Magdalena R. Naylor

Cognitive behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain

UNLABELLED Several studies have reported reduced cerebral gray matter (GM) volume or density in chronic pain conditions, but there is limited research on the plasticity of the human cortex in response to psychological interventions. We investigated GM changes after cognitive-behavioral therapy (CBT) in patients with chronic pain. We used voxel-based morphometry to compare anatomic magnetic resonance imaging scans of 13 patients with mixed chronic pain types before and after an 11-week CBT treatment and to 13 healthy control participants. CBT led to significant improvements in clinical measures. Patients did not differ from healthy controls in GM anywhere in the brain. After treatment, patients had increased GM in the bilateral dorsolateral prefrontal, posterior parietal, subgenual anterior cingulate/orbitofrontal, and sensorimotor cortices, as well as hippocampus, and reduced GM in supplementary motor area. In most of these areas showing GM increases, GM became significantly higher than in controls. Decreased pain catastrophizing was associated with increased GM in the left dorsolateral prefrontal and ventrolateral prefrontal cortices, right posterior parietal cortex, somatosensory cortex, and pregenual anterior cingulate cortex. Although future studies with additional control groups will be needed to determine the specific roles of CBT on GM and brain function, we propose that increased GM in the prefrontal and posterior parietal cortices reflects greater top-down control over pain and cognitive reappraisal of pain, and that changes in somatosensory cortices reflect alterations in the perception of noxious signals. PERSPECTIVE An 11-week CBT intervention for coping with chronic pain resulted in increased GM volume in prefrontal and somatosensory brain regions, as well as increased dorsolateral prefrontal volume associated with reduced pain catastrophizing. These results add to mounting evidence that CBT can be a valuable treatment option for chronic pain.

Estradiol Interacts with the Cholinergic System to Affect Verbal Memory in Postmenopausal Women: Evidence for the Critical Period Hypothesis

Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.

Therapeutic Interactive Voice Response for chronic pain reduction and relapse prevention

&NA; We developed Therapeutic Interactive Voice Response (TIVR) as an automated, telephone‐based tool for maintenance enhancement following group cognitive–behavioral therapy (CBT) for chronic pain. TIVR has four components: a daily self‐monitoring questionnaire, a didactic review of coping skills, pre‐recorded behavioral rehearsals of coping skills, and monthly personalized feedback messages from the CBT therapist based on a review of the patient’s daily reports. The first three components are pre‐recorded and all four can be accessed remotely by patients via touch‐tone telephone on demand. Following 11 weeks of group CBT, 51 subjects with chronic musculoskeletal pain were randomized to one of two study groups. Twenty‐six subjects participated in 4 months of TIVR, while a control group of 25 subjects received standard care only. The TIVR group showed maximum improvement over baseline at the 8‐month follow‐up for seven of the eight outcome measures; improvement was found to be significant for all outcomes (p ⩽ .001). Between‐group analysis of covariance (ANCOVA) revealed significantly greater improvement for the experimental group at both 4‐ and 8‐month follow‐ups for most of the outcomes. Results demonstrate that TIVR can be used to decrease pain, improve coping and decrease likelihood of relapse into pain behavior. Preliminary analysis of medication usage suggests that the superior outcome of the TIVR group was unlikely to be a consequence of differential medication use.

Estrogen treatment effects on anticholinergic-induced cognitive dysfunction in normal postmenopausal women.

Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models. This study investigated the interaction of estrogen and cholinergic system functioning and the effects of this interaction on cognitive task performance in healthy older women. Fifteen post-menopausal women were randomly and blindly placed on 1 mg of 17-β estradiol or placebo for 3 months after which they participated in five anticholinergic challenge sessions, where they were administered one of two doses of the antimuscarinic drug scopolamine (SCOP) or the antinicotinic drug mecamylamine (MECA) or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Performance in multiple domains of cognition was assessed during anticholinergic drug challenge, including attention and verbal and nonverbal learning and memory. Results showed that estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention and tasks with speed components. This study is the first to demonstrate the interaction of estrogen and the cholinergic system and the effects on cognitive performance in humans. The results suggest that estrogen status may affect cholinergic system tone and may be important for cholinergic system integrity.

