P50 inhibitory sensory gating in schizophrenia: analysis of recent studies.

INTRODUCTION: Inhibitory sensory gating of the P50 cerebral evoked potential to paired auditory stimuli (S1, S2) is a widely used paradigm for the study of schizophrenia and related conditions. Its use to measure genetic, treatment, and developmental effects requires a metric with more stable properties than the simple ratio of the paired responses. METHODS: This study assessed the ratio P50S2µV/P50S1µV and P50S2µV co-varied for P50S1µV in all 27 independent published studies that compared schizophrenia patients with healthy controls from 2000 to 2019. The largest study from each research group was selected. The Colorado research group's studies were excluded to eliminate bias from the first report of the phenomenon. RESULTS: Across the 27 studies encompassing 1179 schizophrenia patients and 1091 healthy controls, both P50S2µV co-varied for P50S1µV and P50S2µV/P50S1µV significantly separated the patients from the controls (both P < 0.0001). Effect size for P50S2µV co-varied for P50S1µV is d' = 1.23. The normal distribution of P50S2µV co-varied for P50S1µV detected influences of maternal inflammation and effects on behavior in a recent developmental study, an emerging use for the P50 inhibitory gating measure. P50S2µV/P50S1µV was not normally distributed. Results from two multi-site NIMH genetics collaborations also support the use of P50S2µV as a biomarker. CONCLUSION: Both methods detect an abnormality of cerebral inhibition in schizophrenia with high significance across multiple independent laboratories. The normal distribution of P50S2µV co-varied for P50S1µV makes it more suitable for studies of genetic, treatment, and other influences on the development and expression of inhibitory deficits in schizophrenia.

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

INTRODUCTION: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison. The goal was to utilize the unique opportunity provided by DBS surgery for ET to map the P50 response in multiple deep brain structures in order to determine the utility of intraoperative P50 detection for facilitating DBS targeting of auditory responsive subterritories. MATERIALS AND METHODS: We developed a method to assess P50 response intraoperatively with local field potentials (LFP) using microelectrode recording during routine clinical electrophysiologic mapping for awake DBS surgery in seven ET patients. Recording sites were mapped into a common stereotactic space. RESULTS: Forty significant P50 responses of 155 recordings mapped to the ventral thalamus, RT and CN head/body interface at similar rates of 22.7-26.7%. P50 response exhibited anatomic specificity based on distinct positions of centroids of positive and negative responses within brain regions and the fact that P50 response was not identified in the recordings from either the internal capsule or the dorsal thalamus. CONCLUSIONS: Detection of P50 response intraoperatively may guide DBS targeting RT and subterritories within CN head/body interface-DBS targets with the potential to treat psychosis and shown to modulate schizophrenia-like aberrancies in mouse models.

Effects of phosphatidylcholine and betaine supplements on women's serum choline.

Background: Maternal phosphatidylcholine supplements have shown benefit in the development of the human fetal brain, as assessed both by newborn physiological measurements and by a related decrease in later childhood behavioral abnormalities. However, the relatively low choline component of phosphatidylcholine mandates high doses that are difficult for pregnant women to consume. Objective: Betaine can substitute for some choline effects. The hypothesis was that betaine supplementation would significantly increase women's serum choline. Design: A three-arm crossover clinical trial was used to assess serum concentrations of choline after betaine supplements at two doses, in comparison with phosphatidylcholine supplementation. The effects of both a single dose and of one-week twice-daily doses were assessed in normal non-pregnant women. Results: Betaine supplements at two doses failed to increase serum choline concentrations after single administration or one-week twice-daily dosing. Phosphatidylcholine supplements raised choline concentrations after both single doses (mean change from baseline 8.34 ± 7.29 ng/ml, paired t = 3.24, df 7, p = 0.014, range 1-21 ng/ml, d' = 1.15) and one-week twice-daily doses (mean change from baseline 4.58 ± 3.68 ng/ml standard deviation; paired t = 3.51, df 7, p < 0.001, range 2-13 ng/ml, d' = 2.65). Betaine concentrations rose after both betaine and phosphatidylcholine supplementation. Conclusions: Betaine supplements did not substitute for phosphatidylcholine supplements, which raise serum choline concentrations both after a single dose and after repeated administration. However, serum betaine concentrations did rise after both betaine and phosphatidylcholine consumption and, therefore, betaine may be a stable indicator of choline intake.

