Serenella Tolomeo

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackmans meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.

Structural MRI-Based Predictions in Patients with Treatment-Refractory Depression (TRD).

The application of machine learning techniques to psychiatric neuroimaging offers the possibility to identify robust, reliable and objective disease biomarkers both within and between contemporary syndromal diagnoses that could guide routine clinical practice. The use of quantitative methods to identify psychiatric biomarkers is consequently important, particularly with a view to making predictions relevant to individual patients, rather than at a group-level. Here, we describe predictions of treatment-refractory depression (TRD) diagnosis using structural T1-weighted brain scans obtained from twenty adult participants with TRD and 21 never depressed controls. We report 85% accuracy of individual subject diagnostic prediction. Using an automated feature selection method, the major brain regions supporting this significant classification were in the caudate, insula, habenula and periventricular grey matter. It was not, however, possible to predict the degree of ‘treatment resistance’ in individual patients, at least as quantified by the Massachusetts General Hospital (MGH-S) clinical staging method; but the insula was again identified as a region of interest. Structural brain imaging data alone can be used to predict diagnostic status, but not MGH-S staging, with a high degree of accuracy in patients with TRD.

Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence

BACKGROUND Chronic opioid exposure, as a treatment for a variety of disorders or as drug of misuse, is common worldwide, but behavioural and brain abnormalities remain under-investigated. Only a small percentage of patients who receive methadone maintenance treatment (MMT) for previous heroin misuse eventually achieve abstinence and studies on such patients are rare. METHOD The Cambridge Neuropsychological Test Automated Battery and T1 weighted magnetic resonance imaging (MRI) were used to study a cohort of 122 male individuals: a clinically stable opioid-dependent patient group receiving MMT (n = 48), an abstinent previously MMT maintained group (ABS) (n = 24) and healthy controls (n = 50). RESULTS Stable MMT participants deliberated longer and placed higher bets earlier in the Cambridge Gambling Task (CGT) and showed impaired strategic planning compared with healthy controls. In contrast, ABS participants showed impairment in choosing the least likely outcome, delay aversion and risk adjustment on the CGT, and exhibited non-planning impulsivity compared with controls. MMT patients had widespread grey matter reductions in the orbitomedial prefrontal cortex, caudate, putamen and globus pallidus. In contrast, ABS participants showed midbrain-thalamic grey matter reductions. A higher methadone dose at the time of scanning was associated with a smaller globus pallidus in the MMT group. CONCLUSIONS Our findings support an interpretation of heightened impulsivity in patients receiving MMT. Widespread structural brain abnormalities in the MMT group and reduced brain structural abnormality with abstinence suggest benefit of cessation of methadone intake. We suggest that a longitudinal study is required to determine whether abstinence improves abnormalities, or patients who achieve abstinence have reduced abnormalities before methadone cessation.

Compulsivity in opioid dependence

Objective: This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. Method: We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n = 24), ii) heroin users stabilised on methadone maintenance treatment (n = 48), iii) abstinent participants with a history of opioid dependence due to heroin use (n = 24) and iv) healthy controls (n = 50). Compulsivity was measured using Intra/Extra‐Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT). Structural Magnetic Resonance Imaging (MRI) data were also obtained. Results: As hypothesised, compulsivity was negatively associated with impulsivity (p < 0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group, compared to the other opioid dependent groups. In addition, self‐reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. Conclusion: Our findings are consistent with Volkow & Koobs addiction models and underline the important role of compulsivity versus impulsivity in opioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes. HighlightsBoth heroin and short‐term abstinent groups made significantly more errors on the compulsivity task than healthy controls.Brain structure abnormalities associated with compulsivity and impulsivity were identified.The ratio of compulsivity/impulsivity was inversely related to nucleus accumbens and bed nucleus of stria terminalis white matter integrity.We cannot address causal effects due to the cross‐sectional design of the current study.The findings may not be generalised to female populations as we recruited only treatment‐seeking male individuals.

EPA-1759 - Brain structural abnormalities in medial temporal lobe are associated with mood and anxiety in methadone maintenance treatment

Introduction Several brain circuits are relevant in the neurobiology of addiction. Here we want to highlight symptoms related to the domains of mood, anhedonia and anxiety that may precede drug abuse and represent a specific risk factor for addiction. The mood regulation circuit that contributes to regulation of stress reactivity and the interoception circuit that contributes to awareness of drug craving and mood also participate in addiction but their involvement in the human brain has been much less investigated. Aims Here we aim to investigate mood and anxiety in opiate dependent, treatment-seeking patients receiving Methadone Maintenance Treatment, to test hypothesis of regional grey matter reduction correlating with mood and anxiety. Methods Cambridge Gambling Task (CGT) data were acquired from 30 patients receiving MMT and 23 controls. T 1 weighted Magnetic Resonance Images were acquired from a representative subset of these volunteers. Results MMT patients exhibited grey matter reductions in the orbito-medial prefrontal cortex and basal ganglia. Additionally, patients exhibited significant abnormalities in the clinical rating scales BDI, Anhedonia, HAD-Anxiety, IDS and Snaith Hamilton. Increased BDI, HAD-Anxiety and IDS correlated with grey matter reductions in the hippocampus, amygdala, bed nucleus of stria terminalis and insula. Increased Snaith Hamilton correlated with grey matter reductions in periaqueductal gray, ventral tegmental area and nucleus caudate. Conclusions These findings support an interpretation of a neurobiological underpinning of mood and addiction. However, the anatomically restricted correlates with mood and anxiety suggest that a rationale for adopting a mood addiction model should be further investigated.

EPA-1757 – Globus pallidus abnormalities in opiate dependent patients receiving methadone maintenance therapy

Introduction Preclinical studies have suggested that continuous, long-term opiate exposure may be neurotoxic. There is accumulating evidence for neural and neuropsychological abnormalities in diverse human drug addiction populations. However, the structural and behavioural correlates of human opiate dependency have been less studied than other drugs. Aims We investigated brain structure and neuropsychological functioning in opiate dependent, treatment-seeking patients receiving Methadone Maintenance Treatment, to test hypotheses of regional grey matter reductions correlating with methadone exposure and neuropsychological measures. Methods Cambridge Gambling Task (CGT) data were acquired from 47 patients receiving MMT and 51 controls. T1 weighted Magnetic Resonance Images were acquired from a representative subset of these volunteers. Results MMT patients exhibited grey matter reductions in the orbito-medial prefrontal cortex and basal ganglia. Additionally, patients exhibited significant abnormalities on CGT behavioural measures; risk adjustment, risk taking and impulsivity. Both the initial titration dose of methadone at the commencement of MMT following protocolised tolerance testing, and methadone dose at the time of scanning, correlated with grey matter reductions in the globus pallidus. Abnormal risk adjustment behaviour correlated with reductions in globus pallidus grey matter, increased risk taking with orbitofrontal grey matter reductions, and increased impulsivity with cingulate cortex reductions. Conclusions These findings support an interpretation of heightened risk taking and impulsivity in patients receiving MMT. However, the anatomically restricted correlates with indices of methadone exposure suggest that most structural brain abnormalities are not opiate linked, with the possible exception of the globus pallidus.