Risk of Concussion During Sports Versus Physical Education Among New Mexico Middle and High School Students.

OBJECTIVES: To measure the risk of concussion among New Mexico middle and high school students during both sports and physical education. METHODS: Athletic directors or athletic trainers in 147 schools were asked to report the number of concussions occurring during sports and physical education in the 2013 to 2014 school year. We calculated 1-year cumulative incidence rates. RESULTS: Of the 147 schools, 99 responded (67%). During the school year, 598 students were removed from athletics because of a concussion, a 1-year cumulative incidence of 3.5 per 100. The concussion rate during sports was 3.0: 3.5 for boys and 2.4 for girls (relative risk [RR] = 1.5; 95% confidence interval [CI] = 1.2, 1.7). An additional 335 students experienced concussions during physical education. Concussion rates during physical education were 60% higher than during sports (RR = 1.6; 95% CI = 1.4, 1.8). CONCLUSIONS: In our data, the risk of concussion was higher in physical education than in sports. This suggests that concussions should be tracked for a wide range of youth athletic activities, not just for sports. Monitoring cumulative incidence, in addition to other measures, may allow comparisons across schools and regions. More prevention efforts are needed.

Magnetoencephalographic and functional MRI connectomics in schizophrenia via intra- and inter-network connectivity.

Examination of intrinsic functional connectivity using functional MRI (fMRI) has provided important findings regarding dysconnectivity in schizophrenia. Extending these results using a complementary neuroimaging modality, magnetoencephalography (MEG), we present the first direct comparison of functional connectivity between schizophrenia patients and controls, using these two modalities combined. We developed a novel MEG approach for estimation of networks using MEG that incorporates spatial independent component analysis (ICA) and pairwise correlations between independent component timecourses, to estimate intra- and intern-network connectivity. This analysis enables group-level inference and testing of between-group differences. Resting state MEG and fMRI data were acquired from a large sample of healthy controls (n=45) and schizophrenia patients (n=46). Group spatial ICA was performed on fMRI and MEG data to extract intrinsic fMRI and MEG networks and to compensate for signal leakage in MEG. Similar, but not identical spatial independent components were detected for MEG and fMRI. Analysis of functional network connectivity (FNC; i.e., pairwise correlations in network (ICA component) timecourses) revealed a differential between-modalities pattern, with greater connectivity among occipital networks in fMRI and among frontal networks in MEG. Most importantly, significant differences between controls and patients were observed in both modalities. MEG FNC results in particular indicated dysfunctional hyperconnectivity within frontal and temporal networks in patients, while in fMRI FNC was always greater for controls than for patients. This is the first study to apply group spatial ICA as an approach to leakage correction, and as such our results may be biased by spatial leakage effects. Results suggest that combining these two neuroimaging modalities reveals additional disease-relevant patterns of connectivity that were not detectable with fMRI or MEG alone.

Reliable activation to novel stimuli predicts higher fluid intelligence.

The ability to reliably respond to stimuli could be an important biological determinant of differences in fluid intelligence (Gf). However, most electrophysiological studies of Gf employ event-related potential (ERP) measures that average brain activity over trials, and hence have limited power to quantify neural variability. Time-frequency analyses can capture cross-trial variation in the phase of neural activity, and thus can help address the importance of neural reliability to differences in Gf. This study recruited a community sample of healthy adults and measured inter-trial phase clustering (ITPC), total spectral power, and ERP amplitudes elicited by Repeated and Novel non-target stimuli during two visual oddball tasks. Condition effects, relations among the EEG measures, and relations with Gf were assessed. Early visual responses to Repeated stimuli elicited higher ITPC, yet only ITPC elicited by Novel stimuli was associated with Gf. Analyses of spectral power further highlighted the contribution of phase consistency to the findings. The link between Gf and reliable responding to changing inputs suggests an important role for flexible resource allocation in fluid intellectual skills.