Nicotine restores functional connectivity of the ventral attention network in schizophrenia.

While previous work has suggested that nicotine may transiently improve attention deficits in schizophrenia, the neuronal mechanisms are poorly understood. This study is the first to examine the effects of nicotine on connectivity within the ventral attention network (VAN) during a selective attention task in schizophrenia. Using a crossover design, 17 nonsmoking patients with schizophrenia and 20 age/gender-matched nonsmoking healthy controls performed a go/no-go task with environmental noise distractors during application of a 7 mg nicotine or placebo patch. Psychophysiological interaction analysis was performed to analyze task-associated changes in connectivity between a ventral parietal cortex (VPC) seed and the inferior frontal gyrus (IFG), key components of the human VAN. Effects of nicotine on resting state VAN connectivity were also examined. A significant diagnosis × drug interaction was observed on task-associated connectivity between the VPC seed and the left IFG (F(1,35) = 8.03, p < 0.01). This effect was driven by decreased connectivity after placebo in patients and greater connectivity after nicotine. Resting state connectivity analysis showed a significant main effect of diagnosis between the seed and right IFG (F = 4.25, p = 0.023) due to increased connectivity in patients during placebo, but no drug × diagnosis interactions or main effects of drug. This study is the first to demonstrate that 1) the VAN is disconnected in schizophrenia during selective attention, and 2) nicotine may normalize this pathological state.

Neuronal effects of nicotine during auditory selective attention in schizophrenia.

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention-associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task-associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task-associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention-dependent manner in schizophrenia.

Sensory gating disturbances in the spectrum: similarities and differences in schizotypal personality disorder and schizophrenia.

BACKGROUND: DSM-5 places schizophrenia on a continuum from severe, chronic schizophrenia to the attenuated schizophrenia-like traits of schizotypal personality disorder (SPD), the prototypic schizophrenia-related personality disorder. SPD shares common genetic and neurobiological substrates with schizophrenia, including information processing abnormalities, although they are less marked. This is the first study to directly compare the P50 evoked electroencephalographic response-a measure of sensory gating and a neurophysiological endophenotype-between schizophrenia-spectrum groups. Two hypotheses were tested: (1) Compared with healthy controls (HCs), schizophrenia patients show reduced P50 suppression and SPD patients resemble schizophrenia but exhibit less marked deficits; and (2) Deficient P50 suppression in SPD is associated with greater clinical symptom severity. METHODS: P50 was assessed in 32 schizophrenia-spectrum disorder patients (12 SPD, 20 schizophrenia patients) and 25 demographically-matched HCs. The standard conditioning (C)-testing (T) paradigm was used and P50 suppression was quantified using the T-C difference and the T/C ratio. RESULTS: All P50 measures showed a linear, stepwise pattern with the SPD group intermediate between the HC and schizophrenia groups. Compared with HCs, both patient groups had lower conditioning and T-C difference values. Among the SPD group, greater clinical symptom severity was associated with greater conditioning-response amplitude deficits. CONCLUSION: These findings: (1) are novel in showing that P50 deficits in SPD resemble those observed in schizophrenia, albeit less marked; (2) support the concept that the phenomenological link between SPD and schizophrenia lies in shared neurocognitive/neurophysiological pathologies; and (3) provide evidence that P50 is a neurophysiological endophenotype for schizophrenia-spectrum disorders.

Early sensory processing deficits predict sensitivity to distraction in schizophrenia.