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD)=59.13 (5.5)) were randomly assigned to three months of 1mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.

Therapeutic Interactive Voice Response (TIVR) to Reduce Analgesic Medication Use for Chronic Pain Management

UNLABELLED This paper examines whether a telephone-based, automated maintenance enhancement program can help to reduce opioid and nonsteroidal anti-inflamatory drugs (NSAID) analgesic use in patients with chronic pain. Following 11 weeks of group cognitive-behavioral therapy (CBT), 51 subjects with chronic musculoskeletal pain were randomized to 1 of 2 study groups. Twenty-six subjects participated in 4 months of a Therapeutic Interactive Voice Response (TIVR) program in addition to standard follow-up care, while a control group of 25 subjects received standard follow-up care only. TIVR is an automated, telephone-based tool developed for the maintenance and enhancement of CBT skills. Opioid analgesic use decreased in the experimental group in both follow-ups: 4 and 8 months postCBT. In addition, at 8-month follow-up, 21% of the TIVR subjects had discontinued the use of opioid analgesics, 23% had discontinued NSAIDS, and 10% had discontinued antidepressant medications. In contrast, the control group showed increases in opioid and NSAIDS use. Analysis of covariance (ANCOVA) revealed significant between-group differences in opioid analgesic use at 8-month follow up (P = .004). We have previously demonstrated the efficacy of TIVR to decrease pain and improve coping; this analysis demonstrates that the use of TIVR may also result in concurrent reductions in opioid analgesic and NSAID medications use. PERSPECTIVE This article demonstrates that the Therapeutic Interactive Voice Response maintenance enhancement program can help to reduce opioid analgesic use in patients with chronic pain. This automated maintenance enhancement program could potentially assist patients not only to decrease pain and improve coping, but also to diminish the likelihood of opioid dependence.

Estrogen treatment impairs cognitive performance after psychosocial stress and monoamine depletion in postmenopausal women

Objective:Recent studies have shown that women experience an acceleration of cognitive problems after menopause and that estrogen treatment can improve or at least maintain current levels of cognitive functioning in postmenopausal women. However, we have previously shown that the negative emotional effects of psychosocial stress are magnified in normal postmenopausal women after estrogen treatment. This study examined whether estradiol (E2) administration can modify cognitive performance after exposure to psychological stress and monoamine depletion. Methods:Participants consisted of 22 postmenopausal women placed on either oral placebo or 17&bgr;-E2 (1 mg/d for 1 mo, then 2 mg/d for 2 mo). At the end of the 3-month treatment phase, participants underwent three depletion challenges in which they ingested one of three amino acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or balanced. Five hours later, participants performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings and cognitive testing. Cognitive measures included tests of attention, psychomotor function, and verbal episodic memory. Results:E2-treated compared with placebo-treated participants exhibited significant worsening of cognitive performance on tasks measuring attentional performance and psychomotor speed. Similar trends for impairment were seen in measures of long-term episodic memory compared with placebo-treated postmenopausal women. E2-treated participants also showed a significant increase in negative mood and anxiety compared with placebo-treated women after, but not before, the TSST, although the worsening of both cognitive and behavioral functioning was not correlated. These effects were independent of tryptophan or tyrosine/phenylalanine depletion and were not manifested before the TSST or at baseline. Conclusions:These data suggest that the relationship between estrogen administration and cognitive/behavioral performance in postmenopausal women may be more complex than initially appreciated and that the effects of psychosocial stress may influence whether hormone effects are beneficial.

