Diagnostic Utility of Sodium Lactate Infusion and CO2-35% Inhalation for Panic Disorder.

Laboratory measures have played an integral role in diagnosing pathology; however, compared to traditional medicine, psychiatric medicine has lagged behind in using such measures. A growing body of literature has begun to examine the viability and development of different laboratory measures in order to diagnose psychopathologies. The present review examines the current state of development of both sodium lactate infusion and CO2-35% inhalation as potential ancillary measures to diagnose panic disorder (PD). A previously established 3-step approach to identifying laboratory-based diagnostic tests was applied to available literature assessing the ability of both sodium lactate infusion or CO2-35% inhalation to induce panic attacks in PD patients, healthy controls, and individuals with other psychiatric conditions. Results suggest that across the literature reviewed, individuals with PD were more likely to exhibit panic attacks following administration of sodium lactate or CO2-35% compared to control participants. The majority of the studies examined only compared individuals with PD to healthy controls, suggesting that these ancillary measures are underdeveloped. In order to further determine the utility of these ancillary measures, research is needed to determine if panic attacks following administration of these chemical agents are unique to PD, or if individuals with related pathologies also respond, which may be indicative of transdiagnostic characteristics found across disorders.

Evoked Potentials Investigations of Deficit Versus Nondeficit Schizophrenia: EEG-MEG Preliminary Data.

Heterogeneity of schizophrenia is a major obstacle toward understanding the disorder. One likely subtype is the deficit syndrome (DS) where patients suffer from predominantly negative symptoms. This study investigated the evoked responses and the evoked magnetic fields to identify the neurophysiological deviations associated with the DS. Ten subjects were recruited for each group (Control, DS, and Nondeficit schizophrenia [NDS]). Subjects underwent magnetoencephalography (MEG) and electroencephalography (EEG) testing while listening to an oddball paradigm to generate the P300 as well as a paired click paradigm to generate the mid-latency auditory-evoked responses (MLAER) in a sensory gating paradigm. MEG-coherence source imaging (CSI) during P300 task revealed a significantly higher average coherence value in DS than NDS subjects in the gamma band (30-80 Hz), when listening to standard stimuli but only NDS subjects had a higher average coherence level in the gamma band than controls when listening to the novel sounds. P50, N100, and P3a ERP amplitudes (EEG analysis) were significantly decreased in NDS compared with DS subjects. The data suggest that the deviations in the 2 patient groups are qualitatively different. Deviances in NDS patients suggest difficulty in both early (as in the gating paradigm), as well as later top-down processes (P300 paradigm). The main deviation in the DS group was an exaggerated responsiveness to ongoing irrelevant stimuli detected by EEG whereas NDS subjects had an exaggerated response to novelty.

Evoked potential correlates of post-traumatic stress disorder in refugees with history of exposure to torture.

The presence and magnitude of information processing deviations associated with Post-Traumatic Stress Disorder (PTSD) are far from being well-characterized. In this study we assessed the auditory and visually evoked cerebral responses in a group of Iraqi refugees who were exposed to torture and developed PTSD (N = 20), Iraqi refugees who had been exposed to similar trauma but did not develop PTSD (N = 20), and non-traumatized controls matched for age, gender, and ethnicity (N = 20). We utilized two paired-stimulus paradigms in auditory and visual sensory modalities, respectively. We found significantly smaller amplitudes of both the auditory P50 and the visual N75 responses in PTSD patients compared to controls, reflecting decreased response to simple sensory input during a relatively early phase of information processing (interval 50-75 ms post stimulus). In addition, deficient suppression of the P50/N75 response to repeating stimuli at this early stage in both modalities is indicative of difficulty in filtering out irrelevant sensory input. Among associations between electrophysiological and clinical measures, a significant positive correlation was found between dissociation score and P50 S1 amplitudes (p = 0.024), as well as stronger auditory P50 gating correlated with higher quality-of-life index scores (p = 0.013). In addition, smaller amplitudes of N150 visual evoked response to S1 showed a significant association with higher avoidance scores (p = 0.015). The results of this study highlight the importance of early automatic auditory and visual evoked responses in probing the information processing and neural mechanisms underlying symptomatology in PTSD.

Mapping repetition suppression of the P50 evoked response to the human cerebral cortex.