Patients with schizophrenia frequently report difficulties paying attention during important tasks, because they are distracted by noise in the environment. The neurobiological mechanism underlying this problem is, however, poorly understood. The goal of this study was to determine if early sensory processing deficits contribute to sensitivity to distracting noise in schizophrenia. To that end, we examined the effect of environmentally relevant distracting noise on performance of an attention task in 19 patients with schizophrenia and 22 age and gender-matched healthy comparison subjects. Using electroencephalography, P50 auditory gating ratios also were measured in the same subjects and were examined for their relationship to noise-induced changes in performance on the attention task. Positive symptoms also were evaluated in patients. Distracting noise caused a greater increase in reaction time in patients, relative to comparison subjects, on the attention task. Higher P50 auditory gating ratios also were observed in patients. P50 gating ratio significantly correlated with the magnitude of noise-induced increase in reaction time. Noise-induced increase in reaction time was associated with delusional thoughts in patients. P50 ratios were associated with delusional thoughts and hallucinations in patients. In conclusion, the observation of noise effects on attention in patients is consistent with subjective reports from patients. The observed relationship between noise effects on reaction time and P50 auditory gating supports the hypothesis that early inhibitory processing deficits may contribute to susceptibility to distraction in the illness.

Abnormal auditory N100 amplitude: a heritable endophenotype in first-degree relatives of schizophrenia probands.

BACKGROUND: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. METHODS: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. RESULTS: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. CONCLUSIONS: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder.

OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.

Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia.

BACKGROUND: Startle and its inhibition by weak lead stimuli ("prepulse inhibition": PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies. METHODS: Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the "PPI site" (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI. RESULTS: Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural "drift", which may be particularly relevant to multi-site studies using these measures. CONCLUSION: With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

Improved p50 auditory gating with ondansetron in medicated schizophrenia patients.

OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the alpha-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.

Diminished suppression of the P50 auditory evoked potential in bipolar disorder subjects with a history of psychosis.

OBJECTIVE: People with schizophrenia, schizoaffective disorder, and bipolar illness share clinical symptoms, biological findings, and genetic susceptibility. Diminished suppression of the P50 auditory evoked potential is a phenotype used in studies of genetic susceptibility in schizophrenia. In patients with acute mania, this inhibitory deficit has been correlated with severity of clinical symptoms. This study addresses whether diminished P50 auditory evoked potential suppression represents a phenotype associated with psychosis in bipolar illness. METHOD: The P50 auditory evoked potential response to paired stimuli was measured in 64 subjects with bipolar illness. The Structured Clinical Interview for DSM-IV and a life chart determined diagnosis. The Beck Depression Inventory, Young Mania Rating Scale, and the Positive and Negative Syndrome Scale measured severity of current illness. Groups were compared with previously collected data from 36 schizophrenia patients and 42 healthy subjects. RESULTS: P50 suppression significantly differed between bipolar disorder patients with a lifetime history of psychosis and healthy subjects. P50 suppression in bipolar disorder patients without a history of psychosis did not differ from that of the healthy subjects. Severity of current symptoms did not correlate with P50 suppression. CONCLUSIONS: A longitudinal history of psychosis in subjects with bipolar illness was associated with diminished suppression of the P50 auditory evoked potential. This deficit may represent a common physiological mechanism associated with the vulnerability to psychosis in people with bipolar illness as well as in people with schizophrenia.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.

Sensory gating impairment associated with schizophrenia persists into REM sleep.

Physiological measures of sensory gating are increasingly used to study biological factors associated with attentional dysfunction in psychiatric and neurologic patient populations. The present study was designed to assess sensory gating during rapid eye movement (REM) sleep in patients with schizophrenia, a population bearing a genetic load for gating impairment. Auditory event-related potentials (ERPs) were recorded in response to paired clicks during separate waking and overnight sleep recording sessions in controls and schizophrenia patients. Suppression of ERP component P50 was significantly impaired in the patient group during both waking and REM sleep, whereas the difference between groups for N100 gating was dependent on state. These results suggest that REM sleep is an appropriate state during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in other clinical populations.