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Context: Contrast sensitivity (CS) function is one of the most important tests available for evaluating visual impairment. Multiple sclerosis (MS) can produce highly selective losses in visual function and psychophysical studies have demonstrated CS deficits for some spatial frequencies. Aims: This work studies the differences in CS between a group of controls and a group of MS patients, focusing on the location of the maximum sensitivity peak, shape of the curve, and determination of the most affected spatial frequencies. Materials and Methods: Using a sinusoidal stimulus the authors assessed CS function in 28 subjects with definitive relapsing remitting MS, and in 50 controls with acuities of 20/25 or better. The peaks of the CS curves were studied by fitting third degree polynomials to individual sets of data. Results: Compared with the control group, the CS function curve for MS subjects showed more deficits in extreme points (low- and high-spatial frequencies). Our results display significant CS losses, at the high-frequencies band level, in the beginning of the disease. When the disease progresses and the disabilities appear, there are greater losses at the low-frequencies band level. In average, the CS curve peaks for the MS group were shifted in relation to the control group. Conclusions: CS losses in the MS group suggest an association with ageing and disability level in the expanded disability status scale. The position of the CS function peak is influenced by MS, age, and degree of disability.

Clinical Relevance: Continuous theta burst stimulation may be an important tool in the therapeutic management of amblyopia, when trying to correct the established neuronal imbalance. It is important to understand whether two sessions of continuous theta burst stimulation produce greater and longstanding changes in visual acuity and suppressive imbalance than one session of continuous theta burst stimulation., Background: We hypothesise that through the usage of continuous theta burst stimulation (cTBS) it is possible to change cortical excitability in a situation where visual impairment is present., Methods: We selected 22 adult amblyopes, 18 females and 4 males, with an age range of 20-59 years. They were randomised into two groups: group A with 10 amblyopes was submitted to one session of cTBS and group B with 12 amblyopes submitted to two sessions of cTBS. Visual acuity (VA) and suppressive imbalance (SI) were evaluated immediately before and after stimulation in both groups A and B. A follow-up was done in both groups., Results: For both group A and B, the VA improvements were significant after cTBS ( p  = 0.005 and p  = 0.003, respectively). Regarding SI, both group A and B had significant improvements after cTBS ( p  = 0.03 and p  = 0.005, respectively). Comparing groups, A and B no significant differences were found with regard to the results obtained both for VA ( p  = 0.72) and SI ( p  = 0.24). However, significant differences were found between group A and B with regard to the duration of stimulation effect for VA ( p  = 0.049) and SI ( p  = 0.03)., Conclusion: We conclude that two sessions of cTBS do not produce better results than one session of stimulation. However, it seems that two sessions of cTBS produce longstanding effects in VA and SI.

Introduction: Pattern Electroretinography (PERG) is a highly sensitive electrophysiological technique used as an indicator of changes in retinal macular area. Amblyopia seems to result from a cortical visual imbalance but changes at the retinal level may also be present. The purpose of this systematic review was to evaluate if there are any consistent changes described in the scientific literature in PERG responses of amblyopic eyes., Materials and Methods: Searches were conducted in PubMed and Embase databases, using the keywords "Electroretinography" and "Amblyopia", combined with MeSH or Emtree terms "Pattern Electroretinography", "amblyopia", "PERG" and "amblyopia". PERG P50-N95 amplitude and P50 latency were analysed as well as the methodology used., Results: A total of 234 articles were found and 6 articles were included for review. One of the articles reported results in adults and five of them in children. One of the articles in children reported no changes in either P50-N95 amplitude or P50 latency. All articles that described differences between the amblyopic eye and the normal eye found a decrease in P50-N95 amplitude and/or a delay in P50 latency., Conclusions: This review shows promising findings for the use of PERG in amblyopia as an aid in the diagnostic protocol, since this technique may be able to detect an apparent functional impairment of the amblyopic eye.

