Early Cannabis Use and Neurocognitive Risk: A Prospective Functional Neuroimaging Study.

BACKGROUND: Retrospective neuroimaging studies have suggested an association between early cannabis onset and later neurocognitive impairment. However, these studies have been limited in their ability to distinguish substance use risk factors from cannabis-induced effects on neurocognition. We used a prospective cohort design to test whether neurocognitive differences preceded cannabis onset (substance use risk model) and if early cannabis use was associated with poorer neurocognitive development (cannabis exposure model). METHODS: Participants (N = 85) completed a visuospatial working memory task during functional magnetic resonance imaging and multiple cognitive assessments (Wechsler Intelligence Scale for Children-IV, Cambridge Neuropsychological Test Automated Battery) at 12 years of age, before any reported cannabis use (baseline), and at 15 years of age (follow-up: N = 85 cognitive assessments, n = 67 neuroimaging). By follow-up, 22 participants reported using cannabis and/or failed a Δ9-tetrahydrocannabinol urine screen (users). RESULTS: At baseline, group differences supported a risk model. Those who would initiate cannabis use by 15 years of age had activation differences in frontoparietal (increased) and visual association (decreased) regions and poorer executive planning scores (Stockings of Cambridge) compared with noninitiators. Limited support was found for a cannabis exposure model. At follow-up, activation in the cuneus displayed a significant cannabis dose-response relationship, although neither cannabis dose nor cuneus activation was associated with cognitive performance. CONCLUSIONS: The purported neurocognitive effects of early cannabis onset may not be due to cannabis initiation alone but also driven by limitations or late development of neurocognitive systems predictive of substance use. In addition, more prolonged cannabis exposure may be required to observe the cognitive effects of early cannabis onset.

Functional connectivity differences in autism during face and car recognition: underconnectivity and atypical age-related changes.

Face recognition abilities improve between adolescence and adulthood over typical development (TD), but plateau in autism, leading to increasing face recognition deficits in autism later in life. Developmental differences between autism and TD may reflect changes between neural systems involved in the development of face encoding and recognition. Here, we focused on whole-brain connectivity with the fusiform face area (FFA), a well-established face-preferential brain region. Older children, adolescents, and adults with and without autism completed the Cambridge Face Memory Test, and a matched car memory test, during fMRI scanning. We then examined task-based functional connectivity between the FFA and the rest of the brain, comparing autism and TD groups during encoding and recognition of face and car stimuli. The autism group exhibited underconnectivity, relative to the TD group, between the FFA and frontal and primary visual cortices, independent of age. Underconnectivity with the medial and rostral lateral prefrontal cortex was face-specific during encoding and recognition, respectively. Conversely, underconnectivity with the L orbitofrontal cortex was evident for both face and car encoding. Atypical age-related changes in connectivity emerged between the FFA and the R temporoparietal junction, and R dorsal striatum for face stimuli only. Similar differences in age-related changes in autism emerged for FFA connectivity with the amygdala across both face and car recognition. Thus, underconnectivity and atypical development of functional connectivity may lead to a less optimal face-processing network in the context of increasing general and social cognitive deficits in autism.

Adolescent cannabis use and brain systems supporting adult working memory encoding, maintenance, and retrieval.

