Martin P. Paulus

An Insular View of Anxiety

We propose a general hypothesis that integrates affective and cognitive processing with neuroanatomy to explain anxiety pronenes. The premise is that individuals who are prone to anxiety show an altered interoceptive prediction signal, i.e., manifest augmented detection of the difference between the observed and expected body state. As a consequence, the increased prediction signal of a prospective aversive body state triggers an increase in anxious affect, worrisome thoughts and other avoidance behaviors. The anterior insula is proposed to play a key role in this process. Further testing of this model--which should include investigation of genetic and environmental influences--may lead to the development of novel treatments that attenuate this altered interoceptive prediction signal in patients with anxiety disorders.

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.

New insights into symptoms and neurocircuit function of anorexia nervosa

Individuals with anorexia nervosa have a relentless preoccupation with dieting and weight loss that results in severe emaciation and sometimes death. It is controversial whether such symptoms are secondary to psychosocial influences, are a consequence of obsessions and anxiety or reflect a primary disturbance of brain appetitive circuits. New brain imaging technology provides insights into ventral and dorsal neural circuit dysfunction — perhaps related to altered serotonin and dopamine metabolism — that contributes to the puzzling symptoms found in people with eating disorders. For example, altered insula activity could explain interoceptive dysfunction, and altered striatal activity might shed light on altered reward modulation in people with anorexia nervosa.

The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder

Analyses conducted in 10,526 community respondents investigated by the NIMH Epidemiological Catchment Area (ECA) Program, revealed the 1-month point prevalence of depressive symptoms and disorders in the general population, at the first ECA interview (Wave 1) to be 10%, as follows: 2.3% major depressive disorder (MDD); 2.3% dysthmic disorder (DD); 1.5% minor depressive disorder (MinD); and 3.9% subsyndromal depressive symptoms (SSD, defined as two or more depressive symptoms beneath the diagnostic threshold of MinD, DD or MDD). There appears to be two classes of SSD in this community sample: first, SSD, which occurred as an integral component of the course of unipolar major depressive disorder (MDD); and, second, SSD occurring spontaneously in non-unipolar depressed community subjects. In the first instance, SSD was frequently prodromal to episodes of MinD or MDD or residual to resolving episodes. Analyses also support the conclusion that SSD is a clinically significant, interepisode, depressive subtype of unipolar MDD, since SDD is associated with harmful dysfunction in five of six measures of adverse outcome, has a significantly increased prevalence of past histories of major depressive episodes, and an elevated lifetime prevalence of suicide attempts. Comparison of subsyndromal depressive symptomatology or depressive disorder diagnoses at Wave 1 with diagnoses obtained, 1 year later, at the Wave 2 interview, confirm the persistent and chronic nature of depression in this large representative sample of community respondents, in which 71% of subjects with depressive symptoms or disorders at Wave 1 continued to be symptomatic at Wave 2. In addition, subjects experienced a surprising degree of change in depressive symptom and disorder diagnoses during the 1-year observational window between Wave 1 and Wave 2, in which a remarkable percentage of individuals, who began the year in a depressive symptom or disorder diagnostic category, ended the year in another. This has led us to hypothesize that the typical clinical picture of unipolar MDD is dynamic and pleomorphic in nature, characterized by substantial symptomatic fluidity, in which patients frequently change diagnoses from one depressive subtype to another during their courses of illness.

Neurobiology of Decision Making: A Selective Review from a Neurocognitive and Clinical Perspective

We present a temporal map of key processes that occur during decision making, which consists of three stages: 1) formation of preferences among options, 2) selection and execution of an action, and 3) experience or evaluation of an outcome. This framework can be used to integrate findings of traditional choice psychology, neuropsychology, brain lesion studies, and functional neuroimaging. Decision making is distributed across various brain centers, which are differentially active across these stages of decision making. This approach can be used to follow developmental trajectories of the different stages of decision making and to identify unique deficits associated with distinct psychiatric disorders.

