Neural oscillatory characteristics of feedback-associated activity in globus pallidus interna.

Neural oscillatory activities in basal ganglia have prominent roles in cognitive processes. However, the characteristics of oscillatory activities during cognitive tasks have not been extensively explored in human Globus Pallidus internus (GPi). This study aimed to compare oscillatory characteristics of GPi between dystonia and Parkinson's Disease (PD). A dystonia and a PD patient performed the Intra-Extra-Dimension shift (IED) task during both on and off-medication states. During the IED task, patients had to correctly choose between two visual stimuli containing shapes or lines based on a hidden rule via trial and error. Immediate auditory and visual feedback was provided upon the choice to inform participants if they chose correctly. Bilateral GPi Local Field Potentials (LFP) activity was recorded via externalized DBS leads. Transient high gamma activity (~ 100-150 Hz) was observed immediately after feedback in the dystonia patient. Moreover, these bursts were phase synchronous between left and right GPi with an antiphase clustering of phase differences. In contrast, no synchronous high gamma activity was detected in the PD patient with or without dopamine administration. The off-med PD patient also displayed enhanced low frequency clusters, which were ameliorated by medication. The current study provides a rare report of antiphase homotopic synchrony in human GPi, potentially related to incorporating and processing feedback information. The absence of these activities in off and on-med PD patient indicates the potential presence of impaired medication independent feedback processing circuits. Together, these findings suggest a potential role for GPi's synchronized activity in shaping feedback processing mechanisms required in cognitive tasks.

Paired Acute Invasive/Non-invasive Stimulation (PAINS) study: A phase I/II randomized, sham-controlled crossover trial in chronic neuropathic pain.

BACKGROUND: Dorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. OBJECTIVE: We employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. METHODS: Sixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to 'MEG (magnetoencephalography) localized' tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. RESULTS: All participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. CONCLUSION: Our results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

Dynamic changes in rhythmic and arrhythmic neural signatures in the subthalamic nucleus induced by anaesthesia and tracheal intubation.

BACKGROUND: Subcortical structures, including the basal ganglia, have been proposed to be crucial for arousal, consciousness, and behavioural responsiveness. How the basal ganglia contribute to the loss and recovery of consciousness during anaesthesia has, however, not yet been well characterised. METHODS: Twelve patients with advanced Parkinson's disease, who were undergoing deep brain stimulation (DBS) electrode implantation in the subthalamic nucleus (STN), were included in this study. Local field potentials (LFPs) were recorded from the DBS electrodes and EEG was recorded from the scalp during induction of general anaesthesia (with propofol and sufentanil) and during tracheal intubation. Neural signatures of loss of consciousness and of the expected arousal during intubation were sought in the STN and EEG recordings. RESULTS: Propofol-sufentanil anaesthesia resulted in power increases in delta, theta, and alpha frequencies, and broadband power decreases in higher frequencies in both STN and frontal cortical areas. This was accompanied by increased STN-frontal cortical coherence only in the alpha frequency band (119 [68]%; P=0.0049). We observed temporal activity changes in STN after tracheal intubation, including power increases in high-beta (22-40 Hz) frequency (98 [123]%; P=0.0064) and changes in the power-law exponent in the power spectra at lower frequencies (2-80 Hz), which were not observed in the frontal cortex. During anaesthesia, the dynamic changes in the high-gamma power in STN LFPs correlated with the power-law exponent in the power spectra at lower frequencies (2-80 Hz). CONCLUSIONS: Apart from similar activity changes in both STN and cortex associated with anaesthesia-induced unresponsiveness, we observed specific neuronal activity changes in the STN in response to the anaesthesia and tracheal intubation. We also show that the power-law exponent in the power spectra in the STN was modulated by tracheal intubation in anaesthesia. Our results support the hypothesis that subcortical nuclei may play an important role in the loss and return of responsiveness.

Role of diffusion-weighted imaging in monitoring treatment response following high-intensity focused ultrasound ablation of recurrent sacral chordoma.

