A comparison of clinical-pathological characteristics between symptomatic and interval breast cancer.

BACKGROUND: An association between interval breast cancers (cancer detected after a normal mammogram and before the next scheduled mammogram) and tumour aggressiveness has been postulated which may reflect their relatively poor overall prognosis. The aim of this study was to evaluate known prognostic features of screen detected breast cancers compared to interval breast cancers. METHODS: Patients diagnosed with breast cancer between January 2010 and 2013 at a single unit of the National Breast Screening Program (NBSP) in Ireland and those between the ages of 50 and 65 diagnosed at a symptomatic breast clinic were included in the study. Patients who had not had a screening mammogram within the proceeding two years or had a previous history of breast cancer were excluded. Data were retrospectively collected on patient demographics, tumour type, grade, hormone receptor status and stage of disease at presentation. RESULTS: There were 915 patients included in the study, with 92% (n = 844) diagnosed through the NBSP. Ductal carcinoma in-situ accounted for 19% (n = 160) of screen-detected breast cancers but only 2.8% of interval cancers (p < 0.05). The most common type of invasive cancer was invasive ductal carcinoma. Tumour grade was significantly higher in interval breast cancers (p < 0.05). Interval cancers were identified at a significantly higher stage (Stage 1 versus 2; p < 0.001) than screen-detected cancers. Interval breast cancers were less likely to be ER positive (76% versus 81%; p < 0.05) and significantly more likely to over-express HER2 (20% vs 10%, p < 0.05) than screen-detected cancers. CONCLUSION: This study highlights the fact that interval cancers appear to have a number of adverse prognostic markers for overall breast cancer survival when compared to women with screen-detected breast cancers. Interval cancers were more likely to be invasive, of a higher grade and stage and with a greater predominance of HER2 and triple negative molecular subtypes. Therefore this heterogeneous group of tumours may be biologically more aggressive and account disproportionately to overall breast cancer mortality.

Adaptation of surround inhibition in the human motor system.

Adaptation of a rapid ballistic movement requires that commands for the next movement are updated on the basis of sensory error signals from the current movement. Previous experiments, mostly using visual feedback, have demonstrated that adaptation is highly sensitive to the timing of feedback and can be substantially impaired by delays of 100 ms or so. Here, we use the phenomenon of surround inhibition (SI) to explore the consequences of somatosensory feedback delay in a task requiring participants to flex the index finger without generating any electromyographical (EMG) activity in other fingers. Participants were requested to perform brief isolated flexion movements of the index finger. After a short period of practice, SI in the distant abductor digiti minimi (ADM) muscle was quantified by measuring the amplitude of EMG responses evoked by a standard pulse of transcranial magnetic stimulation to the contralateral motor cortex at the onset of flexion. SI indicates that the response during flexion was smaller than the response at rest. After this, two training blocks were performed in which the ADM muscle was vibrated (80 Hz, 100 ms) either at the onset (VIB(onset)) of finger flexion or with a delay of 100 ms (VIB(100)). SI was reassessed after training. SI measured after VIB(onset) training was transiently more effective than at baseline. In contrast, SI was unchanged compared to baseline after VIB(100). The present study demonstrates that SI can be modified by experience. The timing of the sensory stimulation was found to be critical for the modification of SI, suggesting that only sensory signals closely related to the movement onset can induce adaptive changes, presumably through a feed-forward process.

Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex.

Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where the P value should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input-output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABA(A) activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1: r = 0.33, P = 0.31; Experiment 2: r = -0.23, P = 0.46) or GABA(B) activity (long-interval intracortical inhibition (LICI); Experiment 1: r = -0.47, P = 0.51; Experiment 2: r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r = -0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone.

Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy.

Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for

Rapid rate magnetic stimulation of human sacral nerve roots alters excitability within the cortico-anal pathway.

