Bruce E. Wexler

Amygdala Hyperreactivity in Borderline Personality Disorder: Implications for Emotional Dysregulation.

BACKGROUND Disturbed interpersonal relations and emotional dysregulation are fundamental aspects of borderline personality disorder (BPD). The amygdala plays important roles in modulating vigilance and generating negative emotional states and is often abnormally reactive in disorders of mood and emotion. The aim of this study was to assess amygdala reactivity in BPD patients relative to normal control subjects. We hypothesized that amygdala hyperreactivity contributes to hypervigilance, emotional dysregulation, and disturbed interpersonal relations in BPD. METHODS Using functional magnetic resonance imaging, we examined neural responses to 20-sec blocks of neutral, happy, sad, and fearful facial expression (or a fixation point) in 15 BPD and 15 normal control subjects. The DSM IV-diagnosed BPD patients and the normal control subjects were assessed by a clinical research team in a medical school psychiatry department. RESULTS Borderline patients showed significantly greater left amygdala activation to the facial expressions of emotion (vs. a fixation point) compared with normal control subjects. Post-scan debriefing revealed that some borderline patients had difficulty disambiguating neutral faces or found them threatening. CONCLUSIONS Pictures of human emotional expressions elicit robust differences in amygdala activation levels in borderline patients, compared with normal control subjects, and can be used as probes to study the neuropathophysiologic basis of borderline personality disorder.

Cue-induced brain activity changes and relapse in cocaine-dependent patients

This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.

An fMRI study of the human cortical motor system response to increasing functional demands

Functional magnetic resonance imaging (fMRI) was used to study activation changes in the human primary motor-sensory areas (MAs), supplementary motor areas (SMAs), premotor areas (PMAs) and the superior and inferior parietal areas (SPAs, IPAs) during right hand finger movements as the rate, force and complexity of movement were varied. A preliminary reproducibility study of a single subject doing the same repetitive index finger movements in nine different sessions over a six week period demonstrated highly consistent and highly localized activation in the contralateral MA. ANOVAs demonstrated highly significant main effects of increasing the force and complexity of movement, thereby illustrating the distributed and integrated systemic character of the cortical motor system. Interactions between brain region and the rate and complexity of movements suggested functional specialization of some components of the system. Increasing the rate of movement led to increased activity only in the contralateral MA; increasing complexity led to greater increases in activity in the left and right SPAs and the left IPA than in other areas. Although activation was evident in varying degree throughout the multiple motor areas, only the MAs showed consistent lateralization of activation.

Effects of Smoking Abstinence on Visuospatial Working Memory Function in Schizophrenia

Schizophrenic patients have impairments in cognitive function, including deficits in visuospatial working memory (VSWM). VSWM is mediated, in part, by prefrontal cortical dopamine (DA) function, and dysregulation of prefrontal cortical DA systems may contribute to the pathophysiology of schizophrenia. Nicotine has complex effects on spatial working memory (SWM) in animal studies, with most studies demonstrating enhancement of SWM. Cigarette smoking is highly prevalent in schizophrenia, and these patients may smoke cigarettes to remediate cognitive deficits. The present study examined the effects of acute (<1 week) and prolonged (8–10 weeks) smoking abstinence on VSWM in schizophrenic (n = 23) and control (n = 29) nicotine-dependent cigarette smokers during placebo-controlled smoking cessation trials. Schizophrenic and control smoking patients had significant impairments in VSWM compared to non-smoking controls, after adjusting for differences in age, education and depressive symptoms. Schizophrenic smokers who quit smoking had further impairments in VSWM, and control quitters had improvements in VSWM. Abstinence-induced changes in VSWM varied as a function of gender in controls, but not in schizophrenics. These changes in VSWM appeared to be independent of study medications, and smoking abstinence did not significantly alter performance on the Stroop Color Word Test in either group. These results suggest that smoking abstinence differentially alters VSWM in schizophrenic vs. control smokers, and that cigarette smoking has beneficial effects on VSWM in schizophrenic, but not control, smokers.

Increasing the power of dichotic methods: The fused rhymed words test

A dichotic test made up of monosyllabic rhymed CVC words was modified to minimize stimulus dominance and errors and then administered to 194 dextrals and 175 sinistrals in four different laboratories. The proportion of subjects with left ear advantages in both the right and left-handed groups closely approximated that expected from neurologic data. This dichotic test appears to reflect hemispheric specialization for language function more accurately than previously available tests. Further direct validation studies are needed, however, comparing direction of ear asymmetry and other indices of hemispheric specialization for language on a subject by subject basis.