Chordoma is the most common malignant tumor of the sacrum and is associated with significant neurologic morbidity. Local recurrence is very common, and the long-term prognosis is poor. High-intensity focused ultrasound (HIFU) is a noninvasive and nonionising ablative therapy that has been successful in treating other tumor types and is being evaluated as a new therapy for sacral chordoma. Contrast-enhanced magnetic resonance imaging is typically used to evaluate tumor perfusion following HIFU; however, its utility is limited in poorly perfused tumors. Diffusion-weighted imaging (DWI) provides tissue contrast based on differences in the diffusion of extracellular water without using gadolinium-based contrast agents. We present novel DWI findings following a planned partial HIFU ablation of a large sacral chordoma which had recurred after radiotherapy. Following HIFU, the treated tumor volume demonstrated loss of restriction on DWI correlating with photopenia on positron emission tomography. This suggests successful ablation and tumor necrosis. This novel finding may provide guidance for sequence selection when evaluating HIFU therapy for sacral chordoma and other tumor types for which contrast-enhanced magnetic resonance imaging may have limited utility.

Direct neurophysiological evidence for a role of the human anterior cingulate cortex in central command.

INTRODUCTION: The role of the anterior cingulate cortex (ACC) is still controversial. The ACC has been implicated in such diverse functions as cognition, arousal and emotion in addition to motor and autonomic control. Therefore the ACC is the ideal candidate to orchestrate cardiovascular performance in anticipation of perceived skeletal activity. The aim of this experiment was to investigate whether the ACC forms part of the neural network of central command whereby cardiovascular performance is governed by a top-down mechanism. METHODS & RESULTS: Direct local field potential (LFP) recordings were made using intraparenchymal electrodes in six human ACC's to measure changes in neuronal activity during performance of a motor task in which anticipation of exercise was uncoupled from skeletal activity itself. Parallel cardiovascular arousal was indexed by electrocardiographic changes in heart rate. During anticipation of exercise, ACC LFP power within the 25-60 Hz frequency band increased significantly by 21% compared to rest (from 62.7 µV2/Hz (±SE 4.94) to 76.0µV2/Hz (±SE 7.24); p = 0.004). This 25-60 Hz activity increase correlated with a simultaneous heart rate increase during anticipation (Pearson's r = 0.417, p = 0.016). CONCLUSIONS/SIGNIFICANCE: We provide the first invasive electrophysiological evidence to support the role of the ACC in both motor preparation and the top-down control of cardiovascular function in exercise. This further implicates the ACC in the body's response to the outside world and its possible involvement in such extreme responses as emotional syncope and hyperventilation. In addition we describe the frequency at which the neuronal ACC populations perform these tasks in the human.

Dorsal Anterior Cingulate Cortices Differentially Lateralize Prediction Errors and Outcome Valence in a Decision-Making Task.

The dorsal anterior cingulate cortex (dACC) is proposed to facilitate learning by signaling mismatches between the expected outcome of decisions and the actual outcomes in the form of prediction errors. The dACC is also proposed to discriminate outcome valence-whether a result has positive (either expected or desirable) or negative (either unexpected or undesirable) value. However, direct electrophysiological recordings from human dACC to validate these separate, but integrated, dimensions have not been previously performed. We hypothesized that local field potentials (LFPs) would reveal changes in the dACC related to prediction error and valence and used the unique opportunity offered by deep brain stimulation (DBS) surgery in the dACC of three human subjects to test this hypothesis. We used a cognitive task that involved the presentation of object pairs, a motor response, and audiovisual feedback to guide future object selection choices. The dACC displayed distinctly lateralized theta frequency (3-8 Hz) event-related potential responses-the left hemisphere dACC signaled outcome valence and prediction errors while the right hemisphere dACC was involved in prediction formation. Multivariate analyses provided evidence that the human dACC response to decision outcomes reflects two spatiotemporally distinct early and late systems that are consistent with both our lateralized electrophysiological results and the involvement of the theta frequency oscillatory activity in dACC cognitive processing. Further findings suggested that dACC does not respond to other phases of action-outcome-feedback tasks such as the motor response which supports the notion that dACC primarily signals information that is crucial for behavioral monitoring and not for motor control.