OBJECTIVE: The cerebral network subserving repetition suppression (RS) of the P50 auditory evoked response as observed using paired-identical-stimulus (S1-S2) paradigms is not well-described. METHODS: We analyzed S1-S2 data from electrodes placed on the cortices of 64 epilepsy patients. We identified regions with maximal amplitude responses to S1 (i.e., stimulus registration), regions with maximal suppression of responses to S2 relative to S1 (i.e., RS), and regions with no or minimal RS 30-80 ms post stimulation. RESULTS: Several temporal, parietal and cingulate area regions were shown to have significant initial registration activity (i.e., strong P50 response to S1). Moreover, prefrontal, cingulate, and parietal lobe regions not previously proposed to be part of the P50 habituation neural circuitry were found to exhibit significant RS. CONCLUSIONS: The data suggest that the neural network underlying the initial phases of the RS process may include regions not previously thought to be involved like the parietal and cingulate cortexes. In addition, a significant role for the frontal lobe in mediating this function is supported. SIGNIFICANCE: A number of regions of interest are identified through invasive recording that will allow further probing of the RS function using less invasive technology.

Neural activations during auditory oddball processing discriminating schizophrenia and psychotic bipolar disorder.

BACKGROUND: Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ) but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain, given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatiotemporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders. METHODS: Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multisensor electroencephalography. Principal components analysis was used to reduce multisensor data before evaluating group differences on voltage and frequency of neural responses over time. RESULTS: Linear discriminant analysis revealed five variables that best differentiated groups: 1) late beta activity to standard stimuli; 2) late beta/gamma activity to targets discriminated BPP from other groups; 3) midlatency theta/alpha activity to standards; 4) target-related voltage at the late N2 response discriminated both psychosis groups from H; and 5) target-related voltage during early N2 discriminated BPP from H. CONCLUSIONS: Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.

Single-trial analysis of auditory evoked potentials improves separation of normal and schizophrenia subjects.

OBJECTIVE: In this study, we employed iterative independent component analysis of single-trial auditory evoked responses to identify features of the P50 and N100 components that provide maximum separation between normal controls and schizophrenia subjects and compared the results against classical ensemble averaging. METHOD: We analyzed data from 13 schizophrenia and 20 normal control subjects. Responses were obtained in a paired-stimulus paradigm, in which an auditory stimulus S(1) is followed by an identical S(2). The amplitude and latency of the P50 and N100 components in response to the S(1) and S(2) stimuli were measured in each single trial and used as features to classify the responses into two groups. Several methods were used for classification, while their performance was quantified in a 10-fold stratified cross-validation approach. RESULTS: We found that normal controls tended to respond earlier and their individual responses had significantly higher amplitude (p<0.01) and significantly less latency variability (p<0.01) compared to schizophrenia patients. The S(1) latency was the most significant discriminatory feature (p<0.01) followed by S(2) latency (p<0.01). The S(2) amplitude, though relatively larger in normal subjects (p<0.05), was the least discriminatory feature. Classification based on single-trial analysis yielded 100% accuracy, while the classical ensemble averaging yielded only a maximum of 76% accuracy. CONCLUSIONS: Our results demonstrate that single-trial analysis can accurately separate schizophrenia patients from normal controls and suggest that inter-trial variability plays a significant role in information processing in the human brain. SIGNIFICANCE: The proposed technique may have a significant impact as a clinical tool in the quest for identifying physiological markers of schizophrenia.

Mapping repetition suppression of the N100 evoked response to the human cerebral cortex.

BACKGROUND: Repetition suppression (RS) phenomena, such as those observed using paired-identical-stimulus (S1-S2) paradigms, likely reflect adaptive functions such as habituation and, more specifically, sensory gating. METHODS: To better characterize the neural networks underlying RS, we analyzed auditory S1-S2 data from electrodes placed on the cortices of 64 epilepsy patients who were being evaluated for surgical therapy. We identified regions with maximal amplitude responses to S1 (i.e., stimulus registration regions), regions with maximal suppression of responses to S2 relative to S1 (i.e., RS), and regions with no or minimal RS. RESULTS: Auditory perceptual regions, such as the superior temporal gyri, were shown to have significant initial registration activity (i.e., strong response to S1). Several prefrontal, cingulate, and parietal lobe regions were found to exhibit stronger RS than those recorded from the auditory perceptual areas. CONCLUSIONS: The data strongly suggest that the neural network underlying repetition suppression may include regions not previously thought to be involved, such as the parietal and cingulate cortexes. In addition, the data also support the notion that the initial response to stimuli and the ability to suppress the stimuli if repeated are two separate, but likely related, functions.

