A novel and effective item-source complex trial protocol: Discrimination of guilty from both knowledgeable and unknowledgeable innocent subjects.

Innocent subjects who are knowledgeable of crime-related information will often be misclassified as "guilty" in P300-based complex trial protocol (CTP). Therefore, it is necessary to develop a more rigorous CTP that can effectively discriminate the guilty from both the knowledgeable and the unknowledgeable innocents. Sometimes the guilty and the knowledgeable innocents possess the same item memories but different source memories. The present study designed a novel item-source complex trial protocol based on the differences of source memory among the three kinds of individuals. Either the crime-related probe (e.g., the stolen ring) or one of the crime-unrelated stimuli (e.g., watch, earring, bracelet, or bangle) (item memory) was presented in the first part of each trail, and either a stealing-source word (e.g., stole) or other-source word (e.g., fetched) (source memory) was presented in the second part of each trail. The results showed that: (1) the P300 evoked by item memory could effectively discriminated the guilty from the unknowledgeable innocent (AUC = 0.76) but failed to effectively discriminate the guilty from the knowledgeable innocent (AUC = 0.60); (2) the late positive component evoked by source memory could effectively discriminated the guilty from both the knowledgeable innocent (AUC = 0.94) and the unknowledgeable innocent (AUC = 0.84) in one test.

The effects of practicing a novel countermeasure on both the semantic and episodic memory-based complex trial protocols.

This study applied a countermeasure-resistant version of the Concealed Information Test - the Complex Trial Protocol (CTP) - in an information recognition scenario. We replicated and extended the effects of a novel countermeasure developed by Lukács et al., (2016) on both Semantic and Episodic CTPs. We measured participants' response time and P300 event-related potential to rare, crime-relevant probe stimuli, or frequent, non-crime-relevant irrelevant stimuli in two ways: 1) probe vs the average of all irrelevants (PvIall), and 2) probe vs the maximum irrelevant (PvImax). We hypothesized that countermeasure use would only impair information recognition (as indexed by P300) when participants had practiced the countermeasure beforehand. We further hypothesized that recognition of less salient, Episodic information (i.e., jewelry items from a mock crime) would be impaired by countermeasure use more than the recognition of highly salient, Semantic information (i.e., birthdates). Individual diagnostics based on the area under the receiver operating characteristic curve (Semantic CTP: practice n = 22, non-practice n = 23; Episodic CTP: practice n = 19, non-practice n = 18) revealed that the Semantic CTP was affected by the novel countermeasure, but both PvIall and PvImax analyses remained diagnostically useful. The Episodic CTP's performance, however, was reduced to chance, regardless of practice or analysis type. These results are important for both the field of deception detection and the CTP literature. Research on improvements to the Episodic CTP is required.

Bayesian Data Analysis: A Fresh Approach to Power Issues and Null Hypothesis Interpretation.

One of the first things one learns in a basic psychology or statistics course is that you cannot prove the null hypothesis that there is no difference between two conditions such as a patient group and a normal control group. This remains true. However now, thanks to ongoing progress by a special group of devoted methodologists, even when the result of an inferential test is p > .05, it is now possible to rigorously and quantitatively conclude that (a) the null hypothesis is actually unlikely, and (b) that the alternative hypothesis of an actual difference between treatment and control is more probable than the null. Alternatively, it is also possible to conclude quantitatively that the null hypothesis is much more likely than the alternative. Without Bayesian statistics, we couldn't say anything if a simple inferential analysis like a t-test yielded p > .05. The present, mostly non-quantitative article describes free resources and illustrative procedures for doing Bayesian analysis, with t-test and ANOVA examples.

Workplace intervention programmes for decreasing alcohol use in military personnel: a systematic review.