Group II Metabotropic Glutamate Receptors Mediate Presynaptic Inhibition of Excitatory Transmission in Pyramidal Neurons of the Human Cerebral Cortex.

Group II metabotropic glutamate receptor (mGluR) ligands are potential novel drugs for neurological and psychiatric disorders, but little is known about the effects of these compounds at synapses of the human cerebral cortex. Investigating the effects of neuropsychiatric drugs in human brain tissue with preserved synaptic circuits might accelerate the development of more potent and selective pharmacological treatments. We have studied the effects of group II mGluR activation on excitatory synaptic transmission recorded from pyramidal neurons of cortical layers 2-3 in acute slices derived from surgically removed cortical tissue of people with epilepsy or tumors. The application of a selective group II mGluR agonist, LY354740 (0.1-1 µM) inhibited the amplitude and frequency of action potential-dependent spontaneous excitatory postsynaptic currents (sEPSCs). This effect was prevented by the application of a group II/III mGluR antagonist, CPPG (0.1 mM). Furthermore, LY354740 inhibited the frequency, but not the amplitude, of action potential-independent miniature EPSCs (mEPSCs) recorded in pyramidal neurons. Finally, LY354740 did slightly reduce cells' input resistance without altering the holding current of the neurons recorded in voltage clamp at -90 mV. Our results suggest that group II mGluRs are mainly auto-receptors that inhibit the release of glutamate onto pyramidal neurons in layers 2-3 in the human cerebral cortex, thereby regulating network excitability. We have demonstrated the effect of a group II mGluR ligand at human cortical synapses, revealing mechanisms by which these drugs could exert pro-cognitive effects and treat human neuropsychiatric disorders.

Thalamic Deep Brain Stimulation for Neuropathic Pain: Efficacy at Three Years' Follow-Up.

OBJECT: Chronic neuropathic pain is estimated to affect 3-4.5% of the worldwide population, posing a serious burden to society. Deep Brain Stimulation (DBS) is already established for movement disorders and also used to treat some "off-label" conditions. However, DBS for the treatment of chronic, drug refractory, neuropathic pain, has shown variable outcomes with few studies performed in the last decade. Thus, this procedure has consensus approval in parts of Europe but not the USA. This study prospectively evaluated the efficacy at three years of DBS for neuropathic pain. METHODS: Sixteen consecutive patients received 36 months post-surgical follow-up in a single-center. Six had phantom limb pain after amputation and ten deafferentation pain after brachial plexus injury, all due to traumas. To evaluate the efficacy of DBS, patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, University of Washington Neuropathic Pain Score (UWNPS), Brief Pain Inventory (BPI), and 36-Item Short-Form Health Survey (SF-36). RESULTS: Contralateral, ventroposterolateral sensory thalamic DBS was performed in sixteen patients with chronic neuropathic pain over 29 months. A postoperative trial of externalized DBS failed in one patient with brachial plexus injury. Fifteen patients proceeded to implantation but one patient with phantom limb pain after amputation was lost for follow-up after 12 months. No surgical complications or stimulation side effects were noted. After 36 months, mean pain relief was sustained, and the median (and interquartile range) of the improvement of VAS score was 52.8% (45.4%) (p = 0.00021), UWNPS was 30.7% (49.2%) (p = 0.0590), BPI was 55.0% (32.0%) (p = 0.00737), and SF-36 was 16.3% (30.3%) (p = 0.4754). CONCLUSIONS: DBS demonstrated efficacy at three years for chronic neuropathic pain after traumatic amputation and brachial plexus injury, with benefits sustained across all pain outcomes measures and slightly greater improvement in phantom limb pain.

Consent: an event or a memory in lumbar spinal surgery? A multi-centre, multi-specialty prospective study of documentation and patient recall of consent content.

