrual phases. CONCLUSION: From the study it can be concluded that sympathetic nervous activity in secretory phase is greater than in the proliferative phase, whereas parasympathetic nervous activity is predominant in proliferative phase.

Visual Evoked Potentials: Normative Values and Gender Differences.

INTRODUCTION: Visual evoked potentials (VEP) are used to assess the visual pathways through the optic nerves and brain. A normal VEP response to a pattern-reversal stimulus is a positive mid occipital peak that occurs at a mean latency of 100 ms. VEP may be affected by variety of physiological factors including age, sex, visual acuity and pupillary size. AIMS AND OBJECTIVES: The present study was performed on healthy medical students to determine the normative values and to investigate the effect of sex and anthropometric parameters on visual evoked potentials. MATERIALS AND METHODS: The study was conducted on 100 healthy medical students of Government Medical College, Patiala in the age group of 17-20 years, in which there were 50 males and 50 females. The anthropometric parameters including age, height, weight, BMI, BSA and Head circumference were recorded in all the subjects. VEP was recorded with a PC based, 2 channel, RMS EMG EP mark II machine and standard silver-silver chloride disc electrodes. A VEP monitor displaying checker board was used to give the pattern reversal stimulus. The VEP parameters recorded were latencies to N70, P100 and N155 waves, and peak to peak amplitude of P100 wave. RESULTS: Our results showed that the latencies of N70, P100 and N155 waves were significantly longer in males as compared to females. The amplitude of P100 wave was higher in females in both left and right eye as compared to males. No significant correlation was found between VEP parameters and head circumference in both male and female subjects in our study. CONCLUSION: Gender is an important variable affecting the VEP. The exact reason of gender difference is not clear, but it may be related to anatomical or endocrinal differences in the two sexes.

A comparative study of visual and auditory reaction times on the basis of gender and physical activity levels of medical first year students.

BACKGROUND: Reaction time (RT) is a measure of the response to a stimulus. RT plays a very important role in our lives as its practical implications may be of great consequences. Factors that can affect the average human RT include age, sex, left or right hand, central versus peripheral vision, practice, fatigue, fasting, breathing cycle, personality types, exercise, and intelligence of the subject. AIM: The aim was to compare visual RTs (VRTs) and auditory RTs (ARTs) on the basis of gender and physical activity levels of medical 1(st) year students. MATERIALS AND METHODS: The present cross-sectional study was conducted on 120 healthy medical students in age group of 18-20 years. RT for target stimulus that is, for the beep tone for measuring ART, and red circle for measuring VRT was determined using Inquisit 4.0 (Computer Software) in the laptop. The task was to press the spacebar as soon as the stimulus is presented. Five readings of each stimulus were taken, and their respective fastest RT's for each stimuli were recorded. Statistical analysis was done. RESULTS: In both the sexes' RT to the auditory stimulus was significantly less (P < 0.001) as compared to the visual stimulus. Significant difference was found between RT of male and female medical students (P < 0.001) as well as between sedentary and regularly exercising healthy medical 1(st) year students. CONCLUSION: The ART is faster than the VRT in medical students. Furthermore, male medical students have faster RTs as compared to female medical students for both auditory as well as visual stimuli. Regularly exercising medical students have faster RTs when compared with medical students with sedentary lifestyles.

Increased visual gamma power in schizoaffective bipolar disorder.

BACKGROUND: Electroencephalography and magnetoencephalography (MEG) studies have identified alterations in gamma-band (30-80 Hz) cortical activity in schizophrenia and mood disorders, consistent with neural models of disturbed glutamate (and GABA) neuron influence over cortical pyramidal cells. Genetic evidence suggests specific deficits in GABA-A receptor function in schizoaffective bipolar disorder (SABP), a clinical syndrome with features of both bipolar disorder and schizophrenia. This study investigated gamma oscillations in this under-researched disorder. METHOD: MEG was used to measure induced gamma and evoked responses to a visual grating stimulus, known to be a potent inducer of primary visual gamma oscillations, in 15 individuals with remitted SABP, defined using Research Diagnostic Criteria, and 22 age- and sex-matched healthy controls. RESULTS: Individuals with SABP demonstrated increased sustained visual cortical power in the gamma band (t 35 = -2.56, p = 0.015) compared to controls. There were no group differences in baseline gamma power, transient or sustained gamma frequency, alpha band responses or pattern onset visual-evoked responses. CONCLUSIONS: Gamma power is increased in remitted SABP, which reflects an abnormality in the cortical inhibitory-excitatory balance. Although an interaction between gamma power and medication can not be ruled out, there were no group differences in evoked responses or baseline measures. Further work is needed in other clinical populations and at-risk relatives. Pharmaco-magnetoencephalography studies will help to elucidate the specific GABA and glutamate pathways affected.

BOLD Responses in Human Primary Visual Cortex are Insensitive to Substantial Changes in Neural Activity.