Probing the relative contribution of the first and second responses to sensory gating indices: a meta-analysis.

Sensory gating deficit in schizophrenia patients has been well-documented. However, a central conceptual issue, regarding whether the gating deficit results from an abnormal initial response (S1) or difficulty in attenuating the response to the repeating stimulus (S2), raise doubts about the validity and utility of the S2/S1 ratio as a measure of sensory gating. This meta-analysis study, therefore, sought to determine the consistency and relative magnitude of the effect of the two essential components (S1 and S2) and the ratio. The results of weighted random effects meta-analysis revealed that the overall effect sizes for the S1 amplitude, S2 amplitude, and P50 S2/S1 ratio were -0.19 (small), 0.65 (medium to large), and 0.93 (large), respectively. These results confirm that the S2/S1 ratio and the repeating (S2) stimulus differ robustly between schizophrenia patients and healthy controls in contrast to the consistent but smaller effect size for the S1 amplitude. These findings are more likely to reflect defective inhibition of repeating redundant input rather than an abnormal response to novel stimuli.

Relationships between sensory "gating out" and sensory "gating in" of auditory evoked potentials in schizophrenia: a pilot study.

The interrelationship between the ability to inhibit incoming redundant input (gating out) and the ability of the brain to respond when the stimulus changes (gating in), has not been extensively examined. We administered a battery of auditory evoked potential tests to a group of chronic, medicated schizophrenia patients (N=12) and a group of healthy subjects (N=12) in order to examine relationships between "gating out" measures (suppression with repetition of the P50, N100, and P200 evoked responses), and the mismatch negativity (MMN) and the P300 event related potentials as measures of "gating in". Gating ratios for N100 and P200 in a visual attention paired-click task differed significantly between groups. Mismatch negativity and P300 potential amplitudes were also significantly reduced in the patient group. When including all subjects (N=24) a negative correlation was found between the P50 gating and the amplitude of the MMN. In healthy subjects this correlation was significantly stronger compared to schizophrenia patients. While no significant correlation was noted between the amplitudes of the P300 and any gating measures when all 24 subjects were included, a significant negative correlation was seen between the P200 gating and the P300 amplitudes in schizophrenia patients; an opposite trend was noted in healthy subjects. Finally, a positive correlation was seen between the P300 and MMN (to abstract deviance) amplitudes in healthy subjects, but the opposite was found in patients. These results suggest that further study of these interrelationships could inform the understanding of information processing abnormalities in schizophrenia.

Auditory evoked potential variability in healthy and schizophrenia subjects.

OBJECTIVES: To investigate if the reduced P50, N100 and P200 auditory evoked potential (EP) components and gating deficits seen in schizophrenia can be explained in terms of response incompleteness. METHODS: Twenty-five healthy and schizophrenia participants were studied using pairs of 1000Hz tones (S1 and S2, 0.5s apart) separated by 8.0s. A correlation-based clustering method identified the responses containing P50, N100, and/or P200 related-activity. RESULTS: Schizophrenia participants produced fewer S1 and S2 responses containing all three EP components than healthy participants. Healthy participants, but not the patient population, produced fewer and smaller S2 than S1 responses containing all three EP components. However, the S2 responses following complete S1 responses were smaller than the complete S1 responses in both populations. CONCLUSIONS: The gating deficits observed in schizophrenia are due to two mechanisms. First, the S1 response consistency is less in schizophrenia than in health. Second, the S2 responses are attenuated less in schizophrenia. SIGNIFICANCE: This research contributes to the understanding of response variability and sensory gating in health and schizophrenia. It also extends previous reports that fewer and smaller P300 components are produced in schizophrenia than in health to the mid-latency component range.

A pilot study revealing impaired P50 gating in antisocial personality disorder.

The authors investigated preattentive filtering assessed by P50 gating in nine participants with antisocial personality disorder (ASPD) and seven with adult-onset antisocial behavior (AAB). Relative to 15 comparison subjects, gating was impaired in ASPD, suggesting abnormal pre-attentive filtering in pathological impulsivity.

Sensory-gating deficit of the N100 mid-latency auditory evoked potential in medicated schizophrenia patients.