STUDY DESIGN: Prospective, multi-centre, multi-specialty medical notes review and patient interview. PURPOSE: The consenting process is an important communication tool which also carries medico-legal implications. While written consent is a pre-requisite before spinal surgery in the UK, the standard and effectiveness of the process have not been assessed previously. This study assesses standard of written consent for elective lumbar decompressive surgery for degenerative disc disease across different regions and specialties in the UK; level of patient recall of the consent content; and identifies factors which affect patient recall. METHODS: Consent forms of 153 in-patients from 4 centres a, b, c, d were reviewed. Written documentation of intended benefits, alternative treatments and operative risks was assessed. Of them, 108 patients were interviewed within 24 h before or after surgeries to assess recall. RESULTS: The written documentation rates of the operative risks showed significant inter-centre variations in haemorrhage and sphincter disturbance (P = 0.000), but not for others. Analysis of pooled data showed variations in written documentation of risks (P < 0.0005), highest in infection (96.1%) and lowest in recurrence (52.3%). For patient recall of these risks, there was no inter-centre variation. Patients' recall of paralysis as a risk was highest (50.9%) and that of recurrence was lowest (6.5%). Patients <65 years old recalled risks better than those ≥65, significantly so for infection (29.9 vs 9.7%, P = 0.027). Patients consented >14 days compared to <2 days before their surgeries had higher recall for paralysis (65.2 vs 43.7%) and recurrence (17.4 vs 2.8%). Patient recall was independent of consenter grade. CONCLUSION: Overall, the standard of written consent for elective lumbar spinal decompressive surgery was sub-optimal, which was partly reflected in the poor patient recall. While consenter seniority did not affect patient recall, younger age and longer consent-to-surgery time improved it.

High-intensity focused ultrasonic ablation of sacral chordoma is feasible: a series of four cases and details of a national clinical trial.

High-intensity focused ultrasound describes the use of high-intensity focused ultrasound (HIFU) to ablate tumours without requiring an incision or other invasive procedure. This technique has been trialled on a range of tumours including uterine fibroids, prostate, liver and renal cancer. We describe our experience of using HIFU to ablate sacral chordoma in four patients with advanced tumours. Patients were treated under general anaesthetic or sedation using an ultrasound-guided HIFU device. HIFU therapy was associated with a reduction in tumour volume over time in three patients for whom follow up scans were available. Tumour necrosis was reliably demonstrated in two of the three patients. We have established a national trial to assess if HIFU may improve long-term outcome from sacral chordoma, details are given.

Rechargeable vs. nonrechargeable internal pulse generators in the management of dystonia.

OBJECTIVE: To test if deep brain stimulation (DBS) treatment of dystonia was similar in patients before and after implantation of rechargeable internal pulse generators (IPGs). MATERIALS AND METHODS: The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores were compared in patients before DBS insertion, 24 months after DBS insertion with a nonrechargeable IPG, and after implantation of a rechargeable IPG. RESULTS: No significant differences were observed between dystonia control in patients before and after implantation of a rechargeable IPG. CONCLUSIONS: Rechargeable IPGs should be the IPGs of choice for dystonic patients receiving DBS as IPGs offer similar treatment efficacy to nonrechargeable IPGs with advantages in terms of costs and reductions in reimplantation frequency.

Everything to gain: Sir Hugh Cairns' treatment of central nervous system infection at Oxford and abroad.

Antibiotics have revolutionized survival from central nervous system (CNS) infections. Sixty years after the death of Sir Hugh Cairns, we present archive material of historical interest from the Radcliffe Infirmary in Oxford from the time of his first trials of penicillin for CNS infection. We discuss Cairns' important wartime and subsequent contributions to antibiosis in CNS infection and include drawings by Audrey Arnott illustrating the surgical techniques used to treat abscesses at the time.

A pitfall in the interpretation of plain abdnominal radiographs in neonatal intestinal perforation: a case report.