Theta Burst Stimulation (TBS) is a non-invasive neurophysiological technique, able to induce changes in synaptic activity. Research suggests that TBS may induce changes in cerebral oxygenation, cerebral blood flow, blood pressure and heart rate but there are conflicting results across studies. Thus, the objective of our sham-controlled study is to evaluate if TBS applied to the dorsolateral prefrontal cortex (DLPFC) of healthy volunteers produces changes in cerebral oximetry, heart rate and blood pressure. Forty-nine volunteers of both sexes were randomly allocated to one of five stimulation groups. Before and after real TBS or sham stimulation, blood pressure, heart rate, and cerebral oxygenation of the volunteers were measured. Cerebral oxygenation values were obtained with a near infra-red spectroscopy system. We found a significant reduction in left cortex oximetry after continuous TBS (cTBS) over the left DLPFC (p = 0.039) and a non-significant reduction in right cortex oximetry (p = 0.052). Right hemisphere inhibition (using cTBS) seemed to originate a significant reduction of 8 mmHg in systolic arterial pressure. No other changes were seen in oximetry, cardiac frequency and diastolic arterial pressure. In our group of normal subjects, cTBS applied to the left DLPFC was able to reduce oxygenation in the left cortex. Right hemisphere inhibition was associated with a significant reduction in systolic pressure., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This TBS sham-controlled study aimed to evaluate the effects of intermittent TBS (iTBS) and continuous TBS (cTBS) upon ipsilateral hearing thresholds after stimulation on the left auditory cortex., Methods: Sixty healthy adults, aged between 19 and 32 years (median of 23 years), were randomly distributed into three groups and underwent iTBS, cTBS or sham stimulation. Each double-blind experimental session comprised two pure tone audiometric evaluations per subject, before and after stimulation. To assess volunteer safety, a follow-up of at least 48 hours was implemented., Results: The iTBS group mean thresholds displayed a tendency to decrease after stimulation, predominantly in the 500 Hz-6000 Hz interval and group comparisons revealed significant differences between the iTBS and sham groups for 500 Hz (p = 0.041) and between the iTBS and cTBS groups for 4000 Hz (p = 0.038). Neither relevant side effects nor any significant hearing threshold impairment after active or sham stimulation were found., Conclusions: A single stimulation session led to an effective neuromodulation of the auditory cortex, reflected in lower thresholds when using iTBS., Significance: These encouraging results with this safe noninvasive tool suggest that iTBS may have the potential to positively influence hearing thresholds., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Resource rationalization and reduction of waiting lists for surgery are two main guidelines for hospital units outlined in the Portuguese National Health Plan. This work is dedicated to an elective surgery scheduling problem arising in a Lisbon public hospital. In order to increase the surgical suite's efficiency and to reduce the waiting lists for surgery, two objectives are considered: maximize surgical suite occupation and maximize the number of surgeries scheduled. This elective surgery scheduling problem consists of assigning an intervention date, an operating room and a starting time for elective surgeries selected from the hospital waiting list. Accordingly, a bicriteria surgery scheduling problem arising in the hospital under study is presented. To search for efficient solutions of the bicriteria optimization problem, the minimization of a weighted Chebyshev distance to a reference point is used. A constructive and improvement heuristic procedure specially designed to address the objectives of the problem is developed and results of computational experiments obtained with empirical data from the hospital are presented. This study shows that by using the bicriteria approach presented here it is possible to build surgical plans with very good performance levels. This method can be used within an interactive approach with the decision maker. It can also be easily adapted to other hospitals with similar scheduling conditions.