Given prior reports of adverse effects of cannabis use on working memory, an executive function with a protracted developmental course during adolescence, we examined associations between developmental patterns of cannabis use and adult working memory (WM) processes. Seventy-five adults with longitudinal assessments of cannabis use (60 with reported use, 15 with no reported use) and prenatal drug exposure assessment completed a spatial WM task during fMRI at age 28. All subjects passed a multi-drug urine screen on the day of testing and denied recreational drug use in the past week. A fast event-related design with partial trials was used to separate the BOLD response associated with encoding, maintenance, and retrieval periods of the WM task. Behavioral results showed that subjects who began using cannabis earlier in adolescence had longer reaction times (RT) than those with later initiation. Cannabis age of onset was further associated with reduced posterior parietal cortex (PPC) encoding BOLD activation, which significantly mediated age of onset WM RT associations. However, cannabis age of onset brain-behavior associations did not differ between groups with a single reported use and those with repeated use, suggesting age of onset effects may reflect substance use risk characteristics rather than a developmentally-timed cannabis exposure effect. Within repeated cannabis users, greater levels of total cannabis use were associated with performance-related increases in dorsolateral prefrontal cortex (DLPFC) activation during maintenance. This pattern of significant results remained unchanged with inclusion of demographic and prenatal measures as covariates. Surprisingly, however, at the group level, cannabis users generally performed better than participants who reported never using cannabis (faster RT, higher accuracy). We extend previous investigations by identifying that WM associations with cannabis age of onset may be primary to PPC stimulus encoding activity, while the amount of cannabis use is associated with DLPFC maintenance processes. Poorer performance of participants who reported never using cannabis and the consistency of cannabis age of onset associations across single and repeated users limit interpretation of direct developmental effects of cannabis on WM in adulthood.

Differentiating between clinical and behavioral phenotypes in first-episode psychosis during maintenance of visuospatial working memory.

INTRODUCTION: We probed the neural basis of working memory in individuals with first episode of psychosis (FEP) and assessed how these neural abnormalities are associated with behavioral performance and/or core to psychosis pathophysiology. METHODS: FEP (N=35) and matched controls (N=25) performed a visuospatial working memory task during fMRI acquisition. We isolated neural activity during the maintenance period and examined neural activity within regions typically engaged during a working memory task. Functional connectivity estimates were derived using psychophysiological interaction analysis. We examined correlations between brain function and behavioral performance and clinical symptomatology. RESULTS: FEP had reduced accuracy and slower reaction times compared to controls (p<0.05, q<0.05). During the maintenance period, FEP exhibited reduced right dorsolateral prefrontal cortex (DLPFC) activation compared to controls (p=0.007, q=0.01), even when behavioral performance was matched between groups (p=0.01, q=0.03). Unlike controls, FEP failed to show increased dorsal anterior cingulate (dACC) activity with increased load level (p=0.02, q=0.06). Compared to controls, FEP showed increased negative DLPFC-dACC coupling during the maintenance period (p=0.05). Increased DLPFC activation was significantly associated with greater negative symptoms (p<0.005, q=0.02), while greater dACC activation was significantly associated with better performance in FEP (p<0.05, q<0.17). CONCLUSION: WM impairment in psychosis may be specific to abnormalities in the ability of frontal systems processing executive commands (DLPFC) and monitoring performance (dACC) during the maintenance of information. Our results add to accumulating evidence indicating that DLPFC abnormalities may be core to psychosis psychopathology. We also provide new insights regarding how DLPFC abnormalities may undermine dACC processing during the maintenance of information.

Protracted development of executive and mnemonic brain systems underlying working memory in adolescence: A longitudinal fMRI study.

Working memory (WM), the ability to hold information on-line to guide planned behavior, improves through adolescence in parallel with continued maturation of critical brain systems supporting cognitive control. Initial developmental neuroimaging studies with one or two timepoints have provided important though varied results limiting our understanding of which and how neural systems change during this transition into mature WM. In this study, we leverage functional magnetic resonance imaging (fMRI) longitudinal data spanning up to 9 years in 129 normally developing individuals to identify which systems demonstrate growth changes that accompany improvements in WM performance. We used a memory guided saccade task that allowed us to probe encoding, pure maintenance, and retrieval neural processes of WM. Consistent with prior research, we found that WM performance continued to improve into the early 20's. fMRI region of interest (ROI) analyses revealed developmental (1) increases in sensorimotor-related (encoding/retrieval) activity in visual cortex from childhood through early adulthood that were associated with WM accuracy and (2) decreases in sustained (maintenance) activity in executive regions from childhood through mid-adolescence that were associated with response latency in childhood and early adolescence. Together these results provide compelling evidence that underlying the maturation of WM is a transition from reliance on executive systems to specialized regions related to the domain of mnemonic requirements of the task leading to optimal performance.

Developmental stages and sex differences of white matter and behavioral development through adolescence: a longitudinal diffusion tensor imaging (DTI) study.