INTRODUCTION: The recognition of neonatal intestinal perforation relies on identification of free gas in the peritoneum on plain abdominal radiographs and the associated clinical signs. The neonatal bowel takes several hours to fill with gas, potentially obscuring one of the radiological signs of bowel perforation in the neonate. CASE PRESENTATION: We describe the case of a male, Caucasian neonate, born prematurely at 35+2 weeks of gestation, who was suspected before birth to be at risk of intestinal perforation, based on antenatal ultrasound signs of bowel obstruction. However, the diagnosis of intestinal perforation after birth was initially delayed because the first abdominal radiograph, requested by the neonatal team, was taken too early in the clinical progression of the neonate's condition. As a consequence, this delayed referral to the paediatric surgical team and definitive management. CONCLUSION: This case illustrates how consideration of the timing of abdominal radiographs in suspected intestinal perforation in the neonate may avoid misinterpretation of radiographic signs, thereby avoiding delays in referral and treatment in the crucial first few hours of life.

An unusual cause of a superior mediastinal mass in an infant.

Tuberculosis has not been reported to be a cause of mediastinal masses in previous case series of mediastinal masses in children. We report the case of a 7-month-old infant with a superior mediastinal mass extending into the right chest, who was referred to the paediatric surgical team for biopsy and further management. Clinical and radiological findings were suggestive of a malignancy. However, thoracoscopic biopsy revealed the presence of a tuberculous mass.

Beta rhythms (15-20 Hz) generated by nonreciprocal communication in hippocampus.

Generation of gamma rhythms in reciprocally connected areas of cortex produces synchronous neuronal firing, although little is known about the consequences of gamma rhythms when generated in nonreciprocally connected regions. This nonreciprocity exists in hippocampus, where gamma rhythms are generated in area CA3 in vitro and in vivo and nonreciprocally projected to area CA1 by the Schaffer collateral pathway. Here we demonstrate how this CA3 gamma rhythm generates two different patterns of local CA1 oscillation dependent on the degree of output from area CA1. 1) In conditions where activity projected to area CA1 produces only very low principal cell recruitment the local population rhythm mimics the gamma rhythm projected from CA3. This activity is generated predominantly by recruitment of CA1 basket cells in a manner dependent on phasic, feedforward excitation of this interneuron subclass. Interneurons in stratum oriens, not receiving CA3 feedforward input, fired at theta frequencies. 2) In the presence of serotonin CA1 principal cell recruitment was appreciably enhanced, resulting in dual activation of CA1 basket cells through both feedforward and feedback excitations. Feedback excitation to CA1 stratum oriens interneurons was also enhanced. The resulting change in interneuron network dynamics generated a beta-frequency CA1 rhythm (as a near-subharmonic of the gamma rhythm projected from CA3). These findings demonstrate that in nonreciprocally connected networks, the frequency of population rhythms in target areas serves to code for degree of principal cell recruitment by afferent input.

Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness.

Psychiatric illnesses, particularly schizophrenia, are associated with disrupted markers for interneuronal function and interneuron-mediated brain rhythms such as gamma frequency oscillations. Here we investigate a possible link between these two observations in the entorhinal cortex and hippocampus by using a genetic and an acute model of psychiatric illness. Lysophosphatidic acid 1 receptor-deficient (LPA1-deficient) mice show psychomotor-gating deficits and neurochemical changes resembling those seen in postmortem schizophrenia studies. Similar deficits are seen acutely with antagonism of the NMDA subtype of glutamate receptor. Neither model induced any change in power or frequency of gamma rhythms generated by kainate in hippocampal slices. In contrast, a dramatic decrease in the power of gamma oscillations was seen in superficial, but not deep, medial entorhinal cortex layers in both models. Immunolabeling for GABA, parvalbumin, and calretinin in medial entorhinal cortex from LPA1-deficient mice showed an approximately 40% reduction in total GABA- and parvalbumin-containing neurons, but no change in the number of calretinin-positive neurons. This deficit was specific for layer II (LII). No change in the number of neurons positive for these markers was seen in the hippocampus. Acute NMDA receptor blockade, which selectively reduces synaptic drive to LII entorhinal interneurons, also disrupted gamma rhythms in a similar manner in superficial entorhinal cortex, but not in hippocampus. These data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.

Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network.

The oriens-lacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8-12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells.