Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P < 0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose-response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence.

Trajectories of brain development reveal times of risk and factors promoting resilience to alcohol use during adolescence.

Alcohol use disorder (AUD) is recognized as harmful for the developing brain. Numerous studies have sought environmental and genetic risk factors that predict the development of AUD, but recently identified resilience factors have emerged as protective. This chapter reviews normal processes of brain development in adolescence and emerging adulthood, delineates disturbed growth neurotrajectories related to heavy drinking, and identifies potential endogenous, experiential, and time-linked brain markers of resilience. For example, concurrent high dorsolateral prefrontal activation serving inhibitory control and low nucleus accumbens activation serving reward functions engender positive adaptation and low alcohol use. Also discussed is the role that moderating factors have in promoting risk for or resilience to AUD. Longitudinal research on the effects of all levels of alcohol drinking on the developing brain remains crucial and should be pursued in the context of resilience, which is a promising direction for identifying protective biomarkers against developing AUDs.

The neural correlates of priming emotion and reward systems for conflict processing in alcoholics.

Emotional dysregulation in alcoholism (ALC) may result from disturbed inhibitory mechanisms. We therefore tested emotion and alcohol cue reactivity and inhibitory processes using negative priming. To test the neural correlates of cue reactivity and negative priming, 26 ALC and 26 age-matched controls underwent functional MRI performing a Stroop color match-to-sample task. In cue reactivity trials, task-irrelevant emotion and alcohol-related pictures were interspersed between color samples and color words. In negative priming trials, pictures primed the semantic content of an alcohol or emotion Stroop word. Behaviorally, both groups showed response facilitation to picture cue trials and response inhibition to primed trials. For cue reactivity to emotion and alcohol pictures, ALC showed midbrain-limbic activation. By contrast, controls activated frontoparietal executive control regions. Greater midbrain-hippocampal activation in ALC correlated with higher amounts of lifetime alcohol consumption and higher anxiety. With negative priming, ALC exhibited frontal cortical but not midbrain-hippocampal activation, similar to the pattern observed in controls. Higher frontal activation to alcohol-priming correlated with less craving and to emotion-priming with fewer depressive symptoms. The findings suggest that neurofunctional systems in ALC can be primed to deal with upcoming emotion- and alcohol-related conflict and can overcome the prepotent midbrain-limbic cue reactivity response.

Brain responses to emotional salience and reward in alcohol use disorder.

Heightened neural responsiveness of alcoholics to alcohol cues and social emotion may impede sobriety. To test mesocorticolimbic network responsivity, 10 (8 men) alcohol use disorder (AUD) patients sober for 3 weeks to 10 months and 11 (8 men) controls underwent fMRI whilst viewing pictures of alcohol and non-alcohol beverages and of emotional faces (happy, sad, angry). AUD and controls showed similarities in mesocorticolimbic activity: both groups activated fusiform for emotional faces and hippocampal and pallidum regions during alcohol picture processing. In AUD, less fusiform activity to emotional faces and more pallidum activity to alcohol pictures were associated with longer sobriety. Using graph theory-based network efficiency measures to specify the role of the mesocorticolimbic network nodes for emotion and reward in sober AUD revealed that the left hippocampus was less efficiently connected with the other task-activated network regions in AUD than controls when viewing emotional faces, while the pallidum was more efficiently connected when viewing alcohol beverages. Together our findings identified lower occipito-temporal sensitivity to emotional faces and enhanced striatal sensitivity to alcohol stimuli in AUD than controls. Considering the role of the striatum in encoding reward, its activation enhancement with longer sobriety may reflect adaptive neural changes in the first year of drinking cessation and mesocorticolimbic system vulnerability for encoding emotional salience and reward potentially affecting executive control ability and relapse propensity during abstinence.

Dissociation of preparatory attention and response monitoring maturation during adolescence.

