Sarah Whittle

Regional brain abnormalities associated with long-term heavy cannabis use.

CONTEXT Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain. OBJECTIVE To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala. DESIGN Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. SETTING Participants were recruited from the general community and underwent imaging at a hospital research facility. PARTICIPANTS Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years). MAIN OUTCOME MEASURES Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. RESULTS Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group. CONCLUSIONS These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

The neurobiological basis of temperament: Towards a better understanding of psychopathology

The ability to characterise psychopathologies on the basis of their underlying neurobiology is critical in improving our understanding of disorder etiology and making more effective diagnostic and treatment decisions. Given the well-documented relationship between temperament (i.e. core personality traits) and psychopathology, research investigating the neurobiological substrates that underlie temperament is potentially key to our understanding of the biological basis of mental disorder. We present evidence that specific areas of the prefrontal cortex (including the dorsolateral prefrontal, anterior cingulate, and orbitofrontal cortices) and limbic structures (including the amygdala, hippocampus and nucleus accumbens) are key regions associated with three fundamental dimensions of temperament: Negative Affect, Positive Affect, and Constraint. Proposed relationships are based on two types of research: (a) research into the neurobiological correlates of affective and cognitive processes underlying these dimensions; and (b) research into the neurobiology of various psychopathologies, which have been correlated with these dimensions. A model is proposed detailing how these structures might comprise neural networks whose functioning underlies the three temperaments. Recommendations are made for future research into the neurobiology of temperament, including the need to focus on neural networks rather than individual structures, and the importance of prospective, longitudinal, multi-modal imaging studies in at-risk youth.

Sex differences in the neural correlates of emotion: Evidence from neuroimaging

Sex differences in emotional processes represent some of the most robust sex stereotypes worldwide. However, empirical support for these stereotypes is lacking, especially from research utilizing objective measures, such as neuroimaging methodologies. We conducted a selective review of functional neuroimaging studies that have empirically tested for sex differences in the association between brain function and emotional processes (including perception, reactivity, regulation and experience). Evidence was found for marked sex differences in the neural mechanisms underlying emotional processes, and in most cases suggested that males and females use different strategies during emotional processing, which may lead to sex differences in the observed (or subjectively reported) emotional process. We discuss how these findings may offer insight into the mechanisms underlying sex differences in emotional behaviors, and outline a number of methodological considerations for future research. Importantly, results suggest that sex differences should not be ignored in research investigating the neurobiology of emotion.

Functional brain imaging studies of youth depression: A systematic review

Background There is growing interest in understanding the neurobiology of major depressive disorder (MDD) in youth, particularly in the context of neuroimaging studies. This systematic review provides a timely comprehensive account of the available functional magnetic resonance imaging (fMRI) literature in youth MDD. Methods A literature search was conducted using PubMED, PsycINFO and Science Direct databases, to identify fMRI studies in younger and older youth with MDD, spanning 13–18 and 19–25 years of age, respectively. Results Twenty-eight studies focusing on 5 functional imaging domains were identified, namely emotion processing, cognitive control, affective cognition, reward processing and resting-state functional connectivity. Elevated activity in “extended medial network” regions including the anterior cingulate, ventromedial and orbitofrontal cortices, as well as the amygdala was most consistently implicated across these five domains. For the most part, findings in younger adolescents did not differ from those in older youth; however a general comparison of findings in both groups compared to adults indicated differences in the domains of cognitive control and affective cognition. Conclusions Youth MDD is characterized by abnormal activations in ventromedial frontal regions, the anterior cingulate and amygdala, which are broadly consistent with the implicated role of medial network regions in the pathophysiology of depression. Future longitudinal studies examining the effects of neurodevelopmental changes and pubertal maturation on brain systems implicated in youth MDD will provide a more comprehensive neurobiological model of youth depression.