The effect of days since last concussion and number of concussions on cognitive functioning in Division I athletes.

OBJECTIVE: Cognitive recovery from sports concussion may be incomplete after resolution of other symptoms. It was hypothesized that independent effects of the number of days since last concussion (Days) and total number of concussions (Number) would predict poorer cognitive functioning. METHODS AND PROCEDURES: Cognition was assessed in an NCAA Division I student-athlete population (n = 87) using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery. In a MANOVA, the five ImPACT Composite scores were dependent variables, with Group (Concussion, Unaffected) as the independent variable and prior number of concussions (Number) and days since last concussion (Days; 68-2495 days) entered as covariates. OUTCOMES AND RESULTS: The hypothesis that Days and Number would each independently affect cognitive functioning (as assessed by ImPACT Composite scores) was only partly supported. A significant, multivariate, main effect of Days (p = 0.01) indicated that more Days predicted better cognitive functioning overall (p = 0.01). Univariate effects emerged such that more Days specifically predicted better visual memory (p = 0.004) and faster reaction times (p = 0.02). A trend toward a Group*Days*Number three-way interaction for reaction time emerged (p = 0.06), such that smaller Number and more Days each predicted slower reaction time. CONCLUSIONS: Cognitive recovery following sports concussion may take far longer than was previously thought, the aetiology of cognitive reductions may be very complex and the ImPACT appears to be sensitive to subtle changes in cognition across time.

White matter volume in alcohol use disorders: a meta-analysis.

Atrophy of brain white matter (WM) often is considered a signature injury of alcohol use disorders (AUDs). However, investigations into AUD-related changes in WM volume have yielded complex findings that are difficult to synthesize in a narrative review. The objective of this study was to obtain an averaged effect size (ES) for WM volume reduction associated with AUD diagnosis and to test potential moderators of ES. Study inclusion criteria were: (1) English language; (2) peer reviewed; (3) published before December 2011; (4) use of magnetic resonance imaging (MRI); (5) human participants; (6) inclusion of AUD group; (7) inclusion of non-AUD comparison group; and (8) reporting or testing of total or cerebral WM volume. Moderators included study design, MRI methodology and AUD characteristics. Nineteen studies with a total of 1302 participants (70% male) were included, and calculated ESs were confirmed by the corresponding author for 12 studies. The magnitude of the averaged ES adjusted for small sample bias (Hedges' g) for WM reduction in AUDs was 0.304 (standard error = 0.134, range = -0.57-1.21). Hierarchical linear modeling indicated that the overall ES differed significantly from 0, t(18) = 2.257, P = 0.037, and that the distribution of the 19 ESs showed significant heterogeneity beyond sampling error, χ(2) (18) = 52.400, P < 0.001. Treatment-seeking status and length of abstinence were significant moderators of ES distribution. These results are suggestive of WM recovery with sustained abstinence and point to the need for further investigation of factors related to treatment-seeking status.

Bilateral hippocampal dysfunction in schizophrenia.

The hippocampus has long been known to be important for memory, with the right hippocampus particularly implicated in nonverbal/visuo-spatial memory and the left in verbal/narrative or episodic memory. Despite this hypothesized lateralized functional difference, there has not been a single task that has been shown to activate both the right and left hippocampi differentially, dissociating the two, using neuroimaging. The transverse patterning (TP) task is a strong candidate for this purpose, as it has been shown in human and nonhuman animal studies to theoretically and empirically depend on the hippocampus. In TP, participants choose between stimuli presented in pairs, with the correct choice being a function of the specific pairing. In this project, TP was used to assess lateralized hippocampal function by varying its dependence on verbal material, with the goal of dissociating the two hippocampi. Magnetoencephalographic (MEG) data were collected while controls performed verbal and nonverbal versions of TP in order to verify and validate lateralized activation within the hippocampi. Schizophrenia patients were evaluated to determine whether they exhibited a lateralized hippocampal deficit. As hypothesized, patients' mean level of behavioral performance was poorer than controls' on both verbal and nonverbal TP. In contrast, patients had no decrement in performance on a verbal and nonverbal non-hippocampal-dependent matched control task. Also, controls but not patients showed more right hippocampal activation during nonverbal TP and more left hippocampal activation during verbal TP. These data demonstrate the capacity to assess lateralized hippocampal function and suggest a bilateral hippocampal behavioral and activation deficit in schizophrenia.

