White matter integrity differences associated with post-traumatic stress disorder are not normalized by concurrent marijuana use.

Marijuana (MJ) use and post-traumatic stress disorder (PTSD) have both been associated with abnormalities in brain white matter tracts, including the cingulum and the anterior thalamic radiations (ATR), which project from subcortical regions to frontal cortex. Studies have not assessed the integrity of these tracts in patients with comorbid PTSD and MJ use. To examine effects of PTSD and MJ use on brain structure, we performed diffusion tensor imaging scans on seventy-two trauma-exposed participants, categorized into four groups: those with PTSD who used MJ at least weekly (PTSD+MJ; n = 20), those with PTSD with no regular MJ use (PTSD; n = 19), trauma-exposed controls without PTSD who used MJ (TEC+MJ; n = 14) and trauma-exposed controls with no PTSD or MJ use (TEC; n = 19). White matter integrity was evaluated by calculating fractional anisotropy (FA). Results showed that while FA values in the right ATR and the cingulum differed across groups, there were no significant interactions between PTSD and MJ in any white matter tracts, indicating that MJ exposure neither normalizes nor worsens white matter abnormalities in those with PTSD. Further study is needed to evaluate the impact of MJ use on other neurobiological markers of PTSD.

Delta-9-tetrahydrocannabinol intoxication is associated with increased prefrontal activation as assessed with functional near-infrared spectroscopy: A report of a potential biomarker of intoxication.

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5-50 mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 min (when peak effects were expected), and at 200 min after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) response significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 min after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.

Anterior cingulate GABA and glutamate concentrations are associated with resting-state network connectivity.

In recent years, resting-state (RS) networks and RS function have received increased attention, highlighting their importance in both cognitive function and psychopathology. The neurochemical substrates underlying RS networks and their interactions, however, have not yet been well established. Even though prior research has provided first evidence for a negative association between brain GABA levels and RS connectivity, these findings have been limited to within network connectivity, and not network interactions. In this multi-modal imaging study, we investigated the role of the main inhibitory neurotransmitter У-aminobutyric acid (GABA) and the main excitatory neurotransmitter glutamate (Glx) on RS network function and network coupling of three core networks: the default-mode network (DMN), salience network (SN), and central executive network (CEN). Resting-state functional connectivity and GABA and Glx levels in the dorsal anterior cingulate cortex (dACC) were assessed in 64 healthy male participants using functional MRI and magnetic resonance spectroscopy (MRS). Analyses showed that dACC GABA levels were positively correlated with resting-state connectivity in the CEN, and negatively associated with functional coupling of the DMN and CEN. In contrast, GABA/Glx ratios were inversely correlated with the SN and DMN. These findings extend insights into the role of GABA and Glx in individual networks to interactions across networks, suggesting that GABA levels in the SN might play a role in RS functional connectivity within the central executive network, and network interactions with the default-mode network. Our results further suggest a potentially critical role of the relationship between GABA and Glx in RS network function.

Verbal Memory Performance and Reduced Cortical Thickness of Brain Regions Along the Uncinate Fasciculus in Young Adult Cannabis Users.

Introduction: Memory impairment is one of the most commonly reported effects of cannabis use, especially among those who initiate use earlier, perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain. Studies have increasingly investigated whether cannabis use is associated with impairments in verbal memory, and with alterations in brain structures underlying verbal memory. The uncinate fasciculus (UF), a long-range white matter tract, connects regions with densely localized CB1 receptors that are important in verbal memory. This study investigated the impact of cannabis use on UF structures and its association with memory performance in young adult cannabis users (CU) and non-using controls (CON). Materials and Methods: Nineteen CU and 22 CON completed a verbal memory task and a neuroimaging protocol, in which diffusion tensor imaging and structural scans were collected. We compared memory performance, diffusion and tractography measures of the UF, and cortical thickness of regions connected by the UF, between CU and CON. In regions showing a significant group effect, we also examined associations between verbal memory performance, cortical thickness, and age of onset of cannabis use. Results: Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus. Verbal memory performance was significantly associated with age of onset of cannabis use, indicating that those who initiated cannabis use at an earlier age performed worse. Cortical thickness of the entorhinal cortex was significantly correlated with age of first use and memory performance. Conclusion: This study provides evidence that cannabis use, especially when initiated at a young age, may be associated with worse verbal memory and altered neural development along the UF. Reductions in cortical thickness in regions implicated in memory processes may underlie weaknesses in verbal memory performance.

Divergent influences of anterior cingulate cortex GABA concentrations on the emotion circuitry.

Neuroimaging research has revealed that emotion processing recruits a widespread neural network including the dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Recent studies have started to investigate the role of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) on brain function, but little is known about the influences of GABA on this emotion circuitry. Using magnetic resonance spectroscopy, we investigated the role of GABA levels in the dACC on emotion processing by presenting emotional and neutral pictures to 68 healthy male participants during functional magnetic resonance imaging. Results revealed opposing associations of dACC GABA levels and neural activity. GABA levels were positively correlated with blood oxygen level dependent (BOLD) responses to emotional stimuli in the amygdala and to emotional and neutral stimuli in the hippocampus. In contrast, GABA levels were negatively correlated with BOLD responses for the comparison between positive and negative stimuli in the dACC. Our results suggest positive influences of dACC GABA on BOLD responses in the hippocampus and amygdala, and negative influences on BOLD responses in the dACC that are dependent on emotional valence.

GABA Concentrations in the Anterior Cingulate Cortex Are Associated with Fear Network Function and Fear Recovery in Humans.

Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning.

Hyperresponsiveness of the Neural Fear Network During Fear Conditioning and Extinction Learning in Male Cocaine Users.

OBJECTIVE: The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. METHOD: Forty male regular cocaine users and 51 male control subjects underwent a fear conditioning and extinction protocol during functional MRI. Skin conductance response was measured throughout the experiment as an index of conditioned responses. RESULTS: Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning. CONCLUSIONS: Increased sensitivity to aversive conditioned cues in cocaine users might be a risk factor for stress-relief craving in cocaine use disorder. These results support the postulated role of altered aversive conditioning in cocaine use disorder and may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder.

Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder.

Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region.