OBJECTIVE: Substantial brain development occurs during adolescence providing the foundation for functional advancement from stimulus-bound "bottom-up" to more mature executive-driven "top-down" processing strategies. The objective was to assess development of EEG markers of these strategies and their role in both preparatory attention (contingent negative variation, CNV) and response monitoring (Error Related Negativity, ERN, and Correct Related Negativity, CRN). METHODS: CNV, ERN and CRN were assessed in 38 adolescents (18 girls), age 11-18 years, using a variation of a letter discrimination task. RESULTS: Accuracy increased with age and developmental stage. Younger adolescents used a posterior attention network involved in inhibiting irrelevant information. Activity in this juvenile network, as indexed by a posteriorly-biased CNV and CRN decreased with age and advancing pubertal development. Although enhanced frontal CNV, known to be predictive of accuracy in adults, was not detected even in the older adolescents, top-down medial frontal response monitoring processes (ERN) showed evidence of development within the age-range studied. CONCLUSIONS: The data revealed a dissociation of developmental progress, marked by relatively delayed onset of frontal preparatory attention relative to error monitoring. SIGNIFICANCE: This dissociation may render adolescents vulnerable to excessive risk-taking and disinhibited behavior imposed by asynchronous development of component cognitive control processes.

Midbrain-driven emotion and reward processing in alcoholism.

Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli.

White matter fiber compromise contributes differentially to attention and emotion processing impairment in alcoholism, HIV-infection, and their comorbidity.

Alcoholism (ALC) and HIV-1 infection (HIV) each affects emotional and attentional processes and integrity of brain white matter fibers likely contributing to functional compromise. The highly prevalent ALC+HIV comorbidity may exacerbate compromise. We used diffusion tensor imaging (DTI) and an emotional Stroop Match-to-Sample task in 19 ALC, 16 HIV, 15 ALC+HIV, and 15 control participants to investigate whether disruption of fiber system integrity accounts for compromised attentional and emotional processing. The task required matching a cue color to that of an emotional word with faces appearing between the color cue and the Stroop word in half of the trials. Nonmatched cue-word color pairs assessed selective attention, and face-word pairs assessed emotion. Relative to controls, DTI-based fiber tracking revealed lower inferior longitudinal fasciculus (ilf) integrity in HIV and ALC+HIV and lower uncinate fasciculus (uf) integrity in all three patient groups. Controls exhibited Stroop effects to positive face-word emotion, and greater interference was related to greater callosal, cingulum and ilf integrity. By contrast, HIV showed greater interference from negative Stroop words during color-nonmatch trials, correlating with greater uf compromise. For face trials, ALC and ALC+HIV showed greater Stroop-word interference, correlating with lower cingulate and callosal integrity. Thus, in HIV, conflict resolution was diminished when challenging conditions usurped resources needed to manage interference from negative emotion and to disengage attention from wrongly cued colors (nonmatch). In ALC and ALC+HIV, poorer callosal integrity was related to enhanced emotional interference suggesting curtailed interhemispheric exchange needed between preferentially right-hemispheric emotion and left-hemispheric Stroop-word functions.

Neuroradiological characterization of normal adult ageing.

This paper provides a review of MRI and diffusion tensor imaging (DTI) findings in normal ageing as an essential context for evaluating imaging in dementia, and adding to the ever-growing number of such overviews. An additional extensive literature details the physics, MR acquisition, image reconstruction and mathematical computation approaches to both imaging modalities. The aim of this review is to illustrate how MR imaging modalities, spanning structural and diffusion tensor imaging, are suitable for visualizing and quantifying the macrostructural and microstructural disruptions sustained by the brain in normal ageing and to recognize the importance of normative data for identifying abnormalities characterizing neurodegenerative diseases and other conditions affecting brain tissue integrity.

Callosal involvement in a lateralized stroop task in alcoholic and healthy subjects.

