Intan Technologies integrated circuits can produce analog-to-digital conversion artifacts that affect neural signal acquisition.

Objective.Intan Technologies' integrated circuits (ICs) are valuable tools for neurophysiological data acquisition, providing signal amplification, filtering, and digitization from many channels (up to 64 channels/chip) at high sampling rates (up to 30 kSPS) within a compact package (⩽9× 7 mm). However, we found that the analog-to-digital converters (ADCs) in the Intan RHD2000 series ICs can produce artifacts in recorded signals. Here, we examine the effects of these ADC artifacts on neural signal quality and describe a method to detect them in recorded data.Approach.We identified two types of ADC artifacts produced by Intan ICs: 1) jumps, resulting from missing output codes, and 2) flatlines, resulting from overrepresented output codes. We identified ADC artifacts in neural recordings acquired with Intan RHD2000 ICs and tested the repeated performance of 17 ICsin vitro. With the on-chip digital-signal-processing disabled, we detected the ADC artifacts in each test recording by examining the distribution of unfiltered ADC output codes.Main Results.We found larger ADC artifacts in recordings using the Intan RHX data acquisition software versions 3.0-3.2, which did not run the necessary ADC calibration command when the inputs to the Intan recording controller were rescanned. This has been corrected in the Intan RHX software version 3.3. We found that the ADC calibration routine significantly reduced, but did not fully eliminate, the occurrence and size of ADC artifacts as compared with recordings acquired when the calibration routine was not run (p< 0.0001). When the ADC calibration routine was run, we found that the artifacts produced by each ADC were consistent over time, enabling us to sort ICs by performance.Significance.Our findings call attention to the importance of evaluating signal quality when acquiring electrophysiological data using Intan Technologies ICs and offer a method for detecting ADC artifacts in recorded data.

Design and Simulation of a Low Power 384-channel Actively Multiplexed Neural Interface.

Brain computer interfaces (BCIs) provide clinical benefits including partial restoration of lost motor control, vision, speech, and hearing. A fundamental limitation of existing BCIs is their inability to span several areas (> cm2) of the cortex with fine (<100 µm) resolution. One challenge of scaling neural interfaces is output wiring and connector sizes as each channel must be independently routed out of the brain. Time division multiplexing (TDM) overcomes this by enabling several channels to share the same output wire at the cost of added noise. This work leverages a 130-nm CMOS process and transfer printing to design and simulate a 384-channel actively multiplexed array, which minimizes noise by adding front end filtering and amplification to every electrode site (pixel). The pixels are 50 µm × 50 µm and enable recording of all 384 channels at 30 kHz with a gain of 22.3 dB, noise of 9.57 µV rms, bandwidth of 0.1 Hz - 10 kHz, while only consuming 0.63 µW/channel. This work can be applied broadly across neural interfaces to create high channel-count arrays and ultimately improve BCIs.

Layered stigma? Co-occurring depression and obesity in the public eye.

OBJECTIVES: Obesity and depression are common conditions in the general public and show a high level of co-morbidity. Both conditions are stigmatized, i.e., associated with negative attitudes and discrimination. Previous research shows that devalued conditions can overlap or combine to produce a layered stigma which is associated with more negative health outcomes than either single devalued condition alone. This study therefore set out to investigate the double stigma of obesity and depression. METHODS: A telephone-based representative study of the German population was conducted. Vignettes describing women with obesity, depression or both conditions were presented, followed by a set of items on semantic differentials based on previous stigma research of depression (depression stigma DS) and obesity (Fat Phobia Scale FPS). Personal experience with depression and obesity was assessed. RESULTS: All comparisons were significant in univariate ANOVA, showing negative attitudes measured by the FPS and the DS to be most pronounced in the double stigma condition. Multivariate analysis, controlling for age, gender, education and personal experience with the stigma condition (e.g. having obesity or depression), show that the double stigma obesity and depression is associated to more negative attitudes on the FPS (b=0.163, p<0.001) and the DS (b=0.154, p=0.002) compared to the single-stigma condition. CONCLUSIONS: The magnitude of the layered stigma of obesity and depression may need to be considered in mental health settings when treating the depressed patient with obesity, but likewise in obesity care when treating the obese patient with depression.

Diverse autonomic regulation of pupillary function and the cardiovascular system during alcohol withdrawal.