Sacral nerve root stimulation (SNS) can produce dramatic symptomatic improvement in faecal incontinence (FI). However, the physiological mechanism behind this improvement remains unknown. One hypothesis is that SNS may modulate cortico-anal pathways and drive compensatory changes within the spinal cord or cerebral cortex that beneficially alter sphincter function. Our aim was to assess whether short-term experimental SNS can induce changes in the human cortico-anal pathway. Eight healthy volunteers (mean age 30 years) were studied. Subjects were investigated on three separate occasions and randomized to either active (5 and 15 Hz) or sham rapid-rate lumbosacral magnetic stimulation (rLSMS). Anal sphincter electromyograms (EMG) were recorded from an anal probe following single-pulse transcranial magnetic stimulation, at baseline, immediately, 30 and 60 min following rLSMS at either (i) 5 Hz for 15 min, (ii) 15 Hz for 15 min or (iii) sham stimulation for 15 min. In addition, manometry and anal sphincter sensation was measured in a subset of subjects. Interventions were compared to sham using anova. Fifteen hertz rLSMS increased cortico-anal EMG response amplitude in the 1 h postintervention (F(4, 28) = 3.2, P = 0.027), without a shift in response latency. This effect was not demonstrated with either 5 Hz or sham stimulation. rLSMS had no short-term effect on sensation or physiology. Short-term magnetic stimulation of the sacral nerve roots induces changes in cortico-anal excitability which is frequency specific. These data support the hypothesis that SNS produces some of its beneficial effect in patients with FI by altering the excitability of the cortico-anal pathway.

Additive benefits of long-chain n-3 polyunsaturated fatty acids and weight-loss in the management of cardiovascular disease risk in overweight hyperinsulinaemic women.

BACKGROUND: Obesity, inflammation, insulin resistance and cardiovascular disease (CVD) risk are inter-related. Both weight-loss and long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are independently known to reduce metabolic risk, but the combined effects are unclear. OBJECTIVE: This study examines whether addition of LC n-3 PUFA to a low fat/high carbohydrate weight-loss programme results in greater improvements in inflammation, insulin sensitivity and CVD risk, than weight-loss alone. DESIGN: One hundred and sixteen overweight insulin-resistant women entered a 24-week randomised intervention study. Thirty-nine women were randomised to a weight-loss programme, with LC n-3 PUFA (WLFO), 38 to a weight-loss programme with placebo oil (WLPO), and 39 to receive placebo oil, with no weight-loss programme (control). RESULTS: Ninety-three women completed the study (35 WLFO, 32 WLPO and 26 control), with significant weight-loss in WLFO (10.8+/-1.0%) and WLPO (12.4+/-1.0%) compared to the control group (P<0.0001). The WLFO, but not WLPO or control group, showed significant increases in adipose tissue LC n-3 PUFA (0.34+/-0.20 vs 0.17+/-0.10 and 0.16+/-0.10 %DHA, P<0.0001). Weight-loss showed significant improvements in insulin sensitivity (P<0.001), lipid profile (triglycerides P<0.05) and inflammation (sialic acid P<0.05). Time*group effects showed significant decreases in triglycerides (P<0.05) and increases in adiponectin (P<0.01) with LC n-3 PUFA, in the WLFO vs WLPO groups. CONCLUSIONS: Weight-loss improved risk factors associated with CVD, with some additional benefits of LC n-3 PUFA on triglycerides and adiponectin. Given the current low dietary intake of LC n-3 PUFA, greater attention should be given to increase these fatty acids in the treatment of obesity.

Motor unit excitability changes mediating vestibulocollic reflexes in the sternocleidomastoid muscle.

OBJECTIVE: To investigate the patterns of motor unit firing in single motor units from the sternocleidomastoid (SCM) muscles in response to stimuli previously shown to be capable of evoking vestibulocollic reflexes (loud clicks and electrical stimulation) and to relate these to the previously described surface potentials (VEMPs, vestibular evoked myogenic potentials) evoked by the same stimuli. METHODS: Eleven male subjects (30-43-years-old) were studied. Local anaesthetic was used to block the SCM and confirm that the surface potentials (p13n23) arose from it. At another time, fine wire or needle electrodes were used to record single motor unit activity and peristimulus time histograms were constructed. RESULTS: Local anaesthetic block reduced or abolished the p13n23 response in 5 of 6 subjects. A total of 94 histograms of motor unit discharges were recorded. The excitability changes seen were always small. Loud click stimuli given ipsilaterally evoked short latency (mean 14.2 ms, uncorrected for triggering delays), and short duration (mean 3.6 ms) inhibition. Contralaterally, the effect was excitatory (latency 11.9 ms, uncorrected, mean duration 2.3 ms). For electrical stimulation, short latency inhibition occurred ipsilateral to the cathode (average latency 14.0 ms, uncorrected, mean duration 2.9 ms) and excitation occurred contralaterally. CONCLUSIONS: We confirmed that the SCM is the sole or dominant source of the VEMPs recorded from electrodes over it. Short latency, short duration motor unit firing changes are evoked in SCM by loud clicks and electrical stimulation, stimuli known to be capable of evoking vestibulocollic reflexes. VEMPs beginning with a positivity correspond to inhibition of the underlying motor unit firing and those starting with a negativity correspond to an underlying excitation, findings consistent with intracellular recordings of otolith effects. Qualitative explanations of how the surface potentials are generated by these excitability changes and relating to other properties of the surface responses are proposed. SIGNIFICANCE: This study has shown consistent patterns of single motor unit firing which underlie VEMPs evoked by both clicks and short duration galvanic stimulation.

Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction.

A brief period of strong muscle contraction suppresses the amplitude of EMG responses evoked in relaxed muscle by transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Here we investigate this phenomenon in more detail by recording the descending motor volleys evoked by TMS from electrodes in the cervical epidural space of three conscious patients implanted with chronic electrical stimulators for control of pain. We confirm that fatigue suppresses I waves evoked by TMS. In addition, D waves were suppressed in two of the patients, suggesting that axonal excitability might also be compromised by a period of intense muscle contraction.

Direct demonstration of long latency cortico-cortical inhibition in normal subjects and in a patient with vascular parkinsonism.

OBJECTIVE: The motor evoked potential to a single suprathreshold transcranial magnetic stimulus (TMS) is suppressed by a preceding stimulus given 100-200 ms before (long latency intracortical inhibition, LICI). The effect is enhanced in patients with Parkinson's disease. Although previous studies have agreed that the effect is cortical, there is disagreement over exactly which cortical mechanisms are involved. The aim of this study was to provide further evidence for cortical involvement in LICI. METHODS: Recordings of corticospinal volleys evoked by the TMS stimulation were made from electrodes inserted into the cervical epidural space of 4 conscious subjects. Three of the patients had received the electrodes for treatment of lumbo-sacral pain; the other patient had vascular parkinsonism, and had the electrode implanted to evaluate its effect on cerebral blood flow. The number and amplitude of the volleys were compared with and without a conditioning stimulus. RESULTS: In 3 pain patients, a conditioning stimulus suppressed the later components of the corticospinal volley (I2 and later waves) when the interval between stimuli was 100-150 ms; at 50 ms the responses were enhanced. Early components of the volley were not affected. Inhibition was much more pronounced and involved all descending volleys except the D wave in the patient with vascular parkinsonism. CONCLUSIONS: LICI, which is conventionally described in EMG recordings, is also evident in recordings of descending corticospinal volleys and appears enhanced in a patient with vascular parkinsonism.

Coherence between cerebellar thalamus, cortex and muscle in man: cerebellar thalamus interactions.

Local field potentials (LFPs) were recorded in seven unanaesthetized patients between the four adjacent contacts of a macroelectrode stereotactically implanted for the treatment of tremor. The LFPs were presumed to arise predominantly from the nucleus ventralis intermedius (Vim) of the thalamus, the implantation target. They were recorded simultaneously with the ipsilateral EEG and contralateral EMG during an isometric contraction or at rest. The patients had a history of either isolated tremor (essential tremor, n = 2; benign tremulous Parkinson's disease, n = 1) or tremor with signs of a cerebellar syndrome (multiple sclerosis, n = 3; essential tremor and ataxia, n = 1), although clinical tremor was absent at the time of recording because of a temporary microthalamotomy effect in four patients. In patients with isolated tremor, oscillatory activity picked up by contacts in Vim (cerebellar thalamus) was invariably coherent with that in the sensorimotor cortex or contracting muscle in the 8-27 Hz range. Such coherence was absent in two of the four subjects with tremor associated with a cerebellar syndrome. Coherence between LFPs recorded from more caudally placed contacts and the sensorimotor cortex or contracting muscle was negligible in all patients. These caudally placed contacts demonstrated the highest sensory evoked potential in response to median nerve stimulation. Oscillatory activity in the cerebellar thalamus (Vim) lagged behind that in both cortex and muscle. Coherent activity between the cerebellar thalamus (Vim) and the cortex persisted at rest. It is suggested that rhythmicities in the 8-27 Hz range could provide the basis for a temporal framework that is widely distributed within the motor system.

Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex.