Context: Contrast sensitivity (CS) function is one of the most important tests available for evaluating visual impairment. Multiple sclerosis (MS) can produce highly selective losses in visual function and psychophysical studies have demonstrated CS deficits for some spatial frequencies., Aims: This work studies the differences in CS between a group of controls and a group of MS patients, focusing on the location of the maximum sensitivity peak, shape of the curve, and determination of the most affected spatial frequencies., Materials and Methods: Using a sinusoidal stimulus the authors assessed CS function in 28 subjects with definitive relapsing remitting MS, and in 50 controls with acuities of 20/25 or better. The peaks of the CS curves were studied by fitting third degree polynomials to individual sets of data., Results: Compared with the control group, the CS function curve for MS subjects showed more deficits in extreme points (low- and high-spatial frequencies). Our results display significant CS losses, at the high-frequencies band level, in the beginning of the disease. When the disease progresses and the disabilities appear, there are greater losses at the low-frequencies band level. In average, the CS curve peaks for the MS group were shifted in relation to the control group., Conclusions: CS losses in the MS group suggest an association with ageing and disability level in the expanded disability status scale. The position of the CS function peak is influenced by MS, age, and degree of disability.

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

We used the agar dilution method to evaluate the antibacterial effect of Terminalia macroptera leaf (Tml) extract against nine reference and clinical Neisseria gonorrhoeae strains, including penicillin- and tetracycline-resistant and -susceptible strains. Tml possesses anti-N. gonorrhoeae activity against all of the strains and the minimum inhibitory concentrations (MIC) were between 100 and 200 microg ml(-1). We then used a liquid-liquid partition method to divide the Tml extract into five fractions and determined the anti-N. gonorrhoeae activity of each of the fractions. All of the fractions showed antibacterial activity. The most active one was identified as the diethyl ether fraction and had MIC values of between 25 and 50 microg ml(-1) against all of the strains., (Copyright 2002 Federation of European Microbiological Societies)

Objectives: To assess the processing of spectrotemporal sound patterns in multiple sclerosis by using auditory evoked potentials (AEPs) to complex harmonic tones., Methods: 22 patients with definite multiple sclerosis but mild disability and no auditory complaints were compared with 15 normal controls. Short latency AEPs were recorded using standard methods. Long latency AEPs were recorded to synthesised musical instrument tones, at onset every two seconds, at abrupt frequency changes every two seconds, and at the end of a two second period of 16/s frequency changes. The subjects were inattentive but awake, reading irrelevant material., Results: Short latency AEPs were abnormal in only 4 of 22 patients, whereas long latency AEPs were abnormal to one or more stimuli in 17 of 22. No significant latency prolongation was seen in response to onset and infrequent frequency changes (P1, N1, P2) but the potentials at the end of 16/s frequency modulations, particularly the P2 peaking approximately 200 ms after the next expected change, were significantly delayed., Conclusion: The delayed responses appear to be a mild disorder in the processing of change in temporal sound patterns. The delay may be conceived of as extra time taken to compare the incoming sound with the contents of a temporally ordered sensory memory store (the long auditory store or echoic memory), which generates a response when the next expected frequency change fails to occur. The defect cannot be ascribed to lesions of the afferent pathways and so may be due to disseminated brain lesions visible or invisible on magnetic resonance imaging.

Objectives: To determine whether the process responsible for the mismatch negativity (MMN) might be involved in the analysis of temporal sound patterns for information., Methods: Synthesized musical instrument tones of 'clarinet' timbre were delivered in a continuous sequence at 16 tones/s, such that there was virtually no N1 potential to each individual tone. The standard sequence comprised 4 or 5 adjacent notes of the diatonic scale, presented either as a regularly repeated, rising pattern or pseudo-randomly. The deviant stimuli were 1-5 consecutive tones of higher pitch than the standards., Results: A MMN was evoked by a single deviant tone, 1 or 5 semitones above the pitch range of the standards. The response to the 5-semitone deviant was significantly larger (mean of 7.3 microV) when the standard pattern was regular as compared with pseudo-random. The MMN latency, on the other hand, was only influenced by the magnitude of pitch deviation. A second MMN was evoked by a second deviant tone, immediately (SOA 62.5 ms) following the first. Further consecutive MMNs were not consistently evoked., Conclusions: The large amplitude of these MMNs can be attributed to the use of complex tones, continuous presentation and a rapid rate of pitch changes, such that no waveform subtraction was required. Over and above the probability with which each individual tone occurs in the standard sequence, the mismatch process is influenced by its temporal structure, i.e. can be regarded as a temporal pattern analyzer. Contrary to the findings of some other groups, we found that two consecutive deviants can evoke an MMN, even at high rates of presentation such that both occur within the postulated 'temporal window of integration' of ca. 170 ms. These findings suggest that the mismatch process might be involved in the extraction of sequential information from repetitive and non-repetitive sound patterns.