BACKGROUND: Previous research indicated the complexity of autonomic dysfunction during acute alcohol withdrawal. This study aimed to investigate the pupillary light reflex as an indicator of midbrain and brainstem regulatory systems in relation to cardiovascular autonomic function. METHODS: Thirty male patients were included in the study. They were investigated during acute alcohol withdrawal syndrome and 24h later during clomethiazole treatment and compared to healthy controls. Parameters of pupillary light reflex of both eyes as well as heart rate variability, blood pressure variability and baroreflex sensitivity (BRS) were studied. RESULTS: We observed significantly reduced sympathetic (small diameter, e.g., left eye: 5.00 in patients vs. 5.91 mm in controls) and vagal modulation (e.g., prolonged latencies, left eye: 0.28 vs. 0.26 ms) regarding both pupils during acute alcohol withdrawal syndrome. Cardiovascular parameters showed reduced vagal modulation (e.g., b-slope of BRS: 7. 57 vs. 13.59 ms/mm Hg) and mixed results for sympathetic influence. After 24h, autonomic dysfunction improved significantly, both for the pupils (e.g., left diameter: 5.38 mm) and the heart (e.g., b-slope of BRS: 9.34 ms/mm Hg). While parameters obtained from the pupil correlated with cardiac autonomic function (e.g, BRS and left diameter: r=0.564) in healthy controls, no such pattern was observed in patients. CONCLUSION: Results obtained from the pupil during acute alcohol withdrawal do not simply mirror autonomic dysfunction regarding the heart. Pupillary and cardiovascular changes after 24h indicate state dependencies of the results. The findings are discussed with respect to autonomic mechanisms and potentially involved brain regions.

Implanted electrodes for multi-month EEG.

An implanted electroencephalogram (EEG) recorder would help diagnose infrequent seizure-like events. A proof-of-concept study quantified the electrical characteristics of the electrodes planned for the proposed recorder. The electrodes were implanted in an ovine model for eight weeks. Electrode impedance was less than 800 Ohms throughout the study. A frequency-domain determination of sedation performed similarly for surface versus implanted electrodes throughout the study. The time-domain correlation between an implanted electrode and a surface electrode was almost as high as between two surface electrodes (0.86 versus 0.92). EEG-certified clinicians judged that the implanted electrode quality was adequate to excellent and that the implanted electrodes provided the same clinical information as surface electrodes except for a noticeable amplitude difference. No significant issues were found that would stop development of the EEG recorder.

Heart rate turbulence during acute alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal syndrome is associated with an increased incidence of cardiac arrhythmias and sudden cardiac death. Heart rate turbulence (HRT) parameters were applied during withdrawal to estimate cardiac regulation during treatment with clomethiazole. METHODS: Twenty-two patients suffering from alcohol withdrawal syndrome were included in the study. Heart rate regulation was obtained by means of Holter ECG analyzing time intervals before medication, and 2 and 6h after medication. Slope and onset of HRT were calculated in addition to heart rate variability (HRV) parameters. Furthermore, we calculated the slope and the onset of ectopic beat-like events. RESULTS: Heart rate variability parameters indicated a minor reduction of vagal modulation during withdrawal syndrome. Especially, the fractal scaling exponent BBI alpha1 (4-16) indicated the autonomic shift. In contrast to HRV parameters, no significant changes were observed in the HRT parameters. Significant correlations were observed between severity of withdrawal, as assessed by the AWS scale, and the fractal scaling exponent BBI alpha2 (16-64), and the onset and the slope of HRT of ectopic beat-like activity. CONCLUSION: Increased sympathetic modulation during withdrawal and clomethiazole treatment is not associated with changes of heart rate turbulence parameters predictive of cardiac death after myocardial infarction.

Endothelial dysfunction during acute alcohol withdrawal syndrome.