Orbitofrontal Volumes in Early Adolescence Predict Initiation of Cannabis Use: A 4-Year Longitudinal and Prospective Study

BACKGROUND There is growing evidence that long-term, heavy cannabis use is associated with alterations in regional brain volumes. Although these changes are frequently attributed to the neurotoxic effects of cannabis, it is possible that some abnormalities might predate use and represent markers of vulnerability. To date, no studies have examined whether structural brain abnormalities are present before the onset of cannabis use. This study aims to determine whether adolescents who have initiated cannabis use early (i.e., before age 17 years) show premorbid structural abnormalities in the amygdala, hippocampus, orbitofrontal cortex, and anterior cingulate cortex. METHODS Participants (n = 121) were recruited from primary schools in Melbourne, Australia, as part of a larger study examining adolescent emotional development. Participants underwent structural magnetic resonance imaging at age 12 years and were assessed for cannabis use 4 years later, at age 16 years. At the follow-up assessment, 28 participants had commenced using cannabis (16 female subjects [57%]), and 93 had not (43 female subjects [46%]). RESULTS Smaller orbitofrontal cortex volumes at age 12 years predicted initiation of cannabis use by age 16 years. The volumes of other regions (amygdala, hippocampus, and anterior cingulate cortex) did not predict later cannabis use. CONCLUSIONS These findings suggest that structural abnormalities in the orbitofrontal cortex might contribute to risk for cannabis exposure. Although the results have important implications for understanding neurobiological predictors of cannabis use, further research is needed to understand their relationship with heavier patterns of use in adulthood as well as later abuse of other substances.

The influence of sulcal variability on morphometry of the human anterior cingulate and paracingulate cortex

Human anterior cingulate (ACC) and paracingulate (PaC) cortices play an important role in cognitive and affective regulation and have been implicated in numerous psychiatric and neurological conditions. The region they comprise displays marked inter-individual variability in sulcal and gyral architecture, and although recent evidence suggests that this variability has functional significance, it is often ignored in automated and region-of-interest (ROI) morphometric investigations. This has lead to confounded interpretation of results and inconsistent findings across a number of studies and in a variety of clinical populations. In this paper, we present a reliable method for parcellating the dorsal, ventral, and subcallosal ACC and PaC that accounts for individual variation in the local cortical folding pattern. We also investigated the effect of one well characterized morphological variation, the incidence of the paracingulate sulcus (PCS), on regional volumes in 24 (12 male, 12 female) healthy participants. The presence of a PCS was shown to affect both ACC and PaC volumes, such that it was associated with an 88% increase in paracingulate cortex and a concomitant 39% decrease in cingulate cortex. These findings illustrate the potential confounds inherent in morphometric approaches that ignore or attempt to minimize inter-individual variations in sulcal and gyral anatomy and underscore the need to consider this variability when attempting to understand disease processes or characterize brain structure-function relationships.

Emotional inertia prospectively predicts the onset of depressive disorder in adolescence.

Emotional inertia refers to the degree to which a persons current emotional state is predicted by their prior emotional state, reflecting how much it carries over from one moment to the next. Recently, in a cross-sectional study, we showed that high inertia is an important characteristic of the emotion dynamics observed in psychological maladjustment such as depression. In the present study, we examined whether emotional inertia prospectively predicts the onset of first-episode depression during adolescence. Emotional inertia was assessed in a sample of early adolescents (N = 165) based on second-to-second behavioral coding of videotaped naturalistic interactions with a parent. Greater inertia of both negative and positive emotional behaviors predicted the emergence of clinical depression 2.5 years later. The implications of these findings for the understanding of the etiology and early detection of depression are discussed.

Variability of the paracingulate sulcus and morphometry of the medial frontal cortex: associations with cortical thickness, surface area, volume, and sulcal depth.