To investigate the role of interhemispheric attentional processes, 25 alcoholic and 28 control subjects were tested with a Stroop match-to-sample task and callosal areas were measured with magnetic resonance imaging. Stroop color-word stimuli were presented to the left or right visual field (VF) and were preceded by a color cue that did or did not match the word's color. For matching colors, both groups showed a right VF advantage; for nonmatching colors, controls showed a left VF advantage, whereas alcoholic subjects showed no VF advantage. For nonmatch trials, VF advantage correlated with callosal splenium area in controls but not alcoholic subjects, supporting the position that information presented to the nonpreferred hemisphere is transmitted via the splenium to the hemisphere specialized for efficient processing. The authors speculate that alcoholism-associated callosal thinning disrupts this processing route.

fMRI evidence for individual differences in premotor modulation of extrastriatal visual-perceptual processing of redundant targets.

To perceive the vast array of stimuli in the world around us, the visual system employs parallel processing mechanisms that ensure efficiency in perceiving multiple objects in a scene. A way to test this efficiency is to measure reaction time (RT) to pairs of identical stimuli, presented singly or as doublets; typically, the resulting phenomenon is the redundant targets effect (RTE), which manifests as faster RTs to paired than singly presented stimuli. It is controversial, however, whether the neural locus of the parallel processing mechanisms invoked to produce the RTE is perceptual or motor and why some studies observe a substantial RTE and others do not. To resolve these two issues, we measured the RTE in young adults while undergoing functional MRI. Regarding the question of a perceptual or motor basis for the RTE, we observed that bilateral activation of extrastriate cortex was prominent in paired vs. the sum of the two single stimulus conditions, indicating that the RTE invoked perceptual mechanisms; by contrast, the motor cortex was not disproportionately activated in this comparison. Regarding the magnitude of the RTE, we compared activation patterns in individuals with small vs. large RTEs and observed that frontal and premotor areas were activated with small RTEs. These data indicate that the primary processing level of response facilitation, observed as the RTE, is perceptual, but the modulation of the RTE magnitude is premotor and associated with basic aspects of response selection and preparation.

Corpus callosal microstructural integrity influences interhemispheric processing: a diffusion tensor imaging study.

Normal aging and chronic alcoholism result in disruption of brain white matter microstructure that does not typically cause complete lesions but may underlie degradation of functions requiring interhemispheric information transfer. We examined whether the microstructural integrity of the corpus callosum assessed with diffusion tensor imaging (DTI) would relate to interhemispheric processing speed. DTI yields estimates of fractional anisotropy (FA), a measure of orientation and intravoxel coherence of water diffusion usually in white matter fibers, and diffusivity (), a measure of the amount of intracellular and extracellular fluid diffusion. We tested the hypothesis that FA and would be correlated with (i) the crossed-uncrossed difference (CUD), testing visuomotor interhemispheric transfer; and (ii) the redundant targets effect (RTE), testing parallel processing of visual information presented to each cerebral hemisphere. FA was lower and higher in alcoholics than in controls. In controls but not alcoholics, large CUDs correlated with low FA and high in total corpus callosum and regionally in the genu and splenium. In alcoholics but not controls, small RTEs, elicited with equiluminant stimuli, correlated with low FA in genu and splenium and high in the callosal body. The results provide in vivo evidence for disruption of corpus callosum microstructure in normal aging and alcoholism that has functional ramifications for efficiency in interhemispheric processing.

Information fusion in biomedical image analysis: combination of data vs. combination of interpretations.

Information fusion has, in the form of multiple classifier systems, long been a successful tool in pattern recognition applications. It is also becoming increasingly popular in biomedical image analysis, for example in computer-aided diagnosis and in image segmentation. In this paper, we extend the principles of multiple classifier systems by considering information fusion of classifier inputs rather than on their outputs, as is usually done. We introduce the distinction between combination of data (i.e., classifier inputs) vs. combination of interpretations (i.e., classifier outputs). We illustrate the two levels of information fusion using four different biomedical image analysis applications that can be implemented using fusion of either data or interpretations: atlas-based image segmentation, "average image" tissue classification, multi-spectral classification, and deformation-based group morphometry.

In vivo 2D J-resolved magnetic resonance spectroscopy of rat brain with a 3-T clinical human scanner.