A Cultural Neuroscience Approach to the Biosocial Nature of the Human Brain

Cultural neuroscience (CN) is an interdisciplinary field that investigates the relationship between culture (e.g., value and belief systems and practices shared by groups) and human brain functions. In this review we describe the origin, aims, and methods of CN as well as its conceptual framework and major findings. We also clarify several misunderstandings of CN research. Finally, we discuss the implications of CN findings for understanding human brain function in sociocultural contexts and novel questions that future CN research should address. By doing so, we hope to provide a clear picture of the CN approach to the human brain and culture and to elucidate the intrinsically biosocial nature of the functional organization of the human brain.

Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study

ObjectiveStress is known to increase cocaine craving and relapse risk in cocaine dependence. Identifying neural activity associated with stress and stress-induced cocaine craving is important in understanding the neurobiology of cocaine craving and relapse.MethodBlood oxygenation level dependent (BOLD) signal changes were assessed in a functional magnetic resonance imaging (fMRI) session with healthy controls and treatment-engaged, abstinent, cocaine-dependent individuals (patients) as they participated in brief guided imagery and recall of three personal stress and three personal neutral situations.ResultsDuring stress, patients showed significantly less BOLD activation than controls in specific frontal and para-limbic regions, such as the anterior cingulate (AC) region, left hippocampal/parahippocampal region, right fusiform gyrus, and the right postcentral gyrus. On the other hand, patients had increased activity in the caudate and dorsal striatum region during stress, activation that was significantly associated with stress-induced cocaine craving ratings.ConclusionsPatients failed to activate AC and related circuits during stress, regions associated with control, and regulation of emotion and distress states. Instead, they exhibited greater craving-related activation in the dorsal striatum, a region related to reward pathways and part of the obsessive–compulsive circuitry. Such functional alterations in stress processing may underlie the stress-related vulnerability to cocaine relapse often observed in cocaine-dependent individuals in early recovery.

Neurocognitive enhancement therapy with vocational services: Work outcomes at two-year follow-up

UNLABELLED Neurocognitive enhancement therapy (NET) is a remediation program for the persistent and function-limiting cognitive impairments of schizophrenia. In a previous study in veterans, NET improved work therapy outcomes as well as executive function and working memory. The present study aimed to determine whether NET could enhance functional outcomes among schizophrenia and schizoaffective patients in a community mental health center receiving community-based vocational services. METHOD Patients (N=72) participated in a hybrid transitional and supported employment program (VOC) and were randomized to either NET+VOC or VOC only. NET+VOC included computer-based cognitive training, work feedback and a social information information-processing group. VOC only also included two weekly support groups. Active intervention was 12 months with 12 month follow-up. Follow-up rate was 100%. RESULTS NET+VOC patients worked significantly more hours during the 12 month follow-up period, reached a significantly higher cumulative rate of competitive employment by the sixth quarter, and maintained significantly higher rates of employment. CONCLUSION NET training improved vocational outcomes, suggesting the value of combining cognitive remediation with other rehabilitation methods to enhance functional outcomes.

Computer-assisted cognitive remediation in schizophrenia: What is the active ingredient?

An emerging body of research has shown that computer-assisted cognitive remediation, consisting of training in attention, memory, language and/or problem-solving, produces improvement in neurocognitive function that generalizes to untrained neurocognitive tests and may also impact symptoms and work functioning in patients with schizophrenia. The active ingredient of these interventions, however, remains unknown as control groups in these studies have typically included few, if any, of the elements of these complex behavioral treatments. This study compared the effects of an extended (12-month), standardized, computer-assisted cognitive remediation intervention with those of a computer-skills training control condition that consisted of many of the elements of the experimental intervention, including hours spent on a computer, interaction with a clinician and non-specific cognitive stimulation. Forty-two patients with schizophrenia were randomly assigned to one of two conditions and were assessed with a comprehensive neuropsychological test battery before and after treatment. Results revealed that cognitive-remediation training produced a significant improvement in working memory, relative to the computers-skills training control condition, but that there was overall improvement in both groups on measures of working memory, reasoning/executive-function, verbal and spatial episodic memory, and processing speed. Taken together, these findings suggest that specific practice in neurocognitive exercises targeted at attention, memory and language, produce improvements in neurocognitive function that are not solely attributable to non-specific stimulation associated with working with a computer, interacting with a clinician or cognitive challenge, but that non-specific stimulation has a salutary effect on neurocognition as well.

Cognitive remediation of working memory deficits: durability of training effects in severely impaired and less severely impaired schizophrenia

Objective: To determine whether augmenting work therapy (WT) with neurocognitive enhancement therapy (NET) yields greater improvement in working memory performance than WT alone and whether there is an interaction with severity of impairment.