Michiel B. de Ruiter

Response Perseveration and Ventral Prefrontal Sensitivity to Reward and Punishment in Male Problem Gamblers and Smokers

Pathological gambling (PG) is associated with maladaptive perseverative behavior, but the underlying mechanism and neural circuitry is not completely clear. Here, the hypothesis was tested that PG is characterized by response perseveration and abnormalities in reward and/or punishment sensitivity in the ventral frontostriatal circuit. Executive functioning was assessed to verify if these effects are independent of the dorsal frontostriatal circuit. A group of smokers was also included to examine whether impairments in PG generalize to substance use disorders. Response perseveration and reward/punishment sensitivity were measured with a probabilistic reversal-learning task, in which subjects could win and lose money. Executive functioning was measured with a planning task, the Tower of London. Performance and fMRI data were acquired in 19 problem gamblers, 19 smokers, and 19 healthy controls. Problem gamblers showed severe response perseveration, associated with reduced activation of right ventrolateral prefrontal cortex in response to both monetary gain and loss. Results did not fully generalize to smokers. Planning performance and related activation of the dorsal frontostriatal circuit were intact in both problem gamblers and smokers. PG is related to response perseveration and diminished reward and punishment sensitivity as indicated by hypoactivation of the ventrolateral prefrontal cortex when money is gained and lost. Moreover, intact planning abilities and normal dorsal frontostriatal responsiveness indicate that this deficit is not due to impaired executive functioning. Response perseveration and ventral prefrontal hyporesponsiveness to monetary loss may be markers for maladaptive behavior seen in chemical and nonchemical addictions.

Cerebral Hyporesponsiveness and Cognitive Impairment 10 Years After Chemotherapy for Breast Cancer

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long‐term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high‐dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole‐brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high‐dose adjuvant chemotherapy is associated with long‐term cognitive impairments. These impairments are underpinned by (a) task‐specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing. Hum Brain Mapp, 2011.

Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study

Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event‐related cue reactivity paradigm, consisting of gambling, smoking‐related and neutral pictures, was employed in 17 treatment‐seeking non‐smoking PRG, 18 non‐gambling HSM, and 17 non‐gambling and non‐smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking‐related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non‐smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking‐related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto‐limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high‐dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract‐based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H‐MRS) in the left centrum semiovale (white matter) showed a reduction of N‐acetylasparate/creatine indicative of axonal injury. Voxel‐based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H‐MRS only in the chemotherapy group. These results converge to suggest that high‐dose adjuvant chemotherapy for breast cancer is associated with long‐term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment. Hum Brain Mapp, 2012.

Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD

OBJECTIVE Classic posttraumatic stress disorder (PTSD) is associated with smaller hippocampus, amygdala, and anterior cingulate cortex (ACC) volumes. We investigated whether child abuse-related complex PTSD--a severe form of PTSD with affect dysregulation and high comorbidity--showed similar brain volume reductions. METHOD We used voxel-based morphometry to measure gray matter concentrations in referred outpatients with child abuse-related complex PTSD (n = 31) compared to matched healthy nontraumatized controls (n = 28). Complex PTSD was diagnosed using the Structured Clinical Interview for DSM-IV-TR and the Structured Clinical Interview for Disorders of Extreme Stress. All respondents were scanned on a 1.5-T magnetic resonance system at the VU Medical Center, Amsterdam, The Netherlands, between September 2005 and February 2006. RESULTS As was hypothesized, patients with child abuse-related complex PTSD showed reductions in gray matter concentration in right hippocampus (P(SVC corrected) = .04) and right dorsal ACC (P(SVC corrected) = .02) compared to controls. In addition, a reduction in gray matter concentration in the right orbitofrontal cortex (OFC) was found. Severity of child abuse and PTSD-hyperarousal correlated negatively with ACC volume. Impulsivity correlated negatively with hippocampus volume, and anger, with hippocampus and OFC volume. Comorbidity of borderline personality disorder--compared to comorbid cluster C personality disorder--accounted for more extensive reductions in the ACC and OFC volume. CONCLUSIONS In complex PTSD, not only the hippocampus and the ACC but also the OFC seem to be affected, even in the absence of comorbid borderline personality disorder. These results suggest that neural correlates of complex PTSD are more severe than those of classic PTSD.