White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals aged 8-28, who received annual scans for up to 5 years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical-subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition-emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.

Increased intra-individual reaction time variability in attention-deficit/hyperactivity disorder across response inhibition tasks with different cognitive demands.

One of the most consistent findings in children with ADHD is increased moment-to-moment variability in reaction time (RT). The source of increased RT variability can be examined using ex-Gaussian analyses that divide variability into normal and exponential components and Fast Fourier transform (FFT) that allow for detailed examination of the frequency of responses in the exponential distribution. Prior studies of ADHD using these methods have produced variable results, potentially related to differences in task demand. The present study sought to examine the profile of RT variability in ADHD using two Go/No-go tasks with differing levels of cognitive demand. A total of 140 children (57 with ADHD and 83 typically developing controls), ages 8-13 years, completed both a "simple" Go/No-go task and a more "complex" Go/No-go task with increased working memory load. Repeated measures ANOVA of ex-Gaussian functions revealed for both tasks children with ADHD demonstrated increased variability in both the normal/Gaussian (significantly elevated sigma) and the exponential (significantly elevated tau) components. In contrast, FFT analysis of the exponential component revealed a significant task x diagnosis interaction, such that infrequent slow responses in ADHD differed depending on task demand (i.e., for the simple task, increased power in the 0.027-0.074 Hz frequency band; for the complex task, decreased power in the 0.074-0.202 Hz band). The ex-Gaussian findings revealing increased variability in both the normal (sigma) and exponential (tau) components for the ADHD group, suggest that both impaired response preparation and infrequent "lapses in attention" contribute to increased variability in ADHD. FFT analyses reveal that the periodicity of intermittent lapses of attention in ADHD varies with task demand. The findings provide further support for intra-individual variability as a candidate intermediate endophenotype of ADHD.

Decreased connectivity and cerebellar activity in autism during motor task performance.

Although motor deficits are common in autism, the neural correlates underlying the disruption of even basic motor execution are unknown. Motor deficits may be some of the earliest identifiable signs of abnormal development and increased understanding of their neural underpinnings may provide insight into autism-associated differences in parallel systems critical for control of more complex behaviour necessary for social and communicative development. Functional magnetic resonance imaging was used to examine neural activation and connectivity during sequential, appositional finger tapping in 13 children, ages 8-12 years, with high-functioning autism (HFA) and 13 typically developing (TD), age- and sex-matched peers. Both groups showed expected primary activations in cortical and subcortical regions associated with motor execution [contralateral primary sensorimotor cortex, contralateral thalamus, ipsilateral cerebellum, supplementary motor area (SMA)]; however, the TD group showed greater activation in the ipsilateral anterior cerebellum, while the HFA group showed greater activation in the SMA. Although activation differences were limited to a subset of regions, children with HFA demonstrated diffusely decreased connectivity across the motor execution network relative to control children. The between-group dissociation of cerebral and cerebellar motor activation represents the first neuroimaging data of motor dysfunction in children with autism, providing insight into potentially abnormal circuits impacting development. Decreased cerebellar activation in the HFA group may reflect difficulty shifting motor execution from cortical regions associated with effortful control to regions associated with habitual execution. Additionally, diffusely decreased connectivity may reflect poor coordination within the circuit necessary for automating patterned motor behaviour. The findings might explain impairments in motor development in autism, as well as abnormal and delayed acquisition of gestures important for socialization and communication.

fMRI evidence for multisensory recruitment associated with rapid eye movements during sleep.