The clinical and neuro-cognitive correlates of the P50 and N100 auditory evoked responses gating deficits in schizophrenia have thus far eluded identification. Based on our prior results, we hypothesized that, in addition to the P50, gating of the N100 is significantly decreased in schizophrenia and that this deficit correlates with the negative symptoms dimension of schizophrenia. Amplitudes and gating measures of the P50 and N100 were compared between stable out-patients (N=45) (mainly on atypical antipsychotics) with chronic schizophrenia and age- and gender-matched healthy controls (N=49) and the clinical correlates examined. All subjects underwent the paired-stimulus paradigm in 3 or 4 different days. Data from day one and the mean of all days (MOAD) were examined. P50 and N100 amplitudes and gating measures were correlated with PANSS and Wisconsin Card Sorting Test data. Utilizing day one data, no amplitude or gating measures were significantly different between the groups. Utilizing MOAD data, both P50 and N100 gating were significantly decreased in schizophrenia patients. The N100 gating deficit correlated with the negative-symptoms cluster and measures of frontal lobe dysfunction. The data suggest a correlation between N100 gating deficit and the negative-cognitive deficits dimensions of schizophrenia. Data also suggest that improving the signal to noise ratio (MOAD data) increases the sensitivity for detecting gating abnormalities and assessing their clinical correlates.

Diminished P50, N100 and P200 auditory sensory gating in bipolar I disorder.

Bipolar I disorder is associated with diminished gating of the auditory evoked P50 component. P50 gating may relate to early filtering of sensory information, protecting higher-order cognitive functions. Gating of the auditory evoked N100 and P200 components has not been investigated in bipolar I disorder, although N100 and P200 gating could reflect different mechanisms and functions in the process of filtering sensory information in addition to those reflected by P50 gating. We investigated P50, N100, and P200 gating assessed with the paired-click paradigm in 22 subjects with bipolar I disorder and 54 healthy controls. Peak amplitudes and latencies were assessed at Cz for the P50, N100, and P200 components. Gating was defined as the reduction in peak amplitude from the first (S1) to the second stimulus (S2) of a stimulus pair, and expressed as gating ratio ([S2(amplitude)/S1(amplitude)]()100) and difference score (S1(amplitude)-S2(amplitude)). Group differences were detected with multivariate analyses and controlled for differences in age and ethnicity. Subjects with bipolar I disorder had higher P50, N100 and P200 ratios and lower difference scores compared with findings for controls. These findings extend the existing evidence on impaired sensory gating in bipolar I disorder beyond the P50, suggesting impaired filtering at both pre-attentive and early attentive levels in bipolar I disorder.

Reduction of prelimbic inhibitory gating of auditory evoked potentials after fear conditioning.

Inhibitory gating (IG) is a basic central nervous system process for filtering repetitive sensory information. Although IG deficits coincide with cognitive and emotional dysfunction in a variety of neuropsychiatric disorders, limited research has been completed on the basic, functional nature of IG. Persistent IG occurs in rat prelimbic medial prefrontal cortex (mPFC), a crucial site for modulating emotional learning. To investigate the interaction of affect and IG, we recorded local field potentials (LFP) directly from prelimbic mPFC and examined the influence of tone-shock fear conditioning (FC) on IG. Behavioral reactions during IG were observed before and after FC, and increase of orienting response after FC indicated induction of tone-shock association. After FC, some components of LFP response exhibited short-term weakening of IG. On a subsequent day of recording, IG strengthened for all LFP components, but individual components differed in their particular changes. Affective regulation of IG represents an important factor influencing within-subject IG variability, and these results have implications for understanding the role of rapid, implicit neural coding involved in emotional learning and affective disruption in psychiatric disease.

Evoked potential variability.

An unsupervised correlation-based clustering method was developed to assess the trial-to-trial variability of auditory evoked potentials (AEPs). The method first decomposes single trials into three frequency bands, each containing activity primarily associated with one of the three major AEP components, i.e., P50, N100 and P200. Next, single-trial evoked potentials with similar post-stimulus characteristics are clustered and selectively averaged to determine the presence or absence of an AEP component. The method was evaluated on actual AEP and spontaneous EEG data collected from 25 healthy participants using a paradigm in which pairs of identical tones were presented, with the first stimulus (S1) presented 0.5s before the second stimulus (S2). Homogeneous, well-separated clusters were obtained and substantial AEP variability was found. Also, there was a trend for S2 to produce fewer 'complete' (and significantly smaller) responses than S1. Tests conducted on spontaneous EEG produced similar clusters as obtained from EP data, but significantly fewer stimuli produced responses containing all three EP components than seen in AEP data. These findings suggest that the clustering method presented here performs adequately to assess trial-to-trial EP variability. Also, the results suggest that the sensory gating observed in normal controls may be caused by the fact that the second stimulus generates fewer 'responsive' trials than the first stimulus, thus resulting in smaller ensemble averages.