Estrogen Administration Negatively Alters Mood Following Monoaminergic Depletion and Psychosocial Stress in Postmenopausal Women

Differences in the rates of affective disorders between women and men may relate to gender differences in gonadal steroid levels such as estrogen that have effects on brain monoamines important to mood regulation. Changes in estrogen secretion patterns during the perimenopause and menopause may be relevant to the increased risk for affective symptoms at that time. This study examined whether 17β-estradiol (E2) administration can modify the mood effects of experimental psychosocial stress following acute monoamine depletion in postmenopausal women. Subjects consisted of 15 normal postmenopausal women (PMW) (ages 67.1±11.2 years) blindly placed on either oral placebo or E2 (1 mg/day for 1 month, then 2 mg/day for 2 months). At the end of the 3-month treatment phase, subjects participated in three blinded depletion challenges in which they ingested each of three amino-acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or nutritionally balanced. After 5 h, subjects performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings. E2-treated subjects exhibited a significant increase in negative mood and anxiety after the TSST compared to placebo-treated women. These effects were independent of monoamine depletion and were not manifest before the TSST or at baseline. Exogenous estrogen administration in PMW may alter or modulate emotional reactivity to stressful events and may alter the sensitivity of emotional regulation. This modulation appears to be independent of alterations in monoaminergic neurotransmission. The dose of estrogen used after menopause may be important in determining the effects of gonadal steroids on emotional regulation.

White Matter Involvement in Chronic Musculoskeletal Pain

UNLABELLED There is emerging evidence that chronic musculoskeletal pain is associated with anatomic and functional abnormalities in gray matter. However, little research has investigated the relationship between chronic musculoskeletal pain and white matter. In this study, we used whole-brain tract-based spatial statistics and region-of-interest analyses of diffusion tensor imaging data to demonstrate that patients with chronic musculoskeletal pain exhibit several abnormal metrics of white matter integrity compared with healthy controls. Chronic musculoskeletal pain was associated with lower fractional anisotropy in the splenium of the corpus callosum and the left cingulum adjacent to the hippocampus. Patients also had higher radial diffusivity in the splenium, right anterior and posterior limbs of the internal capsule, external capsule, superior longitudinal fasciculus, and cerebral peduncle. Patterns of axial diffusivity (AD) varied: patients exhibited lower AD in the left cingulum adjacent to the hippocampus and higher AD in the anterior limbs of the internal capsule and in the right cerebral peduncle. Several correlations between diffusion metrics and clinical variables were also significant at a P < .01 level: fractional anisotropy in the left uncinate fasciculus correlated positively with total pain experience and typical levels of pain severity. AD in the left anterior limb of the internal capsule and left uncinate fasciculus was correlated with total pain experience and typical pain level. Positive correlations were also found between AD in the right uncinate and both total pain experience and pain catastrophizing. These results demonstrate that white matter abnormalities play a role in chronic musculoskeletal pain as a cause, a predisposing factor, a consequence, or a compensatory adaptation. PERSPECTIVE Patients with chronic musculoskeletal pain exhibit altered metrics of diffusion in the brains white matter compared with healthy volunteers, and some of these differences are directly related to symptom severity.

Increased working memory-related brain activity in middle-aged women with cognitive complaints

Individuals who report subjective cognitive complaints but perform normally on neuropsychological tests might be at increased risk for pathological cognitive aging. The current study examined the effects of the presence of subjective cognitive complaints on functional brain activity during a working memory task in a sample of middle-aged postmenopausal women. Twenty-three postmenopausal women aged 50-60 completed a cognitive complaint battery of questionnaires. Using 20% of items endorsed as the threshold, 12 women were categorized as cognitive complainers (CC) and 11 were noncomplainers (NC). All subjects then took part in a functional magnetic resonance imaging scanning session during which they completed a visual-verbal N-back test of working memory. Results showed no difference in working memory performance between CC and NC groups. However, the CC group showed greater activation relative to the NC group in a broad network involved in working memory including the middle frontal gyrus (Brodmann area [BA] 9 and 10), the precuneus (BA 7), and the cingulate gyrus (BA 24 and 32). The CC group recruited additional regions of the working memory network compared with the NC group as the working memory load and difficulty of the task increased. This study showed brain activation differences during working memory performance in a middle-aged group of postmenopausal women with subjective cognitive complaints but without objective cognitive deficit. These findings suggest that subjective cognitive complaints in postmenopausal women might be associated with increased cortical activity during effort-demanding cognitive tasks.