The object of the study was to look for a neurophysiological substrate of sequential auditory stream segregation. When a sequence of tones alternates rapidly between pitches separated by more than a few semitones, there is a tendency for it to be perceived as two independent "streams". We examined the scalp potentials evoked when the pitch interval abruptly changes, to see whether there are response parameters which might be correlated with sudden stream segregation and/or integration. For 3 s a continuous synthesized tone of "clarinet" timbre oscillated between pitches of F4 and F#4 (one semitone higher) at 16 notes/s, perceived as an integrated stream. The upper note was then raised to E5 (11 semitones above F4, perceived as segregated streams) for a further 3 s and the cycle was repeated 40 times. In a second condition also starting with oscillation between F4 and F#4, the upper note was lowered to E4 (one semitone below F4, still perceived as a single stream). Further conditions examined the changes between oscillations of 1 and 11 semitones down from E5, 1 and 23 semitones up from F4, and 10 and 11 semitones up from F4. Virtually no potentials were detectable during the periods of unchanging oscillation, but an N1/P2 complex was evoked on each change in the pitch interval. The N1 was termed "MN1" on account of its arguable relatedness to the mismatch negativity, recorded in a separate experiment using discontinuous tones at a much slower rate. The mean peak latency of the MN1 varied between 96 and 123 ms, the shortest latencies being recorded, not to the largest changes of pitch interval but to the widest pitch intervals between the new tone and the immediately preceding one. Therefore, although a causal relationship with streaming cannot necessarily be inferred, the MN1 latency appears to mark the degree of pitch contrast between consecutive tones, in correlation with the streaming effect.

Objectives: To examine whether two cortical processes concerned with spectro-temporal analysis of complex tones, a 'C-process' generating CN1 and CP2 potentials at cf. 100 and 180 ms after sudden change of pitch or timbre, and an 'M-process' generating MN1 and MP2 potentials of similar latency at the sudden cessation of repeated changes, are dependent on accumulation of a sound image in the long auditory store., Methods: The durations of steady (440 Hz) and rapidly oscillating (440-494 Hz, 16 changes/s) pitch of a synthesized 'clarinet' tone were reciprocally varied between 0.5 and 4.5 s within a duty cycle of 5 s. Potentials were recorded at the beginning and end of the period of oscillation in 10 non-attending normal subjects., Results: The CN1 at the beginning of pitch oscillation and the MN1 at the end were both strongly influenced by the duration of the immediately preceding stimulus pattern, mean amplitudes being 3-4 times larger after 4.5 s as compared with 0.5 s., Conclusions: The processes responsible for both CN1 and MN1 are influenced by the duration of the preceding sound pattern over a period comparable to that of the 'echoic memory' or long auditory store. The store therefore appears to occupy a key position in spectro-temporal sound analysis. The C-process is concerned with the spectral structure of complex sounds, and may therefore reflect the 'grouping' of frequency components underlying auditory stream segregation. The M-process (mismatch negativity) is concerned with the temporal sound structure, and may play an important role in the extraction of information from sequential sounds.

