Valentina Lorenzetti

Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies

BACKGROUND While there is evidence to suggest that major depressive disorder (MDD) is associated with structural brain abnormalities, the precise nature of these abnormalities remains unclear. AIMS To review recent structural magnetic resonance imaging (MRI) research findings in MDD while considering the potential influence of key clinical and demographic variables. METHOD A selective review of all T1-weighted structural MRI studies published between 2000 and 2007 in adult samples of MDD patients. RESULTS Volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC are consistently found in MDD patients, with more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) being associated with greater impact on regional brain volumes. Gender, medication, stage of illness, and family history all affect the nature of the findings in a regionally specific manner. LIMITATIONS Overall, differences between the samples in factors such as illness severity, medication, gender and family history of mental illness makes difficult to identify their confounding effects on the observed neuroanatomical changes. Also, the tracing protocols used for particular brain regions were different amongst the reviewed studies, making difficult to compare their findings. CONCLUSIONS The data support the notion that MDD involves pathological alterations of limbic and cortical structures, and that they are generally more apparent in patients with more severe or persistent forms of the illness.

Effect of long-term cannabis use on axonal fibre connectivity

Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The aim of this study was to examine axonal fibre pathways across the brain for evidence of microstructural alterations associated with long-term cannabis use and to test whether age of regular cannabis use is associated with severity of any microstructural change. To this end, diffusion-weighted magnetic resonance imaging and brain connectivity mapping techniques were performed in 59 cannabis users with longstanding histories of heavy use and 33 matched controls. Axonal connectivity was found to be impaired in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum and commissural fibres. Radial and axial diffusivity in these pathways were associated with the age at which regular cannabis use commenced. Our findings indicate long-term cannabis use is hazardous to the white matter of the developing brain. Delaying the age at which regular use begins may minimize the severity of microstructural impairment.

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.

Functional Connectivity in Brain Networks Underlying Cognitive Control in Chronic Cannabis Users

The long-term effect of regular cannabis use on brain function underlying cognitive control remains equivocal. Cognitive control abilities are thought to have a major role in everyday functioning, and their dysfunction has been implicated in the maintenance of maladaptive drug-taking patterns. In this study, the Multi-Source Interference Task was employed alongside functional magnetic resonance imaging and psychophysiological interaction methods to investigate functional interactions between brain regions underlying cognitive control. Current cannabis users with a history of greater than 10 years of daily or near-daily cannabis smoking (n=21) were compared with age, gender, and IQ-matched non-using controls (n=21). No differences in behavioral performance or magnitude of task-related brain activations were evident between the groups. However, greater connectivity between the prefrontal cortex and the occipitoparietal cortex was evident in cannabis users, as compared with controls, as cognitive control demands increased. The magnitude of this connectivity was positively associated with age of onset and lifetime exposure to cannabis. These findings suggest that brain regions responsible for coordinating behavioral control have an increased influence on the direction and switching of attention in cannabis users, and that these changes may have a compensatory role in mitigating cannabis-related impairments in cognitive control or perceptual processes.

The association between regular cannabis exposure and alterations of human brain morphology: an updated review of the literature

Cannabis is the most widely used illicit drug worldwide, though it is unclear whether its regular use is associated with persistent alterations in brain morphology. This review examines evidence from human structural neuroimaging investigations of regular cannabis users and focuses on achieving three main objectives. These include examining whether the literature to date provides evidence that alteration of brain morphology in regular cannabis users: i) is apparent, compared to non-cannabis using controls; ii) is associated with patterns of cannabis use; and with iii) measures of psychopathology and neurocognitive performance. The published findings indicate that regular cannabis use is associated with alterations in medial temporal, frontal and cerebellar brain regions. Greater brain morphological alterations were evident among samples that used at higher doses for longer periods. However, the evidence for an association between brain morphology and cannabis use parameters was mixed. Further, there is poor evidence for an association between measures of brain morphology and of psychopathology symptoms/neurocognitive performance. Overall, numerous methodological issues characterize the literature to date. These include investigation of small sample sizes, heterogeneity across studies in sample characteristics (e.g., sex, comorbidity) and in employed imaging techniques, as well as the examination of only a limited number of brain regions. These factors make it difficult to draw firm conclusions from the existing findings. Nevertheless, this review supports the notion that regular cannabis use is associated with alterations of brain morphology, and highlights the need to consider particular methodological issues when planning future cannabis research.