Interoception in anxiety and depression

We review the literature on interoception as it relates to depression and anxiety, with a focus on belief, and alliesthesia. The connection between increased but noisy afferent interoceptive input, self-referential and belief-based states, and top-down modulation of poorly predictive signals is integrated into a neuroanatomical and processing model for depression and anxiety. The advantage of this conceptualization is the ability to specifically examine the interface between basic interoception, self-referential belief-based states, and enhanced top-down modulation to attenuate poor predictability. We conclude that depression and anxiety are not simply interoceptive disorders but are altered interoceptive states as a consequence of noisily amplified self-referential interoceptive predictive belief states.

Behavioral and Functional Neuroimaging Evidence for Prefrontal Dysfunction in Methamphetamine-Dependent Subjects

Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.

Association of Major Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of Heat Pain

CONTEXT Chronic pain and depression are highly comorbid conditions, yet little is known about the neurobiological basis of pain processing in major depressive disorder (MDD). OBJECTIVE To examine the neural substrates underlying anticipation and processing of heat pain in a group of unmedicated young adults with current MDD. DESIGN Functional magnetic resonance neuroimaging data were collected during an event-related factorial experimental pain paradigm. Painful and nonpainful heat stimuli were applied to the left volar forearm while different color shapes explicitly signaled the intensity of the upcoming stimulus. SETTING University brain imaging center. Patients Fifteen (12 female) young adults with current MDD and 15 (10 female) healthy subjects with no history of MDD were recruited and matched for age and level of education. The Structured Clinical Interview for DSM-IV was administered to all participants by a board-certified psychiatrist. Main Outcome Measure Between-group differences in blood oxygen level-dependent functional magnetic resonance neuroimaging signal change to anticipation and processing of painful vs nonpainful temperature stimuli. RESULTS Subjects with MDD compared with healthy controls showed (1) increased activation in the right anterior insular region, dorsal anterior cingulate, and right amygdala during anticipation of painful relative to nonpainful stimuli, (2) increased activation in the right amygdala and decreased activation in periaqueductal gray matter and the rostral anterior cingulate and prefrontal cortices during painful stimulation relative to nonpainful stimulation, and (3) greater activation in the right amygdala during anticipation of pain, which was associated with greater levels of perceived helplessness. CONCLUSIONS These findings suggest that increased emotional reactivity during the anticipation of heat pain may lead to an impaired ability to modulate pain experience in MDD. Future studies should examine the degree to which altered functional brain response during anticipatory processing affects the ability to modulate negative affective states in MDD, which is a core characteristic of this disorder.

Anticipation of Aversive Visual Stimuli Is Associated With Increased Insula Activation in Anxiety-Prone Subjects

BACKGROUND Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image. METHODS 16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they viewed pictures of spiders and snakes. Subjects were prompted 4-6 sec before the onset of each aversive image. Blood oxygenation level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing images. RESULTS As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both within groups and in the combined group. CONCLUSIONS These data suggest that greater activation of the insula during visual anticipation is associated with visual processing of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as such, might be a neuroimaging marker for anxiety proneness.

Functional subdivisions within anterior cingulate cortex and their relationship to autonomic nervous system function.

The anterior cingulate cortex (ACC) has diverse functions and several functional subdivisions. This study implemented a counting Stroop task that presented incongruent (INC) and congruent (CON) stimuli at two speeds to probe dorsal (dACC) and ventral (vACC) using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects completed the task twice: once outside the scanner while heart rate variability (HRV) was recorded and once during fMRI. In both sessions, subjects completed two runs. Stimuli were presented every 2.0 s in one run and every 1.5 s in the other. fMRI data analysis revealed two important findings. First, by computing differential activation between INC and CON stimuli, a cluster of activation related to response inhibition was observed in the left dACC. Additionally, by calculating the interaction of speed with stimulus congruency, a cluster of activation was observed in the left vACC. This activation correlated significantly with high-frequency HRV (P < 0.02 for CON and P < 0.003 for INC) and represents the parasympathetic modulatory role of the vACC. This study supports the notion of functional subdivisions within the ACC and links the processes of cognitive interference and parasympathetic modulation with activation in specific subregions of the ACC, a structure that is critical for the interface between cognition and emotion.