The structural and functional consequences of interindividual variations in cortical morphology are poorly understood. In this study, we examined the relationship between one well‐characterized variation of the medial frontal lobes, variability of the paracingulate sulcus (PCS), and grey matter volume, cortical thickness, surface area, and sulcal depth of the adjacent anterior cingulate cortex (ACC) and paracingulate cortex (PaC). Seventy‐seven healthy individuals were assigned to one of four groups depending on PCS incidence in both hemispheres: left‐present, right‐absent; left‐absent, right‐present; both absent; or both present. Comparing these groups on each measure yielded four primary findings: (1) The presence of a PCS was associated with increased PaC and decreased ACC grey matter volume in the hemisphere in which it was apparent, with an almost identical pattern being observed for surface area; (2) there was a more complex relationship between PCS variability and regional thickness, such that a PCS in the left hemisphere was associated with increased left PaC and right ACC thickness, with no comparable effects being observed for the presence of a right PCS; (3) the depths of all major left hemisphere sulci in the region were strongly positively correlated, whereas no such associations were apparent in the right hemisphere; and (4) a leftward asymmetry in PaC thickness was specifically associated with better performance on a test of spatial working memory ability. These results provide evidence for a complex interhemispheric relationship between sulcal variability and cortical morphometry, and indicate that such relationships may be important for understanding individual differences in cognitive abilities. Hum Brain Mapp, 2008.

Structural MRI Findings in Long-Term Cannabis Users: What Do We Know?

In animal studies, tetrahydrocannabinol (THC) has been found to affect brain morphology, particularly within areas rich in cannabinoid receptors (e.g., hippocampus, cerebral cortex). While cannabis remains the most widely used illicit drug worldwide, there has been limited work investigating its effects on human brain tissue. In this paper, we conducted a systematic review of existing structural magnetic resonance imaging studies to examine whether cannabis use is associated with significant changes in brain anatomy. We identified only 13 structural neuroimaging studies, which were diverse in terms of sample characteristics (e.g., age of participants, duration and frequency of use) and methodology (e.g., image analysis). No study found global structural changes in cannabis users, although six studies reported regional alterations. While changes in the hippocampus and parahippocampus were frequently identified, the findings were inconsistent across studies. The available literature also provides some evidence that regional structural changes are associated with cannabis use patterns (particularly cumulative dosage and frequency of use), as well as measures of psychopathology (e.g., measures of depressive and psychotic symptoms). Together, these structural imaging findings suggest that THC exposure does affect brain morphology, especially in medial–temporal regions. Given the small literature available and the limitations of studies to date, further research is clearly required, particularly given the prevalence of cannabis use worldwide.

Volumetric MRI study of the insular cortex in individuals with current and past major depression

BACKGROUND Functional neuroimaging studies have implicated the insular cortex in emotional processing, including the evaluation of ones own emotion, as well as in the neurobiology of major depressive disorder (MDD). Nevertheless, it remains largely unknown whether MDD patients exhibit morphologic changes of the insular cortex, and whether such changes reflect state or trait markers of the disorder. METHODS We delineated the anterior and posterior insular cortices using magnetic resonance imaging in 29 currently depressed patients (mean age=32.5 years, 7 males), 27 remitted depressed patients (mean age=35.1 years, 9 males), and 33 age- and gender-matched healthy control subjects (mean age=34.0 years, 12 males). RESULTS Both current and remitted MDD patients showed significant volume reduction of the left anterior insular cortex as compared with healthy controls, but there was no group difference in the posterior insular cortex volume. Insular volumes did not correlate with the severity of depressive symptoms. Furthermore, the presence of melancholia and co-morbidity with anxiety disorders did not affect insular cortex volumes. LIMITATIONS Although there was no difference in the insular cortex volume between medicated and unmedicated patients, a comprehensive investigation of medication effects was not possible, as complete data (e.g., dose, duration) were not available. CONCLUSIONS These findings suggest that the morphologic abnormality of the anterior insular cortex, which plays a major role in introspection and emotional control, may be a trait-related marker of vulnerability to major depression, supporting the notion that MDD involves pathological alterations of limbic and related cortical structures.