Adolescent substance abuse: the effects of alcohol and marijuana on neuropsychological performance.

BACKGROUND: Adolescence is a period in which cognition and brain undergo dramatic parallel development. Whereas chronic use of alcohol and marijuana is known to cause cognitive impairments in adults, far less is known about the effect of these substances of abuse on adolescent cognition, including possible interactions with developmental processes. METHODS: Neuropsychological performance, alcohol use, and marijuana use were assessed in 48 adolescents (ages 12 to 18), recruited in 3 groups: a healthy control group (HC, n = 15), a group diagnosed with substance abuse or dependence (SUD, n = 19), and a group with a family history positive for alcohol use disorder (AUD) but no personal substance use disorder (FHP, n = 14). Age, drinks per drinking day (DPDD), percentage days drinking, and percentage days using marijuana were considered as covariates in a MANCOVA in which 6 neuropsychological composites (Verbal Reasoning, Visuospatial Ability, Executive Function, Memory, Attention, and Processing Speed) served as dependent variables. RESULTS: More DPDD predicted poorer performance on Attention and Executive Function composites, and more frequent use of marijuana was associated with poorer Memory performance. In separate analyses, adolescents in the SUD group had lower scores on Attention, Memory, and Processing Speed composites, and FHP adolescents had poorer Visuospatial Ability. CONCLUSIONS: In combination, these analyses suggest that heavy alcohol use in adolescence leads to reduction in attention and executive functioning and that marijuana use exerts an independent deleterious effect on memory. At the same time, premorbid deficits associated with family history of AUD appeared to be specific to visuospatial ability.

Lateralized abnormalities in auditory M50 sensory gating and cortical thickness of the superior temporal gyrus in post-traumatic stress disorder: preliminary results.

Auditory sensory gating deficits have been reported in subjects with post-traumatic stress disorder (PTSD), but the hemispheric and neuronal origins of this deficit are not well understood. The objectives of this study were to: (1) investigate auditory sensory gating of the 50-ms response (M50) in patients diagnosed with PTSD by utilizing magnetoencephalography (MEG); (2) explore the relationship between M50 sensory gating and cortical thickness of the superior temporal gyrus (STG) measured with structural magnetic resonance imaging (MRI); and (3) examine the association between PTSD symptomatology and bilateral sensory gating. Seven participants with combat-related PTSD and eleven controls underwent the paired-click sensory gating paradigm. MEG localized M50 neuronal generators to the STG in both groups. The PTSD group displayed impaired M50 gating in the right hemisphere. Thinner right STG cortical thickness was associated with worse right sensory gating in the PTSD group. The right S1 M50 source strength and gating ratio were correlated with PTSD symptomatology. These findings suggest that the structural integrity of right hemisphere STG cortices play an important role in auditory sensory gating deficits in PTSD.

Resting state and task-induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls.

Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task-related networks permits the quantification of this network both during task (task-induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed-based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed-based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia.

Hippocampus volume and episodic memory in schizophrenia.