The relationship between blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI) and magnetoencephalography (MEG) metrics were explored using low-level visual stimuli known to elicit a rich variety of neural responses. Stimuli were either perceptually isoluminant red/green or luminance-modulated black/yellow square-wave gratings with spatial frequencies of 0.5, 3, and 6 cycles per degree. Neural responses were measured with BOLD-fMRI (3-tesla) and whole head MEG. For all stimuli, the BOLD response showed bilateral activation of early visual cortex that was greater in the contralateral hemisphere. There was variation between individuals but weak, or no evidence, of amplitude dependence on either spatial frequency or the presence of luminance contrast. In contrast, beamformer analysis of MEG data showed activation in contralateral early visual cortex and revealed: (i) evoked responses with stimulus-dependent amplitude and latency; (ii) gamma and high-beta oscillations, with spatial frequency dependent peaks at approximately 30 and 50 Hz, but only for luminance-modulated gratings; (iii) The gamma and beta oscillations appeared to show different spatial frequency tuning profiles; (iv) much weaker gamma and beta responses, and at higher oscillation frequencies, for isoluminant compared to luminance-modulated gratings. The results provide further evidence that the relationship between the fMRI-BOLD response and cortical neural activity is complex, with BOLD-fMRI being insensitive to substantial changes in neural activity. All stimuli were clearly visible to participants and so the paucity of gamma oscillations to isoluminant stimuli is inconsistent with theories of their role in conscious visual perception.

Visual gamma oscillations: the effects of stimulus type, visual field coverage and stimulus motion on MEG and EEG recordings.

Increases in the power of neural oscillations in the gamma (>40 Hz) band are a key signature of information processing in cortical neuronal networks. However, non-invasive detection of these very small oscillations is difficult due to the presence of potential artefacts (both muscular and ocular) in the same frequency band and requires highly optimised paradigms. Numerous studies have shown that the properties of visual gamma-band responses to simple pattern stimuli are highly tuned to the stimuli parameters used. The aim of this work was to compare gamma oscillation response properties across some of the more commonly used stimulus configurations. To do this, MEG and EEG recordings were made during the presentation of eight different stimulus types in a 2 × 2 × 2 design. For the first stimulus factor, "Type", the stimulus pattern was either an annulus grating or a square wave grating. For the second stimulus factor, "Field", stimuli were presented in either four visual field quadrants simultaneously or only in the lower left quadrant. Finally, for the "Move" factor, stimuli either drifted at 1.33°s(-1) or were stationary. For MEG gamma band responses, the following main effects were observed, a) gamma-band power was increased for annular stimuli compared to square wave stimuli, b) gamma-band power was increased for full field stimuli compared to single quadrant stimuli and c) gamma-band power was larger for drifting compared to stationary stimuli and were of significantly higher frequency. For the detectors used, the signal to noise ratio was substantially higher for MEG than EEG. The advantages and disadvantages of the different types of stimulus types are discussed.

The effects of elevated endogenous GABA levels on movement-related network oscillations.

The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.

Radio-toxicity of spent fuel of the advanced heavy water reactor.

The Advanced Heavy Water Reactor (AHWR) is a new power reactor concept being developed at Bhabha Atomic Research Centre, Mumbai. The reactor retains many desirable features of the existing Pressurised Heavy Water Reactor (PHWR), while incorporating new, advanced safety features. The reactor aims to utilise the vast thorium resources available in India. The reactor core will use plutonium as the make-up fuel, while breeding (233)U in situ. On account of this unique combination of fuel materials, the operational characteristics of the fuel as determined by its radioactivity, decay heat and radio-toxicity are being viewed with great interest. Radio-toxicity of the spent fuel is a measure of potential radiological hazard to the members of the public and also important from the ecological point of view. The radio-toxicity of the AHWR fuel is extremely high to start with, being approximately 10(4) times that of the fresh natural U fuel used in a PHWR, and continues to remain relatively high during operation and subsequent cooling. A unique feature of this fuel is the peak observed in its radio-toxicity at approximately 10(5) y of decay cooling. The delayed increase in fuel toxicity has been traced primarily to a build-up of (229)Th, (230)Th and (226)Ra. This phenomenon has been observed earlier for thorium-based fuels and is confirmed for the AHWR fuel. This paper presents radio-toxicity data for AHWR spent fuel up to a period of 10(6) y and the results are compared with the radio-toxicity of PHWR.

Relation between central corneal thickness and intraocular pressure in Punjabi population.

