Meena Vythilingam

Reduced volume of orbitofrontal cortex in major depression.

BACKGROUND Functional neuroimaging studies have implicated dysfunction of orbitofrontal cortex in the symptoms of depression, and a recent postmortem study of depressed patients found reduced density of neurons and glia in this area. The purpose of this study was to measure volume of orbitofrontal cortex and other frontal cortical subregions in patients with major depression. METHODS Magnetic resonance imaging was used to measure volume of the orbitofrontal cortex and other frontal cortical regions in patients with major depression in remission (n = 15) and comparison subjects (n = 20). RESULTS Patients with depression had a statistically significant 32% smaller medial orbitofrontal (gyrus rectus) cortical volume, without smaller volumes of other frontal regions including anterior cingulate Brodmanns area 24 (subgenual gyrus), anterior cingulate Brodmanns area 32, subcallosal gyrus (Brodmanns area 25), or whole brain volume. The findings were significant after statistically controlling for brain size. CONCLUSIONS These findings are consistent with smaller orbitofrontal cortical volume in depression.

Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder

BACKGROUND Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. METHODS Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. RESULTS Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. CONCLUSIONS These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.

Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment.

BACKGROUND Depression has been linked to stress, memory deficits, and hypercortisolemia. However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear and the effects of antidepressant treatment on the measures are not well studied. METHODS Whole hippocampal volume, performance on verbal and visual declarative memory function and cortisol status was evaluated in 38 subjects with major depressive disorder (MDD) and 33 healthy subjects. All measures were repeated in a subgroup (n = 22) of depressed patients after successful selective serotonin reuptake inhibitor (SSRI) treatment. RESULTS Hippocampal volume was not significantly different between patients with untreated MMD and healthy subjects, after controlling for whole brain volume, age and gender. However, depressed subjects had significantly greater deficits in delayed memory and percent retention on the verbal portion of the Wechsler Memory Scale-Revised (WMS-R) compared with healthy subjects, without significant differences in visual memory, attention, vigilance, or distractibility. Baseline plasma or urinary free cortisol (UFC) was not related to either hippocampal volume or memory deficits. Successful treatment with antidepressants did not change hippocampal volume but did result in a significant improvement in memory function and a reduction in UFC excretion. CONCLUSIONS Medication-free nonelderly depressed outpatients without alcohol dependence or adverse experiences in childhood had normal hippocampal volume. Focal declarative memory deficits in depression supported localized hippocampal dysfunction in depressed patients. Treatment with antidepressants significantly improved memory and depression but did not alter hippocampal volume, suggesting that antidepressants may improve hippocampal function in the absence of detectable structural changes.

Modulation of emotion by cognition and cognition by emotion

In this study, we examined the impact of goal-directed processing on the response to emotional pictures and the impact of emotional pictures on goal-directed processing. Subjects (N=22) viewed neutral or emotional pictures in the presence or absence of a demanding cognitive task. Goal-directed processing disrupted the BOLD response to emotional pictures. In particular, the BOLD response within bilateral amygdala and inferior frontal gyrus decreased during concurrent task performance. Moreover, the presence of both positive and negative distractors disrupted task performance, with reaction times increasing for emotional relative to neutral distractors. Moreover, in line with the suggestion of the importance of lateral frontal regions in emotional regulation [Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D., et al. (2004). For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion. NeuroImage, 23(2), 483-499], connectivity analysis revealed positive connectivity between lateral superior frontal cortex and regions of middle frontal cortex previously implicated in emotional suppression [Beauregard, M., Levesque, J., and Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. J. Neurosci., 21 (18), RC165.; Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003). Neural circuitry underlying voluntary suppression of sadness. Biol. Psychiatry, 53 (6), 502-510.; Ohira, H., Nomura, M., Ichikawa, N., Isowa, T., Iidaka, T., Sato, A., et al. (2006). Association of neural and physiological responses during voluntary emotion suppression. NeuroImage, 29 (3), 721-733] and negative connectivity with bilateral amygdala. These data suggest that processes involved in emotional regulation are recruited during task performance in the context of emotional distractors.

Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder

BACKGROUND In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD). METHOD Women with early childhood sexual-abuse-related PTSD (n = 8) and women without abuse or PTSD (n = 11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square. RESULTS Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls. CONCLUSIONS These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder

BACKGROUND The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.

Response to Emotional Expressions in Generalized Social Phobia and Generalized Anxiety Disorder: Evidence for Separate Disorders

OBJECTIVE Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder. METHOD Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N=17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment. RESULTS The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder. CONCLUSIONS These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.

Low cortisol, high DHEA, and high levels of stimulated TNF‐α, and IL‐6 in women with PTSD

Posttraumatic stress disorder (PTSD) has been associated with hypothalamic-pituitary-adrenal (HPA) axis and immune function alterations; however, few studies have simultaneously investigated these systems in participants with PTSD. In this study, HPA axis and immune function in 26 women with PTSD with and without major depressive disorder was compared to 24 traumatized controls and to 21 nontraumatized controls. Posttraumatic stress disorder was associated with low cortisol and higher levels of DHEA and greater production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) compared to traumatized and healthy controls. Women with PTSD and depression exhibited greater production of IL-6 and higher levels of dehydroepiandrosterone (DHEA) than those with PTSD, but without depression. These findings suggest dysregulated HPA axis and immune function in women with PTSD, and that comorbid depression may contribute to these abnormalities.

Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder.

BACKGROUND Uncontrollability and unpredictability are key concepts related to re-experiencing, avoidance, and hypervigilance symptoms of posttraumatic stress disorder (PTSD). However, little is known about the differential sensitivity of PTSD individuals to unpredictable stressors, relative to either healthy individuals or individuals with other anxiety disorders. This study tested the hypothesis that elevated anxious reactivity, specifically for unpredictable aversive events, is a psychophysiological correlate of PTSD. METHODS Sixteen patients with PTSD (34.5 +/- 12.4 years) were compared with 18 patients with generalized anxiety disorder (GAD) (34.0 +/- 10.5 years) and 34 healthy control subjects (30.2 +/- 8.5 years). Participants were exposed to three conditions: one in which predictable aversive stimuli were signaled by a cue, a second in which aversive stimuli were administered unpredictably, and a third in which no aversive stimuli were anticipated. Startle magnitude was used to assess anxious responses to the threat cue and to contexts associated with each condition. RESULTS Posttraumatic stress disorder and GAD patients showed normative enhancement of fear to the predictable threat cue, but the PTSD group displayed elevated anxiety during the unpredictable condition compared with participants with GAD and healthy control subjects. CONCLUSIONS Anxious reactivity to unpredictable aversive events was heightened in PTSD but not in GAD and healthy subjects. Prior works also found signs of increased reactivity to unpredictable threat in panic disorder (PD), suggesting that PTSD and PD may involve shared vulnerability. As such, the current results inform understandings of classification, pathophysiology, and psychopharmacology of anxiety disorders, generally, and PTSD and panic disorder specifically.

Deficits in verbal declarative memory function in women with childhood sexual abuse-related posttraumatic stress disorder.

Several studies have shown deficits in verbal declarative memory function in posttraumatic stress disorder (PTSD). Most of these studies have been performed in men with combat-related PTSD compared with healthy subjects; relatively little is known about memory function in women with abuse-related PTSD, or whether these effects are specific to PTSD or are a nonspecific outcome of exposure to early abuse. The purpose of this study was to assess declarative memory function in women with and without a history of early childhood sexual abuse and PTSD. Forty-three women with and without a history of early childhood sexual abuse and PTSD underwent neuropsychological testing with subtests of the Wechsler Memory Scale—Revised for measurement of verbal and visual memory and subtests of the Wechsler Adult Intelligence Scale for measurement of IQ, and behavioral ratings of PTSD and other psychiatric symptoms. Abused women with PTSD had deficits in verbal declarative memory as measured with the subtests of the Wechsler Memory Scale—Revised compared with women with early abuse without PTSD and nonabused women without PTSD. There were no significant differences in IQ. These findings suggest that early abuse with PTSD is associated with deficits in verbal declarative memory, and that these effects are not related to the nonspecific effects of childhood abuse.