Amygdala volumes in a sample of current depressed and remitted depressed patients and healthy controls

BACKGROUND Major Depressive Disorder is associated with amygdala volumetric alterations. To date, it is still unclear (I) whether amygdala volumetric alterations constitute a state or a trait marker of MDD; (II) what influences the direction of amygdala morphometric changes (i.e., enlargement versus shrinkage); and (III) what the role of laterality is in amygdala volumetric alterations in MDD. METHODS We investigated amygdala volume in a sample of 31 currently depressed patients (cMDD), 31 healthy subjects with a previous diagnosis of MDD (rMDD) and 31 healthy controls, using images obtained from a 1.5 Tesla MRI scanner. The groups were matched for age and gender. RESULTS We found that left amygdala volumes of rMDD subjects were significantly larger as compared to healthy controls, and tended to be larger when compared to cMDD subjects. There was no difference in left amygdala volumes between cMDD patients and healthy controls. Right amygdala volumes did not differ between groups. CONCLUSIONS Given that amygdala alterations were present only in remitted patients, we suggest that such alterations appear to be a state marker of MDD. Further, we found evidence of a lateralization effect, with changes in the left hemisphere only. Left amygdala enlargement in the rMDD group may represent a neurobiological marker of vulnerability to relapse, or may reflect recovery from MDD, whereby volumetric changes have resulted from stress associated with the last depressive episode.

Gross morphological brain changes with chronic, heavy cannabis use

We investigated the morphology of multiple brain regions in a rare sample of 15 very heavy cannabis users with minimal psychiatric comorbidity or significant exposure to other substances (compared with 15 age- and IQ-matched non-cannabis-using controls) using manual techniques. Heavy cannabis users demonstrated smaller hippocampus and amygdala volumes, but no alterations of the orbitofrontal and anterior- and paracingulate cortices, or the pituitary gland. These findings indicate that chronic cannabis use has a selective and detrimental impact on the morphology of the mediotemporal lobe.

Hippocampal harms, protection and recovery following regular cannabis use

Shifting policies towards legalisation of cannabis for therapeutic and recreational use raise significant ethical issues for health-care providers seeking evidence-based recommendations. We investigated whether heavy cannabis use is associated with persistent harms to the hippocampus, if exposure to cannabidiol offers protection, and whether recovery occurs with abstinence. To do this, we assessed 111 participants: 74 long-term regular cannabis users (with an average of 15.4 years of use) and 37 non-user healthy controls. Cannabis users included subgroups of participants who were either exposed to Δ9-tetrahydrocannabinol (THC) but not to cannabidiol (CBD) or exposed to both, and former users with sustained abstinence. Participants underwent magnetic resonance imaging from which three measures of hippocampal integrity were assessed: (i) volume; (ii) fractional anisotropy; and (iii) N-acetylaspartate (NAA). Three curve-fitting models across the entire sample were tested for each measure to examine whether cannabis-related hippocampal harms are persistent, can be minimised (protected) by exposure to CBD or recovered through long-term abstinence. These analyses supported a protection and recovery model for hippocampal volume (P=0.003) and NAA (P=0.001). Further pairwise analyses showed that cannabis users had smaller hippocampal volumes relative to controls. Users not exposed to CBD had 11% reduced volumes and 15% lower NAA concentrations. Users exposed to CBD and former users did not differ from controls on any measure. Ongoing cannabis use is associated with harms to brain health, underpinned by chronic exposure to THC. However, such harms are minimised by CBD, and can be recovered with extended periods of abstinence.

Alteration to hippocampal shape in cannabis users with and without schizophrenia

Abnormalities in hippocampal morphology are characteristic of schizophrenia and have also been reported in chronic cannabis users. There is a paucity of research investigating potential additive effects of cannabis use on brain pathology associated with schizophrenia. In this study, we performed hippocampal shape analysis in cannabis-using and non-using patients with schizophrenia, healthy cannabis users and healthy non-using controls. Hippocampal shape changes were observed in each group relative to controls, with the greatest degree of alterations (i.e., deflations across the hippocampus, and with an anterior predisposition), in cannabis-using schizophrenia patients. These alterations were associated with cannabis use patterns and psychotic symptoms.