INTRODUCTION: Harmful or risky-single occasion drinking (RSOD) alcohol use in the military is a significant problem. However, most studies of interventions have focused on veterans, representing a missed opportunity for intervention with active military personnel. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework, the aim of this systematic review was to analyse and synthesise the evidence related to workplace-based interventions for reducing alcohol use in active-duty military personnel. METHODS: Four electronic databases and reference lists of relevant articles were searched from database inception until 20 January 2020. This review focused on experimental and quasi-experimental studies of active-duty military personnel. Data extraction and methodological quality assessment were independently performed by two reviewers using a standardised checklist. A third reviewer was used to arbitrate the disputed studies for final selection. RESULTS: The search yielded seven studies from an initial 1582 records identified. A range of interventions were used in these studies (four randomised controlled trials, two non-randomised trials and one before and after cohort study), including web-based approaches, telephone-delivered interventions and individual and group-based face-to-face interventions. Seven studies found decreased drinking, measured using a range of outcomes, following the intervention. However, this was not sustained in the longer term in any of the studies. CONCLUSIONS: The low methodological rigour of most studies limited the capacity to demonstrate the efficacy of the interventions studied. Given the importance of reducing harmful or RSOD use of alcohol in the military, future studies would benefit from improved methodological rigour including ensuring adequate study power, randomisation, selection of validated outcome measures, including measures other than consumption (eg, attitudinal measures), and longer-term follow-up. There is also a need to develop methods that ensure participant loss to follow-up is minimised.

Familiarity-related filler items enhance the RT CIT, but not the P300 CIT: Episodic vs. Semantic memory protocols.

The reaction time-based concealed information test (RT CIT) typically uses three types of stimuli: 1) probe (i.e., crime-related item), 2) irrelevant (i.e., crime-unrelated item) and 3) target (i.e., an irrelevant item assigned a unique response so as to ensure attention to the test). Lukács, et al., (2017) introduced familiarity-related filler items to the RT CIT, enhancing the efficacy of the test for both single and multiple probe (per block) protocols. Our study aims to A) replicate the effects of familiarity-related filler items on the RT CIT, B) use P300 to investigate the mechanisms of the fillers-related enhancement effect on the RT CIT, C) investigate whether these fillers can enhance the efficacy of the typical P300-based CIT, and D) explore the effects of fillers on the semantic and episodic versions of the P300 and RT CITs. We replicated a clear fillers-related enhancement of the RT CIT (N = 38 for Fillers, N = 37 for No Fillers). Semantic and Episodic experiments were enhanced equally-well by filler items. No effect of fillers was observed on P300 amplitude for CIT stimuli, however, an interaction involving P300 latency suggests that fillers facilitated the processing of Semantic information over Episodic information. Our study independently replicates a valuable improvement of the traditional RT CIT, investigates the potential mechanisms of this enhancement effect, and demonstrates important differences between the P300 and RT CITs.

Feedback does not influence the recognition-related P300 in a novel concealed information test while feedback-evoked P300 shows promising diagnostic accuracy.

The feedback concealed information test (fCIT) is a novel variant of a CIT, which provides participants with feedback regarding their memory concealment performance during the CIT. Previous studies have found that feedback-related ERPs associated with feedback processing in the fCIT can accurately identify concealed information. However, it is still unknown whether the feedback influences the process and ERP signs of recognition during memory concealment, such as the recognition P300. To address this issue, the present study directly compared the recognition-based P300 in CITs with and without feedback. Results showed that the probe elicited a larger recognition P300 than irrelevants in both CITs with and without feedback, and there were no significant differences in recognition P300 between those two CITs. Moreover, the detection rate for recognition-based P300 in both CITs also had no significant difference. The feedback-related ERPs, especially feedback P300, continued to discriminate guilty and innocent subjects with AUCs well above the chance.

Necessity of the target discrimination in the P300-based complex trial protocol test for concealed information.