BACKGROUND: Endothelial dysfunction (EF) is a central phenomenon in a variety of conditions associated with increased cardiovascular morbidity. Here, we investigated EF during acute alcohol withdrawal syndrome before and 24h after medication. We aimed to analyze microcirculation, applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of EF. Additionally, we explored whether segmentation of spectral analysis data may disclose more detailed information on dynamic blood flow behavior. METHODS: We investigated 30 unmedicated patients during acute alcohol withdrawal syndrome and matched controls. Patients were reinvestigated after 24h when half of them had been treated with clomethiazole. Capillary blood flow was assessed on the right forearm after compression of the brachial artery. Parameters of PORH such as time to peak (TP), slope and PORH indices were calculated. Spectral analysis was performed in order to study five different frequency bands. Withdrawal symptoms were quantified by means of the alcohol withdrawal scale (AW scale). RESULTS: We observed a blunted hyperemic response in patients after occlusion of the brachial artery indicated by significantly increased TP and decreased PORH indices. In contrast, vasomotion as investigated by spectral analysis was not altered. Segmentation analysis revealed some alterations in the cardiac band at rest, and indicated differences between treated and untreated patients after 24h. CONCLUSION: Our results suggest peripheral endothelial dysfunction in patients during acute alcohol withdrawal. No major influence of treatment was observed. Future studies need to address the relation of EF to cardiac morbidity during alcohol withdrawal.

Planar saline bath phantom of the Rush head model.

The Rush head model is an approximation of the volume conducting properties of the human head. A planar saline bath phantom was developed to simulate the key properties of the Rush head model while creating a testing platform for implantable neural devices. The phantom closely mimics electrical properties of human tissue such as increased resistivity through the skull region and current flow that wraps around the head. Preliminary testing shows good agreement of the saline bath phantom to predictions from a computer model.

Does parasympathetic modulation prior to ECT treatment influence therapeutic outcome?

Electroconvulsive therapy (ECT) is an established treatment option for major depressive disorder when other treatments have failed. However, the underlying mechanisms responsible for these therapeutical effects are insufficiently understood to date. Furthermore, treatment outcome is difficult to predict. Recent research suggested an important role of autonomic modulation for successful treatment. We aimed to examine putative associations between autonomic modulation and response to ECT treatment and hypothesized a role for vagal modulation prior to therapy. Twenty-four patients with MDD who received ECT were assessed by means of heart rate and blood pressure variability analysis as well as baroreflex sensitivity measurements before, during and after a course of ECT. Autonomic parameters from the complete study population revealed that ECT did not significantly alter basic autonomic modulation after six sessions. Analyses showed a significant association of the reduction of HAMD scores during therapy when compared with baseline autonomic function as reflected in SDNN(RR) (p<0.004), Forbword(RR) (p<0.025) and compression entropy Hc(RR) (p<0.0003). A significant correlation was observed when overall HAMD reduction and changes of LFnu(RR) (p<0.026) or HFnu(RR) (p<0.026) during the course of therapy were analyzed. Our findings suggest that high levels of parasympathetic modulation at baseline might be associated with a beneficial effect upon ECT treatment. Adding to this, levels of parasympathetic activity seemed to increase in patients who respond to ECT treatment. Given these findings can be confirmed in future studies, autonomic modulation might be used as a predictor for therapeutic efficacy of ECT.

Impaired cerebral autoregulation during acute alcohol withdrawal.

Heavy alcohol consumption increases the risk for all major types of stroke and is associated with autonomic dysfunction during alcohol withdrawal syndrome (AWS). Cerebral autoregulation is the mechanism by which cerebral perfusion is maintained stable, representing an intrinsic protective system of the cerebral circulation. Here, we aimed to analyze the influence of acute AWS on cerebral hemodynamics in alcohol-dependent patients. We investigated 20 men in the unmedicated acute state of AWS and repeated the investigation 24h after initiation of clomethiazole treatment. Dynamic cerebral autoregulation (dCA) was assessed by the correlation coefficient index and transfer function analysis (phase and gain) from oscillations of arterial blood pressure and cerebral blood flow velocity (CBFV). The vasomotor reserve (VMR) was measured by the CO(2)-reactivity test. In addition, we assessed autonomic modulation by means of heart rate variability and baroreflex sensitivity. We observed impaired dynamic autoregulation as shown by a multivariate analysis of variance (p<0.038) including all parameters of dCA. Similar results were found for VMR at admission (p<0.05). Pair-wise comparison between baseline and treatment with clomethiazole revealed a significant improvement for the systolic correlation coefficient index (Sx; p<0.001). Furthermore, we found a strong association of autonomic dysfunction and impaired autoregulation indicated by a correlation between the LF/HF ratio and Sx (p<0.001). In conclusion, cerebral autoregulation and VMR are disturbed during acute AWS. Influences of autonomic dysbalance and mental state during withdrawal are suggested. The finding of an affected autoregulation during acute withdrawal might indicate an increased risk for cerebro-vascular disease.