In order to assess higher auditory processing capabilities, long-latency auditory evoked potentials (AEPs) were recorded to synthesized musical instrument tones in 22 post-comatose patients with severe brain injury causing variably attenuated behavioural responsiveness. On the basis of normative studies, three different types of spectro-temporal modulation were employed. When a continuous 'clarinet' tone changes pitch once every few seconds, N1/P2 potentials are evoked at latencies of approximately 90 and 180 ms, respectively. Their distribution in the fronto-central region is consistent with generators in the supratemporal cortex of both hemispheres. When the pitch is modulated at a much faster rate ( approximately 16 changes/s), responses to each change are virtually abolished but potentials with similar distribution are still elicited by changing the timbre (e.g. 'clarinet' to 'oboe') every few seconds. These responses appear to represent the cortical processes concerned with spectral pattern analysis and the grouping of frequency components to form sound 'objects'. Following a period of 16/s oscillation between two pitches, a more anteriorly distributed negativity is evoked on resumption of a steady pitch. Various lines of evidence suggest that this is probably equivalent to the 'mismatch negativity' (MMN), reflecting a pre-perceptual, memory-based process for detection of change in spectro-temporal sound patterns. This method requires no off-line subtraction of AEPs evoked by the onset of a tone, and the MMN is produced rapidly and robustly with considerably larger amplitude (usually >5 microV) than that to discontinuous pure tones. In the brain-injured patients, the presence of AEPs to two or more complex tone stimuli (in the combined assessment of two authors who were 'blind' to the clinical and behavioural data) was significantly associated with the demonstrable possession of discriminative hearing (the ability to respond differentially to verbal commands, in the assessment of a further author who was blind to the AEP findings). Behavioural and electrophysiological findings were in accordance in 18/22 patients, but no AEPs could be recorded in two patients who had clear behavioural evidence of discriminative hearing. The absence of long-latency AEPs should not, therefore, be considered indicative of complete functional deafness. Conversely, AEPs were substantially preserved in two patients without behavioural evidence of discriminative hearing. Although not necessarily indicative of conscious 'awareness', such AEP preservation might help to identify sentient patients who are prevented by severe motor disability from communicating their perception.

In this study, synthesised instrumental tones were used to examine human auditory cortical processes engaged at the end of a period of rapid pitch modulation. It was previously [S.J. Jones, O. Longe, M. Vaz Pato, Auditory evoked potentials to abrupt pitch and timbre change of complex tones: electrophysiological evidence of 'streaming'?, Electroencephalogr. Clin. Neurophysiol., 108 (1998) 131-142] suggested that the 'change-N1' produced by infrequent changes in pitch or timbre of a continuous complex tone represents the activity of a neuronal population topographically distinct from that responsible for the 'onset-N1' at the beginning of the tone. In the present study a superficially similar negativity was produced when the tone came to rest on a steady pitch after a period of rapid (8-16 changes/s) modulation; its scalp maximum was anterior to that of the two previously identified potentials but similar to that of the mismatch negativity elicited by discontinuous tones. By varying the modulation rate the latency was shown to be relatively constant with respect to the time the next pitch change was expected but failed to occur. The largest responses averaging c. 7 microV were evoked at the end of modulation sequences which were both rhythmic and repetitive, but a potential was still produced when there was no rhythmic pattern or repetition of individual notes. This response to non-occurrence of an expected but not necessarily specified change implies an automatic process for comparing the incoming sound with an extrapolated template of the preceding pattern in which timing as well as pitch information is accurately represented. We suggest this technique offers a robust method for eliciting the mismatch negativity, which may extend the opportunities for electrophysiological investigation of higher auditory processes., (Copyright 1999 Elsevier Science B.V.)

Examination of the cortical auditory evoked potentials to complex tones changing in pitch and timbre suggests a useful new method for investigating higher auditory processes, in particular those concerned with 'streaming' and auditory object formation. The main conclusions were: (i) the N1 evoked by a sudden change in pitch or timbre was more posteriorly distributed than the N1 at the onset of the tone, indicating at least partial segregation of the neuronal populations responsive to sound onset and spectral change; (ii) the T-complex was consistently larger over the right hemisphere, consistent with clinical and PET evidence for particular involvement of the right temporal lobe in the processing of timbral and musical material; (iii) responses to timbral change were relatively unaffected by increasing the rate of interspersed changes in pitch, suggesting a mechanism for detecting the onset of a new voice in a constantly modulated sound stream; (iv) responses to onset, offset and pitch change of complex tones were relatively unaffected by interfering tones when the latter were of a different timbre, suggesting these responses must be generated subsequent to auditory stream segregation.