The two most common types of ERP-based protocols to detect concealed information are the 3-stimulus protocol (3SP) and Complex Trial Protocol (CTP). Both protocols traditionally include presentation of a target (a stimulus with assigned significance requiring a unique behavioral response). The intention of the target presentation is forcing subjects to pay attention to all stimuli, especially to guilty knowledge stimuli, called probes. It was unclear though, how the presence of a targets influences probe recognition, and thus, the concealed information test (CIT) effect-the difference in P300 response to the probe and Irrelevant (crime-unrelated) stimuli. The question of target necessity was first raised in relation to the 3SP, and it was found that although omitting target stimuli reduced P300 amplitudes for all probe and irrelevant stimuli, the CIT effect was not reduced. The current study investigated how the presence or absence of the target/nontarget discrimination in the CTP affects the CIT effect, by comparing two CTP groups both with (T) and without (NT) the target/nontarget discrimination. The results demonstrated that this discrimination significantly increases the P300 effect. We found a greater P300 CIT effect in the T group than in the NT group, suggesting that for field use, it is better to retain the target discrimination in the CTP. CIT effects were also seen with P300 latency, but not reaction time.

The enhancing effect of incongruent verbal priming stimuli on the CIT effect with pictorial probes in the P300-based complex trial protocol.

Previous research (Herring et al., 2011) indicated that certain types of incongruent verbal priming enhance responding to the subsequent (primed) stimuli. By priming participants in a P300-based Concealed Information Test (CIT), we examined the possible enhancement effects of priming stimuli in the P300 based Complex Trial Protocol (CTP) for face recognition. Participants were divided into two groups: one group with priming and one control group without. The probe (Pr) and irrelevants (Iall) of the two groups were faces, namely, pictures of the actor Tom Cruise (Pr) and of other unknown faces (Iall). One group had priming before Pr/Iall and one control group had no priming. The priming group was called the non-identical priming (NIP) group in which the verbal priming item (the name, "Bill Smith") is identical with neither Pr nor any of the Ialls. The group without priming is the control group which is called the non-priming group (NP) that simply experiences the basic Complex Trial Protocol. Results were that non-identical priming produced larger CIT effects than the control group, which is consistent with earlier findings. Also, the amplitude of the probe of the NIP group is larger than that of the NP group, while their irrelevants didn't show any significant difference. This means that the incongruent verbal priming did enhance the P300 CIT effect for the probe, which could further improve the accuracy of CTP for the concealed information test.

P300 in detecting concealed information and deception: A review.

Studies using the P300 ERP in detection of concealed information are reviewed. An overview of the initial findings, methodological issues, and use of bootstrapping methods for data analysis are considered, with various protocols explicated. Applications to forensic issues, employee screening, cognitive deficit malingering, and facial recognition in lineups are outlined. Countermeasures to the original P300-based tests are described, and a possible approach to this problem using a new complex-trial protocol is offered. Applications of this protocol to forensic and antiterror scenarios are then presented, along with its first independent replication. Studies of visual versus auditory stimulus presentation in the complex-trial protocol are evaluated. Findings from attempted voluntary suppression of P300 as a recognition signal are presented, and the effects of motivational manipulations on the P300-based complex-trial protocol are summarized. Limitations of the research are reviewed, and, based on this review, future directions of P300 methods for detection of concealed information and deception are suggested that may guide the development of more precision and reliability of this promising tool.

The effect of retroactive memory interference on the P300-based Complex Trial Protocol (CTP).