Is successful electroconvulsive therapy related to stimulation of the vagal system?

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to exhibit strong beneficial effects in the treatment of major depressive disorder (MDD). While the exact underlying mechanisms are under debate, a role for the sympathetic response upon ECT has been suggested. When assessing patients with MDD for autonomic function, however, a loss of vagal function is prominent. OBJECTIVE: Here, we aimed to assess the immediate effects of ECT on vagal activity and to test the hypothesis that surrogates of the latter correlate with therapeutic outcome. METHODS: Twenty patients with MDD who underwent ECT treatment were assessed regarding their vagal function using electrophysiological measures and determination of pancreatic polypeptide (PP), which is known to be released upon vagal stimulation. Parameters were correlated to the improvement of disease severity upon ECT treatment. RESULTS: Patients showed a significant increase of PP shortly after ECT which correlated with clinical improvement. Furthermore, the described association with the sympathetic phase after ECT could be verified. CONCLUSION: ECT increases vagal activity which might be associated with the beneficial effect seen following this treatment. PP elevation after administration of ECT might be a useful parameter to estimate the degree of such vagal stimulation after treatment.

Increased pain sensitivity in alcohol withdrawal syndrome.

Withdrawal from analgesic and addictive substances such as opioids or ethanol is associated with increased sensitivity to sensory stimulation in animal models. Here, we investigated perception of innocuous and noxious thermal or electric stimuli applied to the left hand or sternum in 30 male patients undergoing withdrawal from alcohol, 30 male abstained alcoholics and matched controls. The alcohol withdrawal scale and the Banger score were obtained to estimate the severity of withdrawal. In addition, the Beck depression inventory was used to estimate the influence of depressive symptoms on pain perception. The data presented provide substantial evidence that subjects undergoing alcohol withdrawal show increased heat pain sensitivity. Interestingly, this effect was observed both on the left hand and sternum. Pain thresholds and tolerances of electric stimuli did not differ between groups. However, in a subgroup analysis, a higher sensitivity for electrical pain thresholds and tolerances was observed in those patients that were identified to require pharmacological treatment for withdrawal according to disease severity. Furthermore, the perceived painful thermal and electrical sensation was substantially influenced by the affective state of patients. No differences were found between patients of the abstained group and control subjects for any pain parameter. In conclusion, we demonstrate withdrawal-induced hyperalgesia upon thermal stimulation in patients. Since the influence of affective symptoms on pain perception during withdrawal is remarkable, we assume that peripheral and central mechanisms might account for this finding, which should be assessed in detail in future studies.

A fully implantable 96-channel neural data acquisition system.

A fully implantable neural data acquisition system is a key component of a clinically viable brain-machine interface. This type of system must communicate with the outside world and obtain power without the use of wires that cross through the skin. We present a 96-channel fully implantable neural data acquisition system. This system performs spike detection and extraction within the body and wirelessly transmits data to an external unit. Power is supplied wirelessly through the use of inductively coupled coils. The system was implanted acutely in sheep and successfully recorded, processed and transmitted neural data. Bidirectional communication between the implanted system and an external unit was successful over a range of 2 m. The system is also shown to integrate well into a brain-machine interface. This demonstration of a high channel-count fully implanted neural data acquisition system is a critical step in the development of a clinically viable brain-machine interface.

Integrated circuit amplifiers for multi-electrode intracortical recording.

Significant progress has been made in systems that interpret the electrical signals of the brain in order to control an actuator. One version of these systems senses neuronal extracellular action potentials with an array of up to 100 miniature probes inserted into the cortex. The impedance of each probe is high, so environmental electrical noise is readily coupled to the neuronal signal. To minimize this noise, an amplifier is placed close to each probe. Thus, the need has arisen for many amplifiers to be placed near the cortex. Commercially available integrated circuits do not satisfy the area, power and noise requirements of this application, so researchers have designed custom integrated-circuit amplifiers. This paper presents a comprehensive survey of the neural amplifiers described in publications prior to 2008. Methods to achieve high input impedance, low noise and a large time-constant high-pass filter are reviewed. A tutorial on the biological, electrochemical, mechanical and electromagnetic phenomena that influence amplifier design is provided. Areas for additional research, including sub-nanoampere electrolysis and chronic cortical heating, are discussed. Unresolved design concerns, including teraohm circuitry, electrical overstress and component failure, are identified.