OBJECTIVES: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABA(A) receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation. METHODS: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus). RESULTS: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm. CONCLUSIONS: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.

Neurophysiologic aspects of deep brain stimulation.

Implanting electrodes for deep brain stimulation (DBS) allows performance of a number of different neurophysiologic studies. Before definitive internalization of the device, recording and stimulation through the electrodes is possible. Stimulation of the globus pallidum produced a mixture of excitation and inhibition of ongoing muscle activity. The excitatory response is probably produced by activation of the large-diameter fibers of the corticospinal tract. Stimulation of the thalamus is mainly associated with EMG inhibition. These findings indicate that the effect of stimulation may vary in different targets and that the mechanism of action of DBS is heterogeneous. A different type of study concerns those undertaken after chronic DBS of the subthalamic nucleus (STN) and globus pallidum internum (GPi) in parkinsonian patients. Cortical mechanisms subserving movement preparation and execution have been assessed. The main findings were that stimulation had a more prominent effect on execution than on preparation and that this was greater in patients treated with STN DBS than GPi DBS.

Afferent input and cortical organisation: a study with magnetic stimulation.

Previously, we had described a technique for investigating probable GABAergic cortical inhibitory circuits in conscious man using transcranial magnetic stimulation. This type of inhibition has been termed intracortical inhibition. During voluntary contraction, activity in the circuits responsible for this inhibition is reduced. The mechanism by which this reduction in activity is brought about is unknown. However, evidence exists to suggest that afferent input may be, at least in part, responsible for the reduction in inhibition. The experiments described here were designed to investigate this possibility further. The results of these experiments showed that afferent input, produced by electrical peripheral-nerve stimulation, reduced the level of intracortical inhibition. Also, motor imagery, which activates similar brain regions as overt movement, but does not result in afferent input, failed to produce significant changes in intracortical inhibition. We conclude from these results that afferent input is capable of altering activity in cortical inhibitory circuits. The relevance of these findings to the mechanisms involved in cortical reorganisation is discussed.

Patterned ballistic movements triggered by a startle in healthy humans.

1. The reaction time to a visual stimulus shortens significantly when an unexpected acoustic startle is delivered together with the 'go' signal in healthy human subjects. In this paper we have investigated the physiological mechanisms underlying this effect. If the commands for the startle and the voluntary reaction were superimposed at some level in the CNS, then we would expect to see alterations in the configuration of the voluntary response. Conversely, if the circuit activated by the startling stimulus is somehow involved in the execution of voluntary movements, then reaction time would be sped up but the configuration of the motor programme would be preserved. 2. Fourteen healthy male and female volunteers were instructed to react as fast as possible to a visual 'go' signal by flexing or extending their wrist, or rising onto tiptoe from a standing position. These movements generated consistent and characteristic patterns of EMG activation. In random trials, the 'go' signal was accompanied by a very loud acoustic stimulus. This stimulus was sufficient to produce a startle reflex when given unexpectedly on its own. 3. The startling stimulus almost halved the latency of the voluntary response but did not change the configuration of the EMG pattern in either the arm or the leg. In some subjects the reaction times were shorter than the calculated minimum time for processing of sensory information at the cerebral cortex. Most subjects reported that the very rapid responses were produced by something other than their own will. 4. We conclude that the very short reaction times were not produced by an early startle reflex adding on to a later voluntary response. This would have changed the form of the EMG pattern associated with the voluntary response. Instead, we suggest that such rapid reactions were triggered entirely by activity at subcortical levels, probably involving the startle circuit. 5. The implication is that instructions for voluntary movement can in some circumstances be stored and released from subcortical structures.

Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex.

Under certain conditions, EMG responses evoked by pairs of transcranial magnetic stimuli over the motor cortex are larger than the sum of the responses to each stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5 and 4.3 ms and could be due to interaction between the responses to each stimulus at either the cortex or spinal cord. We recorded the descending volleys set up by such pairs of stimuli from the cervical epidural space of five patients implanted with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4 and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were accompanied by larger and more numerous descending volleys than expected from the sum of each stimulus alone. We conclude that facilitatory interaction between the stimuli can occur within the cerebral cortex. This may involve elements that produce repetitive I-wave activity in response to a single stimulus.

Vestibular hypersensitivity to clicks is characteristic of the Tullio phenomenon.