A clinical 3-T scanner equipped with a custom-made transmit/receive birdcage coil was used to collect 2D J-resolved single-voxel spectroscopy in vivo of rat brain. Four adult Wistar rats were scanned twice each, with a 2-week interval. Voxel size was approximately 5 x 10 x 5 mm(3). Total spectroscopic acquisition time was 14 min for collection of two 4:20 min water-suppressed acquisitions and one 4:20 min acquisition acquired in the absence of water suppression. The unsuppressed water data were used in post-processing to reduce residual water side bands, as well as for metabolite signal normalization to account for variations in coil loading and voxel size. Peak areas were estimated for resonances from N-acetyl aspartate (NAA), creatine, choline, taurine, glutamate, and combined glutamate and glutamine. T(2)-relaxation times were estimated for NAA and creatine. The average deviation from the mean of repeated measures for glutamate, combined glutamate and glutamine, and taurine ranged from 7.6% to 18.3%, while for NAA, creatine, and choline, the deviation was less than 3%. The estimated T(2) values for NAA (mean +/- SD = 330 +/- 57 ms) and creatine (174 +/- 27 ms) were similar to those reported previously for rat brain and for human gray and white matter. These results indicate that reliable, small animal brain MR spectroscopy can be performed on a human clinical 3-T scanner.

Parallel interhemispheric processing in aging and alcoholism: relation to corpus callosum size.

We tested parallel processing of visual information using the redundant targets effect (RTE) in 12 alcoholics and 13 matched controls. The paradigm was a simple reaction time (RT) task with targets presented in the same (uncrossed), opposite (crossed), or both (redundant) visual-fields. In older alcoholics (>50 years) the RT gain invoked by redundant targets did not exceed probability measures, suggesting compromised interhemispheric processing of parallel information in this subgroup compared with controls or younger alcoholics. The difference between crossed and uncrossed reaction times (CUD), an index of interhemispheric transfer time (ITT), was greater in older than younger subjects. Moreover, the CUD was negatively correlated with the corpus callosum (CC) total area and body in controls, supporting the concept of a structure-function relationship of interhemispheric transfer. This relationship was not found in alcoholics, although the midsagittal area of the CC, genu, and body but not intracranial volume (ICV), was significantly smaller in alcoholics than controls. These results suggest that chronic alcohol abuse together with advancing age exert subtle disruption on parallel interhemispheric processing reliant on callosal connections.

Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study.

OBJECTIVE: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men.

Brain structure changes in size with normal aging, but the rate at which different structures change is controversial. We used magnetic resonance imaging (MRI) performed twice, 4 years apart, to compare rates of age-related size change of the corpus callosum, which has been inconsistently observed to thin with age, with change in the lateral ventricles, which are well established to enlarge. Subjects were 215 community dwelling, elderly men (70-82 years old at initial MRI), who were participants in a longitudinal study of cardiovascular risk factors. Percent change in size was significant for both the callosal and ventricular measures, but annual rate of ventricular expansion (2.9%) was significantly greater than annual rate of callosal thinning (-0.9%). Callosal regions showed statistically equivalent rates of shrinkage; ventricular dilatation was symmetrical. Neither callosal and ventricular rates of change correlated with each other (r = 0.01), nor did genu and splenium rates of change correlate with each other (r = 0.05). Tests of speeded processing were administered contemporaneously with both MRIs to examine functional ramifications of observed brain changes. Decline in the Mini-Mental State Examination was related to thinning of the splenium, and decline in Stroop test word reading was selectively related to thinning of the callosal body. These longitudinal data support the contentions that differential rates of change occur in different brain regions in normal aging, age-related callosal thinning contributes to functional declines, and rate of change in one region can be independent of rate of change in another region, even within a brain structure.

Structural brain abnormalities in patients with schizophrenia, epilepsy, and epilepsy with chronic interictal psychosis.