In a P300-based concealed information test (CIT), an increased response to a crime-related "probe" item of interest suggests concealed knowledge. Because the CIT's detection ability is based on knowledgeable parties recognizing the key item, weakening the crime memory might decrease probe identifiability and reduce diagnostic power. Research on retroactive memory interference (RI) has shown that acquiring new information after encoding a memory can degrade the original memory, which suggests that RI might pose a threat to CITs. To test this, Gronau et al. (2015) had participants complete a mock-crime, followed by either a control task or a RI manipulation task, intended to impair the crime memory. Both the simple guilty control and RI groups were subdivided into three time delay conditions: 1/3 of participants immediately completed the task and CIT, another 1/3 completed the task and returned a week later for the CIT, and the remaining participants completed both the task and CIT a week later. Results showed that RI reduced memory of crime details and skin conductance responses, while respiration line length was unaffected. Here, we extend Gronau et al. (2015), using the Complex Trial Protocol (CTP) version of the P300-based CIT, to investigate the influence of RI on recognition. The CIT effect was obvious in all six group × time delay subconditions, as evidenced by their significantly larger probe vs. irrelevant amplitudes, high percentage of bootstrapped iterations where probe > irrelevants, bootstrapped mean amplitude differences, and satisfactory hit rates. However, these indices of the CIT effect did not differ based on group or time delay, as was the case for target response error rates and P300 latencies. The only outcome of interest to vary by group or time delay was behavioral response times: both probe and combined irrelevant responses were delayed in the control (simple guilty) group. Thus, the evidence suggests that the RI manipulation used here does not threaten the P300-based CTP's accuracy. Results are considered as they compare to previous work, and limitations and possible explanations for our results are discussed.

Deleterious effects of probe-related versus irrelevant targets on the "CIT effect" in the P300- and RT-based three-stimulus protocol for detection of concealed information.

Two groups of participants committed the same mock crime in which one of two items, a watch or a ring, was removed from a drawer and concealed. One group, the crime-familiar group next experienced a three-stimulus protocol (3SP), a Concealed Information Test (CIT), in which they were tested on the stolen (probe) item presented in a random series of five irrelevant (unseen) stimuli from the same jewelry category. A left-hand button press, meaning "I don't recognize" was to follow each of these six items. A right-hand press ("I do recognize") was to follow the one other presented item, the target item, which in the case of the crime-familiar group was the other, not-stolen item in the drawer at the mock crime scene. For the other crime-unfamiliar group, the target was a sixth unseen irrelevant item as in the original P300 CIT. In terms of P300 latency and reaction time (RT), crime-familiar participants processed all stimuli faster than crime-unfamiliar participants. The CIT effects (probe-minus-irrelevant differences) for crime-familiar group members were inferior to those of crime-unfamiliar group members for RT and P300 amplitude measures. Thus, familiar targets negatively impact the 3SP.

Financial Incentive Does Not Affect P300 in the Complex Trial Protocol (CTP) Version of the Concealed Information Test (CIT) in Malingering Detection. II. Uninstructed Subjects.

Well-known research showed that the skin conductance response (SCR) of the Autonomic Nervous System (ANS) in the Concealed Information Test (CIT) is usually augmented in participants who are financially and motivationally incentivized to beat the CIT. This is not what happens with Reaction Time (RT)-based CITs, P300 CITs based on the 3-stimulus protocol, nor on the P300-based complex trial protocol for detection of malingering (however these tests differ from forensic CITs). The present report follows up the Rosenfeld et al. (1, 2) study of motivated malingerers instructed how to beat the test, with uninstructed motivated (paid and unpaid) and unmotivated ("simple malingering") subjects, using episodic and semantic memory probes. The Test of Memory Malingering (TOMM) validated behavioral differences among groups. The "CIT effect" (probe-minus-irrelevant P300 differences) did not differ among incentive groups, although as previously, semantic memory-evoked P300s exceeded episodic memory evoked P300s. An effect of specific test-beating instructions was found to enhance the CIT effect for semantic information.

Visual presentation modality's superiority in the detection of concealed information: A comparison of the efficiencies of the P300-based Complex Trial Protocol in visual versus auditory modalities.

Some studies have shown a superiority of visual vs. auditory item presentation in the Complex Trial Protocol (CTP), which is a countermeasure-resistant version of the P300-based Concealed Information Test (CIT). But those studies used elaborately- rehearsed autobiographical information as stimuli, instead of incidentally-acquired crime-related information. Thus, the relative superiority of the visual as opposed to the auditory modality in detecting episodic crime-related information is still unknown. The present study also improved on the usual mock crime scenario by adding a mock disposal task between a mock theft and administration of a CTP test to increase stimulus saliency. In this CTP, the probe and the irrelevant items were presented visually or acoustically on alternating trials, while target and non-target stimuli were simultaneously presented in visual and auditory modalities. The results showed that the P300 amplitude differences of probe minus irrelevant items presented in the visual modality were significantly larger compared to the auditory modality, and the detection rate of the guilty participants was also significantly higher for the visual (14/16) versus auditory modality (5/16). These results suggest a superiority of visual vs. auditory presentation when a CTP is used to detect crime-related information in a mock crime scenario.