OBJECTIVE: The motive of this study was to determine the variation of central corneal thickness (CCT) in the Punjabi population and to examine its relationship with intraocular pressure (IOP) using a non-contact tonometer. The study and results emphasize the effects of age, sex and refraction on this relationship, which is important for the diagnosis and prevention of glaucoma in adequate time. METHODS: The study design was a cross-sectional, population-based survey. The participants were 279 females and 253 males of Punjab Province, India, in the age group of 21-70 years. The CCT was measured using an ultrasonic pachymeter, and the IOP was measured using an air-puff tonometer in all subjects. RESULTS: The mean values of CCT and IOP were observed to vary imprecisely with age. The measurement of both parameters was also affected by sex and refraction. The linear regression analysis suggests that the mean value of CCT grows progressively with increasing value of mean IOP. A significant positive correlation was identified between CCT and IOP in the age group of 21-70 years. The authors inferred that this correlation value varies prominently with age for both sexes, which needs to be investigated further. CONCLUSIONS: The authors suggest that CCT is a noteworthy source of variation in IOP measurements for males as well as females belonging to different age groups, when assessing IOP as a risk for glaucoma in the Punjabi population.

Spectral properties of induced and evoked gamma oscillations in human early visual cortex to moving and stationary stimuli.

In two experiments, magnetoencephalography (MEG) was used to investigate the effects of motion on gamma oscillations in human early visual cortex. When presented centrally, but not peripherally, stationary and moving gratings elicited several evoked and induced response components in early visual cortex. Time-frequency analysis revealed two nonphase locked gamma power increases-an initial, rapidly adapting response and one sustained throughout stimulus presentation and varying in frequency across observers from 28 to 64 Hz. Stimulus motion raised the sustained gamma oscillation frequency by a mean of approximately 10 Hz. The largest motion-induced frequency increases were in those observers with the lowest gamma response frequencies for stationary stimuli, suggesting a possible saturation mechanism. Moderate gamma amplitude increases to moving versus stationary stimuli were also observed but were not correlated with the magnitude of the frequency increase. At the same site in visual cortex, sustained alpha/beta power reductions and an onset evoked response were observed, but these effects did not change significantly with the presence of motion and did not correlate with the magnitude of gamma power changes. These findings suggest that early visual areas encode moving and stationary percepts via activity at higher and lower gamma frequencies, respectively.

Magnetoencephalographic correlates of processes supporting long-term memory judgments.

The sensitivity of event-related fields (ERFs) to memory retrieval processes is not well determined. This stands in sharp contrast to event-related potential (ERP) studies, as ERPs have been employed widely to address questions about the functional architecture supporting memory retrieval. Despite their success in this endeavour, however, the sensitivity of ERPs to one retrieval process-familiarity-is somewhat limited. This experiment was designed to determine the sensitivity of ERFs to familiarity, and thus to examine the functional leverage that is available to investigate item familiarity via magnetic means of indexing retrieval processing in real-time. The analyses of the ERF data focused on old/new effects, which are differences between the neural activities associated with old (previously studied) and new test items that attract correct memory judgments. The ERFs showed a level of sensitivity to changes in item familiarity superior to that reported previously in very similar studies where ERPs were acquired. Moreover, analyses of the ERF data revealed four functionally distinct old/new effects. These findings provide strong incentives for employing ERFs in subsequent studies of human memory retrieval processing operations.

Transient and linearly graded deactivation of the human default-mode network by a visual detection task.

In this fMRI study, we show that an extended network of brain areas, previously described as the default-mode network, is suppressed during the performance of a global visual motion discrimination task. For the first time, we demonstrate that this network is transiently suppressed in an event-related fashion, reflecting a true negative activation compared to baseline, and that this deactivation occurs in a strongly graded fashion depending on the strength of the global motion signal. Deactivation across the network varied in an inverse linear relationship with motion coherency, demonstrating that the strongest suppression occurs for the most error-prone tasks. Deactivations were absent for the easiest of the tasks (100% coherence). We also show that the magnitude of task-related activation of the individual sub-components of the default-mode network are strongly correlated, indicating a highly integrated system. The results offer a striking indication of a rapid, highly reactive and tunable system within the brain for active suppression of this network of brain areas.

Population-level inferences for distributed MEG source localization under multiple constraints: application to face-evoked fields.

We address some key issues entailed by population inference about responses evoked in distributed brain systems using magnetoencephalography (MEG). In particular, we look at model selection issues at the within-subject level and feature selection issues at the between-subject level, using responses evoked by intact and scrambled faces around 170 ms (M170). We compared the face validity of subject-specific forward models and their summary statistics in terms of how estimated responses reproduced over subjects. At the within-subject level, we focused on the use of multiple constraints, or priors, for inverting distributed source models. We used restricted maximum likelihood (ReML) estimates of prior covariance components (in both sensor and source space) and show that their relative importance is conserved over subjects. At the between-subject level, we used standard anatomical normalization methods to create posterior probability maps that furnish inference about regionally specific population responses. We used these to compare different summary statistics, namely; (i) whether to test for differences between condition-specific source estimates, or whether to test the source estimate of differences between conditions, and (ii) whether to accommodate differences in source orientation by using signed or unsigned (absolute) estimates of source activity.