Neurobrucellosis with thalamic infarction: a case report.

Brucellosis is prevalent in North and East Africa, the Middle East, South and Central Asia, South and Central America and the Mediterranean countries of Europe. In 5% of cases it may lead to central nervous system manifestation presenting most often as a meningitis or meningoencephalitis. Here we report and discuss a case of neurobrucellosis with meningitis with cranial nerves neuritis. A 56-year-old German male was admitted with bilateral abducens nerve palsy, amblyacousia and intractable headaches. An enzyme-linked immunosorbent assay (ELISA) revealed antibodies against Brucella in serum and cerebrospinal fluid (CSF). Additionally, our patient suffered from an infarction of the left thalamus. In conclusion, in cases of unresponsive meningitis or meningoencephalitis and history of travel in endemic regions, neurobrucellosis should be considered. If initial microbiological tests fail, complementary investigations such as ELISA are indicated to detect Brucella species in serum and/or CSF.

Reduced cardio-respiratory coupling in acute alcohol withdrawal.

BACKGROUND: Chronic alcoholism represents a risk factor for cardiac arrhythmias. One underlying mechanism is a sympathetically dominated autonomic imbalance. This is especially apparent during acute withdrawal from alcohol. Since linear analysis of heart rate variability may not be entirely adequate to detect such autonomic dysfunction in acute alcohol withdrawal, we applied novel non-linear parameters and measures for cardio-respiratory coupling. METHODS: 20 patients suffering from acute alcohol withdrawal syndrome and 20 controls were included. For patients, heart rate and respiration were recorded on admission, after medication and at discharge. From these data, complexity measures (symbolic dynamics, approximate entropy) of heart rate modulation and respiration as well as parameters for cardio-respiratory coupling (coherence, cross-approximate entropy) which relate to vagal function were calculated. RESULTS: Heart rate modulation was significantly less complex in patients acutely admitted for alcohol withdrawal. Furthermore, coupling between beat-to-beat (RR) intervals and respiration time series was significantly diminished. Of the parameters assessed, cross-approximate entropy showed a trend for correlation with symptom severity. CONCLUSION: These data indicate diminished vagal function in acute alcohol withdrawal. Applying the methods described thus allows a sensitive detection of vagal neuropathy in this disease.

Decreased sensitivity to thermal pain in rats bred for high anxiety-related behaviour is attenuated by citalopram or diazepam treatment.

Complex interactions between pain perception, anxiety and depressive symptoms have repeatedly been described. However, pathophysiological or biochemical mechanisms underlying the alterations of pain perception in patients suffering from anxiety or depression still remain a matter of debate. Thus, we aimed to perform an investigation on pain perception in an animal model of extremes in anxiety-related behaviour, which might provide a tool for future studies. Here, thermal pain thresholds were obtained from rats with a genetic predisposition to high anxiety-related behaviour (HAB), including signs of comorbid depression-like behaviour and from controls (low-anxiety rats (LAB); cross-bred HAB and LAB rats; Wistar rats). Furthermore, the effect of eight-week antidepressive treatment using citalopram and of short-term anxiolytic treatment with diazepam on pain-related behaviour was assessed. Simultaneously, anxiety-related behaviour was monitored. At baseline, HAB animals showed 35% higher thresholds for thermal pain than controls. These were normalized to control levels after eight weeks of continuous citalopram treatment paralleled by a reduction of anxiety-related behaviour, but also acutely after diazepam administration. Overall, thermal pain thresholds in HAB animals are shifted in a similar fashion as seen in patients suffering from major depressive disorder. Antidepressive, as well as anxiolytic treatments, attenuated these differences. As the relative importance of the factors anxiety and depression cannot be derived from this study with certainty, extending these investigations to additional animal models might represent a valuable tool for future investigations concerning the interrelations between anxiety, depression, and pain at a molecular level.