Previous studies of schizophrenia have suggested a linkage between neuropsychological (NP) deficits and hippocampus abnormality. The relationship between hippocampus volume and NP functioning was investigated in 24 patients with chronic schizophrenia and 24 matched healthy controls. Overall intracranial, white and gray matter, and anterior (AH) and posterior (PH) hippocampus volumes were assessed from magnetic resonance images (MRI). NP domains of IQ, attention, and executive function were also evaluated with respect to volumetric measures. It was hypothesized that AH and PH volumes and episodic memory scores would be positively associated in controls and that the schizophrenia group would depart from this normative pattern. NP functioning was impaired overall and AH volume was smaller in the schizophrenia group. In the controls, the hippocampus-memory relationships involved AH and PH, and correlations were significant for verbal memory measures. In the schizophrenia group, positive correlations were constrained to PH. Negative correlations emerged between AH and verbal and visual memory measures. For both groups, cortical volume negatively correlated with age, but a negative correlation between age and hippocampus volume was found only in the schizophrenia group. In this sample of adults with schizophrenia, atypical relationships between regional hippocampus volumes and episodic memory ability were found, as was an atypical negative association between hippocampus volume and age.

Convergent and discriminant validity of the ImPACT with traditional neuropsychological measures.

Neuropsychological assessment of cognitive sequelae secondary to sports concussion is limited by lengthy administration times and lack of readily available neuropsychologists. Brief computerized test batteries are now under development to address this, but the validity of these measures is not yet established. The validity of one such computerized test battery, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), was administered to 93 healthy NCAA Division I athletes, aged 18-24, along with a battery of traditional, well-described neuropsychological tests. Convergent and discriminant validity between the ImPACT and traditional measures was investigated using multitrait-multimethod matrix (MTMM) analysis. As an example, the ImPACT Visual Motor Speed composite demonstrated reasonably good convergent validity secondary to moderate correlations with traditional measures of processing speed, but it demonstrated relatively poor discriminant validity as it significantly correlated with the Reaction Time composite score. MTMM results were variable across ImPACT composites and data for each are presented. The ImPACT composite's validity was further investigated using exploratory factor analysis (EFA). Six principal components were termed processing speed, visual memory, verbal memory, attention & working memory, and verbal fluency, based upon traditional test loadings, and a sixth loaded only on the ImPACT Reaction Time composite. EFA indicated content validity of moderate strength for the Visual Motor Speed and Visual Memory composites, but revealed problems with specificity for the other composites. Based upon the present findings, validity problems render the interpretability of the ImPACT composites somewhat questionable, and more research is necessary prior to using the ImPACT for assessment of clinical populations.

Dynamic neural activity recorded from human amygdala during fear conditioning using magnetoencephalography.

Magnetoencephalography (MEG) was used to record the dynamics of amygdala neuronal population activity during fear conditioning in human participants. Activation during conditioning training was compared to habituation and extinction sessions. Conditioned stimuli (CS) were visually presented geometric figures, and unconditioned stimuli (US) were aversive white-noise bursts. The CS+ was paired with the US on 50% of presentations and the CS- was never paired. The precise temporal resolution of MEG allowed us to address the issue of whether the amygdala responds to the onset or offset of the CS+, and/or the expectation of the initiation or offset of the an omitted auditory US. Fear conditioning elicited differential amygdala activation for the unpaired CS+ compared to the CS-, extinction and habituation. This was especially robust in the right hemisphere at CS onset. The strongest peaks of amygdala activity occurred at an average of 270 ms in the right and 306 ms in the left hemisphere following unpaired CS+ onset, and following offset at 21 ms in the left and 161 ms in the right (corresponding to an interval of 108 ms and 248 ms after the anticipated onset of the US, respectively). However, the earliest peaks in this epoch preceded US onset in most subjects. Thus, the activity dynamics suggest that the amygdala both differentially responds to stimuli and anticipates the arrival of stimuli based on prior learning of contingencies. The amygdala also shows stimulus omission-related activation that could potentially provide feedback about experienced stimulus contingencies to modify future responding during learning and extinction.

Impaired secondary somatosensory gating in patients with schizophrenia.