We studied the neural correlates of rapid eye movement during sleep (REM) by timing REMs from video recording and using rapid event-related functional MRI. Consistent with the hypothesis that REMs share the brain systems and mechanisms with waking eye movements and are visually-targeted saccades, we found REM-locked activation in the primary visual cortex, thalamic reticular nucleus (TRN), 'visual claustrum', retrosplenial cortex (RSC, only on the right hemisphere), fusiform gyrus, anterior cingulate cortex, and the oculomotor circuit that controls awake saccadic eye movements (and subserves awake visuospatial attention). Unexpectedly, robust activation also occurred in non-visual sensory cortices, motor cortex, language areas, and the ascending reticular activating system, including basal forebrain, the major source of cholinergic input to the entire cortex. REM-associated activation of these areas, especially non-visual primary sensory cortices, TRN and claustrum, parallels findings from waking studies on the interactions between multiple sensory data, and their 'binding' into a unified percept, suggesting that these mechanisms are also shared in waking and dreaming and that the sharing goes beyond the expected visual scanning mechanisms. Surprisingly, REMs were associated with a decrease in signal in specific periventricular subregions, matching the distribution of the serotonergic supraependymal plexus. REMs might serve as a useful task-free probe into major brain systems for functional brain imaging.

Moderate variability in stimulus presentation improves motor response control.

To examine the impact of interstimulus "jitter" (i.e., randomization of the interval between successive stimulus events) on response control during continuous task performance, 41 healthy adults completed four go/no-go tasks that were identical except for interstimulus interval (ISI) jitter: a 0% jitter task with a fixed (1,000-ms) ISI, a 10% jitter task with an ISI range of 900-1,100 ms, a 30% jitter task with an ISI range of 700-1,300 ms, and a 50% jitter task with an ISI range of 500-1,500 ms. Repeated measures analysis of variance (ANOVA) revealed a quadratic effect of jitter on commissions across the group and on intrasubject reaction time variability in men; in both cases, performance was best for the 10% jitter condition. A linear effect of jitter was observed for reaction time (RT) with high levels of jitter (50%) resulting in longer RT. Findings suggest that response selection, including inhibition, is optimized by moderate increases in ISI jitter. More deliberate and controlled responding observed with increasing jitter may have important treatment implications for disorders (e.g., attention-deficit/hyperactivity disorder, ADHD), associated with impaired response control.

fMRI of intrasubject variability in ADHD: anomalous premotor activity with prefrontal compensation.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) consistently display increased intrasubject variability (ISV) in response time across varying tasks, signifying inefficiency of response preparation compared to typically developing (TD) children. Children with ADHD also demonstrate impaired response inhibition; inhibitory deficits correlate with ISV, suggesting that similar brain circuits may underlie both processes. To better understand the neural mechanisms underlying increased ISV and inhibitory deficits in children with ADHD, functional magnetic resonance imaging was used to examine the neural correlates of ISV during Go/No-go task performance. METHOD: Event-related functional magnetic resonance imaging was used to study 25 children with ADHD and 25 TD children ages 8 to 13 years performing a simplified Go/No-go task. Brain-behavior correlations were examined between functional magnetic resonance imaging activation and ISV within and between groups. RESULTS: For TD children, increased rostral supplementary motor area (pre-supplementary motor area) activation during No-go events was associated with less ISV, whereas the reverse was true for children with ADHD for whom increased pre-supplementary motor area activation was associated with more ISV. In contrast, children with ADHD with less ISV showed greater prefrontal activation, whereas TD children with more prefrontal activation demonstrated more ISV. CONCLUSIONS: These findings add to evidence that dysfunction of premotor systems may contribute to increased variability and impaired response inhibition in children with ADHD and that compensatory strategies eliciting increased cognitive control may improve function. However, recruitment of prefrontal resources as a compensatory mechanism for motor task performance may preclude the use of those prefrontal resources for higher order, more novel executive functions with which children with ADHD often struggle.

Response inhibition and response selection: two sides of the same coin.

Response inhibition refers to the suppression of actions that are inappropriate in a given context and that interfere with goal-driven behavior. Studies using a range of methodological approaches have implicated executive control processes mediated by frontal-subcortical circuits as being critical to response inhibition; however, localization within the frontal lobe has been inconsistent. In this review, we present evidence from behavioral, lesion, neuroimaging, electrophysiology, and neurological population studies. The findings lay the foundation for a construct in which response inhibition is akin to response selection, such that pre-SMA circuits are critical to selection of appropriate behavior, including both selecting to engage appropriate motor responses and selecting to withhold (inhibit) inappropriate motor responses. Recruitment of additional prefrontal and posterior cortical circuits, necessary to guide response selection, varies depending on the cognitive and behavioral demands of the task.