Heart rate variability and sympathetic skin response in male patients suffering from acute alcohol withdrawal syndrome.

BACKGROUND: Many symptoms of alcohol withdrawal (AW) such as tachycardia or elevated blood pressure might be explained by increased peripheral and central adrenergic activity. In contrast to many neurochemical studies of sympathetic activation during AW, only very few studies investigated autonomic balance using neurophysiological methods. METHODS: We investigated heart rate variability (HRV) and sympathetic skin response (SSR) in male patients suffering from mild AW syndrome (n = 20, no treatment required) and in patients with moderate to severe AW syndrome (n = 20, clomethiazole treatment) in the acute stage. Sympathovagal influence was quantified using measures of time and frequency domain of HRV as well as modern nonlinear parameters (compression entropy). Furthermore, we obtained latencies and amplitudes of SSR to quantify isolated sympathetic influence. Measures were obtained during the climax of withdrawal symptomatology before treatment, 1 day after climax, and shortly before discharge from hospital. Alcohol withdrawal scores were obtained and correlated to autonomic measures. RESULTS: Ambulatory blood pressure and AW scores revealed characteristic withdrawal symptoms in both patient groups. Apart from the nonlinear parameter compression entropy, Hc, measures of HRV revealed no sign of autonomic dysfunction in contrast to the significantly increased heart rates at the time of admission. Latencies and amplitudes of SSR did not indicate any increase of sympathetic activity. A negative correlation was found between Hc and mental withdrawal symptoms. CONCLUSIONS: We show here that classical measures for autonomic nervous system activity such as HRV and SSR are not suitable for describing the autonomic changes seen in acute AW, although a major role for the sympathetic nervous system has been proposed. This might be due to multiple dysregulation of metabolites in AWS or to subtle alcohol-induced damage to neuronal structures, issues that should be addressed in future studies.

Reduced baroreflex sensitivity in acute alcohol withdrawal syndrome and in abstained alcoholics.

Acute alcohol withdrawal is often associated with increased sympathetic activity, and a decreased baroreflex sensitivity (BRS) can be assumed. Parameters of heart rate variability (HRV), blood pressure variability (BPV), BRS as well as cardiac index (CI), left ventricular work index (LVWI) and total peripheral resistance (TPR) were investigated in 20 patients undergoing acute alcohol withdrawal and matched controls. Measures were obtained during the peak of withdrawal symptomatology prior to treatment as well as 2 and 24h under continuous clomethiazole treatment. Alcohol withdrawal scores were obtained and correlated with autonomic measures. In addition, parameters were assessed in 15 subjects who abstained from alcohol after long-term intake. We found a severe down-regulation of BRS during acute alcohol withdrawal and to a milder extent in abstained alcoholics. Furthermore, HRV and BPV did not unequivocally reveal signs of elevated sympathetic activity. Non-linear parameters of HRV and parameters of BRS correlated with the severity of AWS. The distinct decrease of BRS in AWS and in long-term abstained subjects described here is of importance since similar alterations have been identified as independent prognostic factors for cardiac mortality in other diseases.

Influence of antipsychotic medication on pain perception in schizophrenia.

A number of clinical observations indicate that pain processing might be disturbed in psychotic disorders such as schizophrenia. Only a few studies have investigated pain perception in schizophrenia. The main objective of this study was the investigation of thresholds of warmth perception (WP), thermal pain onset (TPO) and thermal pain tolerance (TPT) in acute schizophrenic patients and the influence of antipsychotic medication on the patients' responses. We investigated 23 schizophrenic subjects who had been not received antipsychotic treatment for 8 weeks, and we then reassessed them 3 days later after the introduction of neuroleptics. Acute symptoms of schizophrenia were measured using the Scales for the Assessment of Positive and Negative Symptoms. Thresholds were determined by a contact thermode on both volar wrists. Schizophrenic patients showed significantly increased thresholds of WP and TPO relative to healthy controls. Antipsychotics did not alter pain thresholds. We found no correlation between pain perception and psychometric scales. Our findings demonstrate altered warmth and heat pain perception in acute schizophrenia. We believe that our findings can be attributed to information-processing abnormalities of the disorder and that they are not specific to pain processing, per se, since both WP and TPO were significantly different. Future studies should evaluate attentional deficits in schizophrenia in relation to pain perception.