A large and growing literature has demonstrated a deficit in auditory gating in patients with schizophrenia. Although that deficit has been interpreted as a general gating problem, no deficit has been shown in other sensory modalities. Recent research in our laboratory has examined sensory gating effects in the somatosensory system showing no difference in gating of the primary somatosensory response between patients with schizophrenia and control subjects. This is consistent with recent structural studies showing no cortical structural abnormality in primary somatosensory area in schizophrenia. However, a significant decrease in cortical thickness and gray matter volume loss in secondary somatosensory cortex has recently been reported, suggesting this as a focus for impaired somatosensory gating. Thus, the current study was designed (1) to replicate previous work showing a lack of schizophrenia deficit in primary somatosensory cortex (SI) gating, and (2) to investigate a possible deficit in secondary somatosensory cortex (SII) gating. In a paired-pulse paradigm, dipolar sources were assessed in SI and SII contralateral to unilateral median nerve stimulation. Patients demonstrated no impairment in SI gating, but a robust gating deficit in SII, supporting the presence of cross modal gating deficits in schizophrenia.

Diminished auditory sensory gating during active auditory verbal hallucinations.

Auditory sensory gating, assessed in a paired-click paradigm, indicates the extent to which incoming stimuli are filtered, or "gated", in auditory cortex. Gating is typically computed as the ratio of the peak amplitude of the event related potential (ERP) to a second click (S2) divided by the peak amplitude of the ERP to a first click (S1). Higher gating ratios are purportedly indicative of incomplete suppression of S2 and considered to represent sensory processing dysfunction. In schizophrenia, hallucination severity is positively correlated with gating ratios, and it was hypothesized that a failure of sensory control processes early in auditory sensation (gating) may represent a larger system failure within the auditory data stream; resulting in auditory verbal hallucinations (AVH). EEG data were collected while patients (N=12) with treatment-resistant AVH pressed a button to indicate the beginning (AVH-on) and end (AVH-off) of each AVH during a paired click protocol. For each participant, separate gating ratios were computed for the P50, N100, and P200 components for each of the AVH-off and AVH-on states. AVH trait severity was assessed using the Psychotic Symptoms Rating Scales AVH Total score (PSYRATS). The results of a mixed model ANOVA revealed an overall effect for AVH state, such that gating ratios were significantly higher during the AVH-on state than during AVH-off for all three components. PSYRATS score was significantly and negatively correlated with N100 gating ratio only in the AVH-off state. These findings link onset of AVH with a failure of an empirically-defined auditory inhibition system, auditory sensory gating, and pave the way for a sensory gating model of AVH.

Impairment on the hippocampal-dependent virtual Morris water task in schizophrenia.

Traditional neuropsychological tests of visual and verbal memory have been used to evaluate memory deficits in schizophrenia. However, these tests cannot be used in non-human animal research, which is important for the discovery of treatments that will improve cognition and for study of the etiology of schizophrenia. To help bridge the gap between human and non-human animal research on hippocampal function in schizophrenia, this study sought to characterize the behavioral performance exhibited by patients using the Morris water task (MWT). The MWT has been shown in human and non-human animal studies to be hippocampus-dependent. In the virtual MWT, human subjects navigate a computer-generated on-screen environment to escape from the "water" by locating a platform. Patients with schizophrenia and controls performed two versions of the virtual MWT: a hippocampal-dependent hidden-platform version, relying on allocentric navigational abilities, and a non-hippocampal-dependent visible-platform version, relying on cued-navigational abilities. Patients traveled further and took longer to find the hidden platform over training blocks and spent less time in the correct quadrant during a probe trial. There was no deficit in the visible-platform condition. These findings identify a behavioral impairment on a hippocampal-dependent task in schizophrenia and support using the MWT in testing animal models of schizophrenia.

Functional MRI Evaluation of Multiple Neural Networks Underlying Auditory Verbal Hallucinations in Schizophrenia Spectrum Disorders.