Comparing short versions of the Alcohol Use Disorders Identification Test (AUDIT) in a military cohort.

BACKGROUND: The Alcohol Use Disorders Identification Test (AUDIT) is widely used for monitoring harmful alcohol consumption among high-risk populations. A number of short versions of AUDIT have been developed for use in time-constrained settings. In military populations, a range of AUDIT variations have been used, but the optimal combination of AUDIT items has not been determined. METHODS: A total of 952 participants (80% male), recruited as part of a wider study, completed the AUDIT-10. We systematically assessed all possible combinations of three or four AUDIT items and established AUDIT variations using the following statistics: Cronbach's alpha (internal consistency), variance explained (R2) and Pearson's correlation coefficient (concurrent validity). RESULTS: Median AUDIT-10 score was 7 for males and 6 for females, and 380 (40%) participants were classified as having a score indicative of harmful or hazardous alcohol use (≥8) according to WHO classifications.A novel four-item AUDIT variation (3, 4, 8 and 9) performed consistently higher than established variations across statistical measures; it explained 85% of variance in AUDIT-10, had a Pearson's correlation of 0.92 and Cronbach's alpha was 0.63. The FAST, an established shortened AUDIT variant, together with several other four-item novel variants of AUDIT-10 performed similarly. The AUDIT-C performed consistently low on all measures, but with a satisfactory level of internal consistency (75%). CONCLUSION: Shortened AUDIT variations may be suitable alternatives to the full AUDIT for screening hazardous alcohol consumption in military populations. Four-item AUDIT variations focused on short-term risky drinking and its consequences performed better than three item versions. TRIAL REGISTRATION NUMBER: ACTRN12614001332617.

Risk of Alzheimer's Disease in Obstructive Sleep Apnea Syndrome: Amyloid-ß and Tau Imaging.

BACKGROUND: An association between obstructive sleep apnea (OSA) and Alzheimer's disease has been suggested but little is known about amyloid-ß and tau deposition in this syndrome. OBJECTIVE: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. METHODS: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18F-florbetaben and 18F-AV1451, to quantify amyloid and tau burden. RESULTS: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p = 0.04). There were more apolipoprotein E ɛ4 allele (APOE ɛ4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18F-AV1451 uptake between the two groups. CONCLUSIONS: Obstructive sleep apnea is associated with Alzheimer's disease pathology, but this relationship is moderated by APOE ɛ4 and BMI.

The effect of countermeasures against the reaction time based concealed information test on the P300 index of knowledge recognition: A combined RT and P300-based test.

Behavioral reaction time (RT) to key (probe) stimuli in a concealed information test (CIT) is usually greater than RT to irrelevant stimuli, and this difference has been utilized as a sign of recognition of concealed information. The ability to voluntarily increase irrelevant RT would appear to be an obvious countermeasure to the RT-based CIT. This study examined the effect of such countermeasure use on the simultaneously recorded P300 event related potentials. There were two blocks of trials in the present study, based on the 3-stimulus protocol. On the first trial block, half the participants were tested on concealed recognition of their phone numbers without a countermeasure. In the second block, this subset of participants were tested on their birth dates, while they applied a countermeasure consisting of the mental statement of the phrase "yes sir" prior to the button press signaling irrelevant stimulus. The other half of the subjects received the reverse order of stimulus categories. Results were that probe RT exceeded irrelevant RT in the first block, but that this relationship was reversed on the second block. In contrast, although the probe P300 exceeded the irrelevant P300 in the first block, this difference significantly increased in the second (RT countermeasure) block, leading to more detections based on P300. Thus, there was a differential effect of this novel countermeasure (directed at countering RT) on RT and P300, which actually led to improved detection with P300, suggesting that both measures might be profitably used in field applications.