Auditory evoked potential abnormalities in cluster headache.

Mid-latency and long-latency auditory evoked responses were investigated in 27 patients with cluster headache who had a mean age of 38.7+/-9.7 years and who were free of pain at the time of testing. Twenty-five age-matched healthy persons served as controls. Latencies and amplitudes of corresponding responses (N100, P200, and P300) were measured. The parameters were calculated at Pz for the P300 and Cz electrodes for the N100 and P200. Multiple analysis of variance revealed a significant overall effect of group (P=0.011). P200 amplitude was significantly smaller in cluster headache patients (P=0.0002). No differences were found for N100 or P300. These data suggest a hitherto unrecognized defect in the information processing pathways, in the early attentive phase represented by the P200 component.

Reduced auditory evoked potential component N100 in schizophrenia--a critical review.

The role of a reduced N100 (or N1) component of the auditory event related potential as a potential trait marker of schizophrenia is critically discussed in this review. We suggest that the extent of the N100 amplitude reduction in schizophrenia depends on experimental and subject factors, as well as on clinical variables: N100 is more consistently reduced in studies using interstimulus intervals (ISIs) >1 s than in studies using shorter ISIs. An increase of the N100 amplitude by allocation of attention is often lacking in schizophrenia patients. A reduction of the N100 amplitude is nevertheless also observed when such an allocation is not required, proposing that both endogenous and exogenous constituents of the N100 are affected by schizophrenia. N100 is more consistently reduced in medicated than unmedicated patients, but a reduction of the N100 amplitude as a consequence of antipsychotic medication was shown in only two of seven studies. In line with that, the association between the N100 reduction and degree of psychopathology of patients appears to be weak overall. A reduced N100 amplitude is found in first degree relatives of schizophrenia patients, but the risk of developing schizophrenia is not reflected in the N100 amplitude reduction.

Evidence for a frontal cortex role in both auditory and somatosensory habituation: a MEG study.

Auditory and somatosensory responses to paired stimuli were investigated for commonality of frontal activation that may be associated with gating using magnetoencephalography (MEG). A paired stimulus paradigm for each sensory evoked study tested right and left hemispheres independently in ten normal controls. MR-FOCUSS, a current density technique, imaged simultaneously active cortical sources. Each subject showed source localization, in the primary auditory or somatosensory cortex, for the respective stimuli following both the first (S1) and second (S2) impulses. Gating ratios for the auditory M50 response, equivalent to the P50 in EEG, were 0.54+/-0.24 and 0.63+/-0.52 for the right and left hemispheres. Somatosensory gating ratios were evaluated for early and late latencies as the pulse duration elicits extended response. Early gating ratios for right and left hemispheres were 0.69+/-0.21 and 0.69+/-0.41 while late ratios were 0.81+/-0.41 and 0.80+/-0.48. Regions of activation in the frontal cortex, beyond the primary auditory or somatosensory cortex, were mapped within 25 ms of peak S1 latencies in 9/10 subjects during auditory stimulus and in 10/10 subjects for somatosensory stimulus. Similar frontal activations were mapped within 25 ms of peak S2 latencies for 75% of auditory responses and for 100% of somatosensory responses. Comparison between modalities showed similar frontal region activations for 17/20 S1 responses and for 13/20 S2 responses. MEG offers a technique for evaluating cross modality gating. The results suggest similar frontal sources are simultaneously active during auditory and somatosensory habituation.

Attentional deficits in cocaine-dependent patients: converging behavioral and electrophysiological evidence.

Although there are several reports of patients with cocaine dependence displaying cognitive deficits, the nature of their information processing deficits is not well characterized. In the present study, the attentional performance of cocaine-dependent patients (n=14) was examined and compared with that of healthy control individuals (n=15). Attention was assessed using an auditory oddball event-related task as well as the Continuous Performance Test (CPT, Identical Pairs version). The cocaine-dependent group displayed P300 amplitude reduction compared to controls. The group difference in P300 response latency did not reach significance. On the CPT, the cocaine-dependent patients displayed significantly poorer discriminability and greater errors of commission than the controls. There was a positive correlation between performance on the oddball event-related task and performance on the CPT. This investigation provides converging behavioral and electrophysiological evidence of attentional deficits in cocaine-dependent patients.