Similar hyporesponsiveness of the dorsomedial prefrontal cortex in problem gamblers and heavy smokers during an inhibitory control task

BACKGROUND Behavioral addictions like pathological gambling share many clinical characteristics with substance dependence. In addition, both types of disorders are associated with impairments in inhibitory control. Studies in patients with substance use disorders point to hyporesponsiveness of the dorsomedial prefrontal cortex. However, no such data exist on behavioral addictions. METHODS Using functional magnetic resonance imaging, we investigated the neural circuitry associated with impaired response inhibition in a group of male problem gamblers (n=17) using a stop signal task. We included control conditions tailored to specifically isolate neural correlates of inhibitory control. To investigate the specificity of effects, a group of heavy smokers (n=18) and a group of healthy controls (n=17) were also included. RESULTS Groups did not differ in behavioral performance on the stop signal task. However, both problem gamblers and heavy smokers showed hyporesponsiveness of the dorsomedial prefrontal cortex compared to healthy controls, during successful as well as failed response inhibition. These effects were robust against adjustments for depression and adult attention deficit scores. CONCLUSIONS These findings suggest that hypoactivation of the inhibition circuit is a shared neural mechanism in substance use disorders and behavioral addictions. As such, they support the reclassification of pathological gambling as a behavioral addiction in DSM-V.

Increased activation of the left hippocampus region in Complex PTSD during encoding and recognition of emotional words: a pilot study.

To gain insight into memory disturbances in Complex Posttraumatic Stress Disorder (Complex PTSD), we investigated declarative memory function and medial temporal lobe activity in patients and healthy non-traumatized controls. A case-control study was performed in nine patients with Complex PTSD and nine controls. All respondents performed a declarative memory task with neutral and emotional, negative words during functional magnetic resonance imaging. Memory performance of neutral words was impaired in Complex PTSD with a relative conservation of recall of negative words. Deep encoding of later remembered negative words, as well as correct recognition of negative words and false alarms, was associated with an enhanced Blood Oxygenation Level Dependent (BOLD) response in the left hippocampus extending into the parahippocampal gyrus of Complex PTSD patients compared with controls. Post-hoc volumetric comparisons did not reveal significant anatomical differences in the medial temporal lobe between Complex PTSD patients and controls. We conclude that in Complex PTSD preferential recall of negative words is associated with increased activation in the left hippocampus and parahippocampal gyrus during both successful and false recall. These findings support a model of an abnormally functioning hippocampus in Complex PTSD.

Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy

To date, only four small studies have investigated the effects of adjuvant chemotherapy for breast cancer on the microstructure of cerebral white matter with magnetic resonance imaging (MRI). These studies, which were conducted shortly up to 10 years post‐treatment, showed that chemotherapy is associated with focal loss of microstructural white matter integrity. We investigated the long‐term effect of chemotherapy on white matter microstructural integrity by comparing the brains of chemotherapy‐exposed breast cancer survivors to those of a population‐based sample of women without a history of cancer.

Neural correlates of enhanced working-memory performance in dissociative disorder : a functional MRI study

BACKGROUND Memory functioning has been highlighted as a central issue in pathological dissociation. In non-pathological dissociation, evidence for enhanced working memory has been found, together with greater task-load related activity. So far, no imaging studies have investigated working memory in dissociative patients. METHOD To assess working memory in dissociative patients functional magnetic resonance imaging was used during performance of a parametric, verbal working-memory task in patients with a dissociative disorder (n=16) and healthy controls (n=16). RESULTS Imaging data showed that both groups activated brain regions typically involved in working memory, i.e. anterior, dorsolateral and ventrolateral prefrontal cortex (PFC), and parietal cortex. Dissociative patients showed more activation in these areas, particularly in the left anterior PFC, dorsolateral PFC and parietal cortex. In line with these findings, patients made fewer errors with increasing task load compared to controls, despite the fact that they felt more anxious and less concentrated during task performance. CONCLUSIONS These results extend findings in non-pathological high dissociative individuals, suggesting that trait dissociation is associated with enhanced working-memory capacities. This may distinguish dissociative patients from patients with post-traumatic stress disorder, who are generally characterized by impaired working memory.

Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words

Post-traumatic stress disorder (PTSD) is associated with impaired memory performance coupled with functional changes in brain areas involved in declarative memory and emotion regulation. It is not yet clear how symptom severity and comorbidity affect neurocognitive functioning in PTSD. We performed a functional magnetic resonance imaging (fMRI) study with an emotional declarative memory task in 28 Complex PTSD patients with comorbid depressive and personality disorders, and 21 healthy non-trauma-exposed controls. In Complex PTSD patients--compared to controls--encoding of later remembered negative words vs baseline was associated with increased blood oxygenation level dependent (BOLD) response in the left ventral anterior cingulate cortex (ACC) and dorsal ACC extending to the dorsomedial prefrontal cortex (dmPFC) together with a trend for increased left hippocampus activation. Patients tended to commit more False Alarms to negative words compared to controls, which was associated with enhanced left ventrolateral prefrontal and orbitofrontal cortex (vlPFC/OFC) responses. Severity of child abuse was positively correlated with left ventral ACC activity and severity of depression with (para) hippocampal and ventral ACC activity. Presented results demonstrate functional abnormalities in Complex PTSD in the frontolimbic brain circuit also implicated in fear conditioning models, but generally in the opposite direction, which may be explained by severity of the trauma and severity of comorbid depression in Complex PTSD.