Suppression of 12-Hz SSVEPs when viewing familiar faces: An electrophysiological index to detect recognition.

Criminal investigation often involves finding out what a suspect knows about people, such as victims and confederates, who are involved in the crime. This study explored the possibility of determining a person's recognition of other individuals by analyzing the steady-state visually evoked potentials (SSVEP) triggered by visual oscillations of familiar and unfamiliar faces. In our study, 23 adult (10 men) participants gave subjective familiarity ratings (in a 7-point Likert scale) of >300 celebrities' and strangers' faces. For each participant, ten familiar and ten unfamiliar faces were selected based on his/her ratings. The selected faces were presented at 6 Hz while the participants performed a color change detection task orthogonal to the attributes of faces. The task was designed to maintain participants' visual attention towards the faces throughout the stimulus oscillations. Any difference between conditions would indicate modulation of visual attention by face familiarity. Results showed that the 12-Hz event-related spectral perturbations (ERSPs in decibel) at parietal-occipital electrodes were significantly lower when viewing familiar faces compared to unfamiliar faces. In individual level analysis, 18 out of 23 (78%) participants had significantly lower 12-Hz ERSPs at left parietal-occipital ROI in familiar face than unfamiliar face trials. This is the first study to demonstrate that SSVEPs triggered by stimulus oscillations can reveal people's recognition of faces with only 20 trials per condition and 10-s for each trial.

Moderate financial incentive does not appear to influence the P300 Concealed Information Test (CIT) effect in the Complex Trial Protocol (CTP) version of the CIT in a forensic scenario, while affecting P300 peak latencies and behavior.

Previous research indicated that the skin conductance response (SCR) of the Autonomic Nervous System (ANS) in the Concealed Information Test (CIT) is typically increased in subjects who are financially and otherwise incentivized to defeat the CIT (the paradoxical "motivational impairment" effect). This is not the case for RT-based CITs, nor for P300 tests based on the 3-stimulus protocol or Complex Trial Protocol for detection of cognitive malingering (although these are not the same as forensic CITs). The present report extends earlier studies of malingerers by running five groups of subjects (15-16 per group yielding 78 total) in a mock crime (forensic) scenario: paid (to beat the test) and unpaid, instructed and uninstructed, and simply guilty. There was no evidence that the "CIT effect" (probe-minus-irrelevant P300 differences) differed among groups, although behavioral differences among groups were seen.

Inferior detection of information from collaborative versus individual crimes based on a P300 Concealed Information Test.

The present study used a P300-based Concealed Information Test (CIT) to detect individual and collaborative crimes and to explore whether or not the P300 index is effective in identifying collaborative crime members. Participants were divided into two groups to either steal a ring alone (individual group) or collaboratively with another companion participant (collaborative group) before taking the Complex Trial Protocol test that is regarded as an accurate version of the P300-based CIT. The ERP results revealed that both groups showed significantly larger P300s to probe (the ring) than to all irrelevant stimuli (other jewelery), but the P300 amplitude difference of probe stimulus versus irrelevant stimuli in the collaborative group was significantly less than that in the individual group. For the individual diagnosis, using P300 index, the detection rate was significantly inferior for collaborative crime than individual crime, probably related to weakness of collaborative encoding. The ROC curve comparisons showed the individual guilty was effectively discriminated from the simulated-innocent (AUC = .84) and from the collaborative guilty (AUC = .83), but the collaborative guilty was not discriminable from the simulated-innocent (AUC = .66). These findings suggest that collaborative encoding of crime-related information impacts the efficiency of the P300 index, and that the P300-based CIT is not applicable when used to identify collaborative crime perpetrators.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.