Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

The impact of age on olfactory alcohol cue-reactivity: A functional magnetic resonance imaging study in adolescent and adult male drinkers.

BACKGROUND: Adolescence is marked not only by rapid surges in the prevalence of alcohol use disorders (AUDs) but also by remarkable recovery rates, as most adolescent-onset AUDs naturally resolve over time. Little is known about the differential vulnerability of adolescents and adults. Therefore, this study aimed to unravel the moderating role of age by comparing neural alcohol cue-reactivity, an important AUD biomarker, between low-to-high beer-drinking adolescent (n = 50, 16 to 18 years), and adult (n = 51, 30 to 35 years) males matched on drinking severity. METHODS: Associations between beer odor-induced brain activity and AUD diagnosis, severity of alcohol use-related problems, recent alcohol use, binge-drinking frequency, and task-induced craving were investigated across and between age groups in regions of interest thought to be central in alcohol cue-reactivity: the medial prefrontal cortex, anterior cingulate cortex, and striatal subregions (nucleus accumbens and caudate putamen). These analyses were complemented by exploratory whole-brain analyses. RESULTS: Pre-task beer craving increased pre-to-post task in adolescents only. Individual differences in alcohol use, binge drinking, and craving did not relate to beer odor-induced activity. Although region-of-interest analyses did not reach significance, whole-brain analyses showed that adolescents with AUD, compared with adolescents without AUD and adults with AUD, had higher beer odor-induced activity in a large mesocorticolimbic cluster encompassing the right caudate, nucleus accumbens, orbitofrontal cortex, and the olfactory sulcus. Activity in the right caudate and putamen was positively associated with the severity of alcohol use-related problems in adolescents but negatively associated in adults. CONCLUSION: These findings suggest a differential role of alcohol cue-reactivity in adolescents compared with adults with AUD and highlight the need for further studies investigating the role of age in the fundamental processes underlying the development of and recovery from of AUD.

Direct Effects of Cannabis Intoxication on Motivations for Softer and Harder Drug Use: An Experimental Approach to the Gateway Hypothesis.

Aims: This study experimentally tested whether there is a gateway-type effect of cannabis administration on tobacco and cocaine motivation and whether motivational responses predicted use 6 months later. Methods: A 2 (condition: active cannabis vs. placebo joint)×3 (substance stimulus type: tobacco, cannabis, and cocaine) factor within-subjects design for both implicit and explicit motivation. Both experimental sessions were conducted in a cannabis dispensary ("coffeeshop") in Amsterdam and were separated by ∼1 week, followed by a 6-month online follow-up. Eighty-five participants between 18 and 27 years of age (57% male), who used cannabis, tobacco, and cocaine <15 times per month, participated in session 1 (session 2: N=79 and follow-up: N=81). Counterbalanced over sessions, participants smoked an active and a placebo joint following a paced puffing procedure. Before and after smoking, craving and avoidance (explicit motivation) were assessed using visual analog scales, and after smoking, the stimulus response compatibility test was completed to assess approach biases (implicit motivation). Self-reported intoxication and similarity to their usual smoking experience were assessed at the end of both sessions. Self-reported frequency/quantity and dependence symptoms for tobacco, cannabis, and cocaine were assessed at all time points. A linear mixed model approach was used to assess the effects of condition, substance stimulus type, and their interactions on explicit and implicit motivation. Results: In the active condition, participants reported higher levels of intoxication and an experience more similar to their usual smoking experience than in the placebo condition. There was no significant effect of condition, substance type, or their interaction on approach bias. Participants exhibited increased cannabis craving during the placebo condition only and increased explicit cannabis avoidance during the active condition only. Explicit tobacco avoidance decreased during both conditions. Baseline measures did not predict use at 6-month follow-up. Conclusions: In light users, cannabis intoxication did not affect implicit and explicit tobacco or cocaine motivations. Tobacco avoidance decreased regardless of condition, indicating that the cannabis cue-rich setting-rather than tetrahydrocannabinol itself-may momentarily increase the likelihood to smoke tobacco. However, motivation at baseline did not predict use 6 months later, deeming any gateway-like function unlikely.

The neurobiology of treatment-resistant depression: A systematic review of neuroimaging studies.

Treatment-resistant depression (TRD) is a debilitating condition associated with higher medical costs, increased illness burden, and reduced quality of life compared to non-treatment-resistant major depressive disorder (MDD). The question arises whether TRD can be considered a distinct MDD sub-type based on neurobiological features. To answer this question we conducted a systematic review of neuroimaging studies investigating the neurobiological differences between TRD and non-TRD. Our main findings are that patients with TRD show 1) reduced functional connectivity (FC) within the default mode network (DMN), 2) reduced FC between components of the DMN and other brain areas, and 3) hyperactivity of DMN regions. In addition, aberrant activity and FC in the occipital lobe may play a role in TRD. The main limitations of most studies were related to inherent confounding factors for comparing TRD with non-TRD, such as differences in disease chronicity/severity and medication history. Future studies may use prospective longitudinal neuroimaging designs to delineate which effects are present in treatment-naive patients and which effects are the result of disease progression.