OBJECTIVES: The frequency of pathologically reduced click thresholds for vestibular activation was explored in patients with the Tullio phenomenon (sound induced vestibular activation). METHODS: Seven patients (eight affected ears) with symptoms of oscillopsia and unsteadiness in response to loud external sounds or to the patient's own voice were examined. In all but one patient, vestibular hypersensitivity to sound was confirmed by the fact that eye movements could be produced by pure tones of 110 dB intensity or less. Conventional diagnostic imaging was normal in all cases and three of the patients had normal middle ears at surgical exploration. Thresholds for click evoked vestibulocollic reflexes were compared with those of a group of normal subjects. Galvanic stimulation was used as a complementary method of examining the excitability of vestibular reflexes. RESULTS: All the patients showed a reduced threshold for click activation of vestibulocollic reflexes arising from the affected ear. Short latency EMG responses to clicks were also present in posterior neck and leg muscles, suggesting that these muscles receive vestibular projections. Galvanic stimulation produced a normal pattern of body sway in four of the five patients tested. CONCLUSIONS: A pathologically reduced threshold to click activation (< or = 70 dB NHL (average normal hearing level)) seems to be a consistent feature of the Tullio phenomenon and a useful diagnostic criterion. This in turn is most likely to be due to an increased effectiveness of the transmission of sound energy to saccular receptors. Activation of these receptors probably contributed to the vestibular symptoms experienced by the patients.

Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease.

High-frequency electrical stimulation of the internal pallidum (GPi) or the subthalamic nucleus (STN) improves clinical symptoms of Parkinson's disease. In 12 parkinsonian patients, 6 with STN and 6 with GPi stimulators, we used H2(15)O positron emission tomography to evaluate whether changes in movement performance were accompanied by change in regional cerebral blood flow (rCBF). Patients were scanned both at rest and while performing a free-choice joystick movement, under conditions of effective and ineffective electrostimulation. During effective STN stimulation, movement-related increases in rCBF were significantly higher in supplementary motor area, cingulate cortex, and dorsolateral prefrontal cortex (DLPFC) than during ineffective stimulation. No significant change was observed in any of these areas during GPi stimulation. The difference between the effect of STN and GPi stimulation on movement-related activity was mainly localized to DLPFC. These results confirm the dominant role of nonprimary motor areas in the control of movement in parkinsonian patients and demonstrate the importance of STN input in the control of these areas.

Click-evoked vestibulocollic reflexes in torticollis.

A total of 26 patients with torticollis were studied using a recently developed technique for recording vestibulocollic reflexes from the sternocleidomastoid muscles in addition to conventional caloric tests of vestibular function. Previous reports of abnormalities of vestibulo-ocular reflexes in these patients were confirmed with just fewer than half having significant canal pareses or directional preponderances (nine of 20 tested). In addition, there was a high incidence of abnormal click-evoked vestibulocollic reflexes (17 of 26 tested), which were not simply the result of prior treatment with botulinum toxin, nor due to unequal levels of muscle activation. In patients never previously treated with botulinum toxin (14 patients), the effect almost always consisted of suppressed responses in the sternocleidomastoid muscle ipsilateral to the direction of head turning. Because responses were not abnormal in all patients tested, and more commonly so in those with a history of torticollis of > or = 5 years (eight of nine patients) than in de novo patients, we suggest that the changes are more likely to be compensatory than causal.

Short-latency trigemino-cervical reflexes in man.

We describe a reflex evoked in neck muscles by stimulation of afferent fibres in the trigeminal nerve. The clearest responses were seen in averaged, unrectified, monopolar surface electromyographic (EMG) recordings from active sternocleidomastoid muscles after stimulation of the infraorbital nerve. They consisted of a bilateral positive/negative (p19, n31) wave with a mean onset latency of 12.9 ms which corresponded to a period of inhibition in the underlying motor unit activity. Responses also could be seen in splenius and trapezius, but not in arm muscles. Stimuli to other branches of the trigeminal nerve (supraorbital or mental) did not produce such clear effects. The threshold for the reflex was relatively low (2-4 times perceptual threshold) and its size scaled with the level of background EMG in an approximately linear fashion. Responses to infraorbital stimulation did not interact with other short-latency inhibitory responses in the sternocleidomastoid muscle evoked by loud acoustic clicks or stimulation of the median nerve at the wrist. We suggest that the infraorbital response is part of a head withdrawal reflex involving an oligosynaptic trigemino-cervical system similar to that described in the cat.