Functional MRI studies have identified a distributed set of brain activations to be associated with auditory verbal hallucinations (AVH). However, very little is known about how activated brain regions may be linked together into AVH-generating networks. Fifteen volunteers with schizophrenia or schizoaffective disorder pressed buttons to indicate onset and offset of AVH during fMRI scanning. When a general linear model was used to compare blood oxygenation level dependence signals during periods in which subjects indicated that they were versus were not experiencing AVH ("AVH-on" versus "AVH-off"), it revealed AVH-related activity in bilateral inferior frontal and superior temporal regions; the right middle temporal gyrus; and the left insula, supramarginal gyrus, inferior parietal lobule, and extranuclear white matter. In an effort to identify AVH-related networks, the raw data were also processed using independent component analyses (ICAs). Four ICA components were spatially consistent with an a priori network framework based upon published meta-analyses of imaging correlates of AVH. Of these four components, only a network involving bilateral auditory cortices and posterior receptive language areas was significantly and positively correlated to the pattern of AVH-on versus AVH-off. The ICA also identified two additional networks (occipital-temporal and medial prefrontal), not fully matching the meta-analysis framework, but nevertheless containing nodes reported as active in some studies of AVH. Both networks showed significant AVH-related profiles, but both were most active during AVH-off periods. Overall, the data suggest that AVH generation requires specific and selective activation of auditory cortical and posterior language regions, perhaps coupled to a release of indirect influence by occipital and medial frontal structures.

A specific test of hippocampal deficit in schizophrenia.

Despite numerous studies in which hippocampal abnormalities were found, schizophrenia patients' hippocampal neural activity has not been systematically evaluated on a specific hippocampal-dependent task. The transverse-patterning task (TP) is sensitive to the relational mnemonic capabilities of the hippocampus. Ten schizophrenia patients and 10 controls performed TP and control tasks that are not hippocampal dependent. As predicted, patients displayed a behavioral impairment in TP and not in control tasks. Magnetoencephalography showed controls activating right hippocampus during TP performance. Patients showed more bilateral or left hippocampal activation during TP, and greater left lateralization was associated with better performance on TP. Patients' abnormal hippocampal lateralization may play a role in the hippocampal-dependent behavioral deficit.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

Associations of White Matter Microstructure with Clinical and Demographic Characteristics in Heavy Drinkers.

Damage to the brain's white matter is a signature injury of alcohol use disorders (AUDs), yet understanding of risks associated with clinical and demographic characteristics is incomplete. This study investigated alcohol problem severity, recent drinking behavior, and demographic factors in relation to white matter microstructure in heavy drinkers. Magnetic resonance imaging (MRI) scans, including diffusion tensor imaging (DTI), were collected from 324 participants (mean age = 30.9 ± 9.1 years; 30% female) who reported five or more heavy drinking episodes in the past 30 days. Drinking history and alcohol problem severity were assessed. A common white matter factor was created from fractional anisotropy (FA) values of five white matter tracts: body of corpus callosum, fornix, external capsule, superior longitudinal fasciculus, and cingulate gyrus. Previous research has implicated these tracts in heavy drinking. Structural equation modeling (SEM) analyses tested the hypothesis that, after controlling for duration of alcohol exposure, clinical and behavioral measures of alcohol use severity would be associated with lower white matter factor scores. Potential interactions with smoking status, gender, age, treatment-seeking status, and depression or anxiety symptoms also were tested. Controlling for number of years drinking, greater alcohol problem severity and recent drinking frequency were significantly associated with lower white matter factor scores. The effect of drinking frequency differed significantly for men and women, such that higher drinking frequency was linked to lower white matter factor scores in women but not in men. In conclusion, alcohol problem severity was a significant predictor of lower white matter FA in heavy drinkers, after controlling for duration of alcohol exposure. In addition, more frequent drinking contributed to lower FA in women but not men, suggesting gender-specific vulnerability to alcohol neurotoxicity.