Functional magnetic resonance imaging evidence for abnormalities in response selection in attention deficit hyperactivity disorder: differences in activation associated with response inhibition but not habitual motor response.

Impaired response inhibition is thought to be a core deficit in attention deficit hyperactivity disorder (ADHD). Prior imaging studies investigating response inhibition in children with ADHD have used tasks involving different cognitive resources, thereby complicating the interpretation of their findings. In this study, a classical go/no-go task with a well-ingrained stimulus-response association (green = go; red = no-go) was used in order to minimize extraneous cognitive demands. Twenty-five children with ADHD and 25 typically developing (TD) children between the ages of 8 and 13 years and group-matched for IQ and performance on the go/no-go task were studied using event-related functional magnetic resonance imaging (fMRI). Analyses were used to examine differences in activation between the ADHD and TD groups for "go" (habitual motor response) and "no-go" (requiring inhibition of the motor response) events. Region-of-interest analyses revealed no between-group difference in activation in association with "go" events. For "no-go" events, the children with ADHD demonstrated significantly less activation than did TD controls within a network important for inhibiting a motor response to a visual stimulus, with frontal differences localized to the pre-supplementary motor area. Although blood oxygenation level-dependent fMRI data show no differences between children with ADHD and TD children in association with a habituated motor "go" response, during "no-go" events, which require selecting not to respond, children with ADHD show diminished recruitment of networks important for response inhibition. The findings suggest that abnormalities in circuits important for motor response selection contribute to deficits in response inhibition in children with ADHD and lend support to the growing awareness of ADHD-associated anomalies in medial frontal regions important for the control of voluntary actions.

Meta-analysis of Go/No-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent.

FMRI studies of response inhibition consistently reveal frontal lobe activation. Localization within the frontal cortex, however, varies across studies and appears dependent on the nature of the task. Activation likelihood estimate (ALE) meta-analysis is a powerful quantitative method of establishing concurrence of activation across functional neuroimaging studies. For this study, ALE was used to investigate concurrent neural correlates of successfully inhibited No-go stimuli across studies of healthy adults performing a Go/No-go task, a paradigm frequently used to measure response inhibition. Due to the potential overlap of neural circuits for response selection and response inhibition, the analysis included only event-related studies contrasting No-go activation with baseline, which allowed for inclusion of all regions that may be critical to visually guided motor response inhibition, including those involved in response selection. These Go/No-go studies were then divided into two groups: "simple" Go/No-go tasks in which the No-go stimulus was always the same, and "complex" Go/No-go tasks, in which the No-go stimulus changed depending on context, requiring frequent updating of stimulus-response associations in working memory. The simple and complex tasks demonstrated distinct patterns of concurrence, with right dorsolateral prefrontal and inferior parietal circuits recruited under conditions of increased working memory demand. Common to both simple and complex Go/No-go tasks was concurrence in the pre-SMA and the left fusiform gyrus. As the pre-SMA has also been shown to be involved in response selection, the results support the notion that the pre-SMA is critical for selection of appropriate behavior, whether selecting to execute an appropriate response or selecting to inhibit an inappropriate response.

Functional brain correlates of response time variability in children.

During tasks requiring response inhibition, intra-individual response time variability, a measure of motor response preparation, has been found to correlate with errors of commission, such that individuals with higher variability show increased commission errors. This study used fMRI to examine the neural correlates of response variability in 30 typically developing children, ages 8-12, using a simplified Go/No-go task with minimal cognitive demands. Lower variability was associated with Go activation in the anterior cerebellum (culmen) and with No-go activation in the rostral supplementary motor area (pre-SMA), the postcentral gyrus, the anterior cerebellum (culmen) and the inferior parietal lobule. For both Go and No-go events, higher variability was associated with activation in prefrontal cortex and the caudate. The findings have implications for neuropsychiatric disorders such as ADHD and suggest that during response inhibition, children with more consistent performance are able to rely on premotor circuits involving the pre-SMA, important for response selection; those with less consistent performance instead recruit prefrontal circuits involved in more complex aspects of behavioral control.