Chronic interictal psychotic syndromes, often resembling schizophrenia, develop in some patients with epilepsy. Although widespread brain abnormalities are recognized as characteristic of schizophrenia, prevailing but controversial hypotheses on the co-occurrence of epilepsy and psychosis implicate left temporal lobe pathology. In this study, quantitative MRI methods were used to address the regional specificity of structural brain abnormalities in patients with epilepsy plus chronic interictal psychosis (E+PSY, n=9) relative to three comparison groups: unilateral temporal lobe epilepsy without chronic psychosis (TLE, n=18), schizophrenia (SCZ, n=46), and healthy control subjects (HC, n=57). Brain measures, derived from a coronal spin-echo MRI sequence, were adjusted for age and cerebral volume. Relative to HC, all patient groups had ventricular enlargement and smaller temporal lobe, frontoparietal, and superior temporal gyrus gray matter volumes, with the extent of these abnormalities greatest in E+PSY. Only TLE had temporal lobe white matter deficits, as well as smaller hippocampi, which were ipsilateral to the seizure focus. Structural brain abnormalities in E+PSY are not restricted to the left temporal lobe. The confluence of cortical gray matter deficits in E+PSY and SCZ suggests salience to chronic psychosis.

Motor sequencing deficits in schizophrenia: a comparison with Parkinson's disease.

Motor abnormalities occur in schizophrenia (SZ) and may arise from striatal dysfunction. This study examined whether the pattern of performance on simple and complex motor abilities in SZ was similar to that of patients with Parkinson's disease (PD). Quantitative tests of speeded movement and motor and cognitive sequencing were used to assess 25 SZ, 16 PD, and 84 normal controls (NCs). Sequencing performance was also examined with motor rigidity taken into account. Compared with the NC group, the SZ and PD groups were impaired on measures of motor rigidity and motor sequencing. With rigidity accounted for, the SZ group was significantly more impaired than the PD group on motor sequencing; cognitive and motor processes contributed to the motor deficit. Cognitive sequencing performance predicted motor sequencing performance in PD but not SZ. Although both SZ and PD resulted in significant motor and cognitive sequencing deficits, the pattern and correlates of these deficits differ, suggesting that the affected neural systems underlying motor deficits in SZ are different from those involved in PD.

Magnetic resonance relaxometry reveals central pontine abnormalities in clinically asymptomatic alcoholic men.

BACKGROUND: Central pontine myelinolysis (CPM) is a rare, debilitating, life-threatening condition, associated with chronic alcoholism, rapid correction of hyponatremia, and advanced age. It is unknown, however, whether older alcoholic patients who by age and diagnosis are at risk for CPM have objectively determined neuroimaging evidence of preclinical CPM that could be valuable in understanding its development and in initiating appropriate treatment. Accordingly, we examined central pontine magnetic resonance (MR) transverse relaxation time (T2), which reflects myelin and axonal integrity when measured in white matter and is prolonged with pathology that causes increased free water content in tissue. METHODS: The subjects were 46 alcoholic men who were abstinent from alcohol for about 1 month and were asymptomatic for CPM, 9 men and 1 woman with alcoholic Korsakoff's syndrome (KS), and 74 healthy control men. All subjects received coronally acquired dual-echo MR imaging (MRI), from which T2 times were calculated in central pons. MRI films were read clinically and independently of relaxometry results. Hematological and neuropsychological data were also available for many subjects. RESULTS: Only the KS group showed prolonged T2 times; however, pontine T2 prolongation increased significantly with older age in the asymptomatic alcoholics but not controls. Clinical radiological readings detected pontine signal hyperintensity in five KS subjects (two without dementia and three with dementia), one control, and no alcoholic patient. Hematologic indexes of macrocytic anemia and nutritional deficiency and neuropsychological measures of verbal and nonverbal fluency correlated with prolonged T2 times in alcoholic men. CONCLUSIONS: This CPM-like condition, manifest as prolonged T2, may occur with higher incidence than previously thought in clinically asymptomatic alcoholism and may contribute to neuropsychological compromise of initiation and production. Preclinical detection of abnormal pontine signal properties with MR relaxometry may identify patients at high risk for developing CPM.

Reorganization of frontal systems used by alcoholics for spatial working memory: an fMRI study.

Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal ("Where?") stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral ("What?") stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.