Neurophysiological evidence of corollary discharge dysfunction in schizophrenia.

OBJECTIVE: Speaking is hypothesized to generate a corollary discharge of motor speech commands transmitted to the auditory cortex, dampening its response to self-generated speech sounds. Event-related potentials were used to test whether failures of corollary discharge during speech contribute to the pathophysiology of schizophrenia. METHOD: The N1 component of the event-related potential elicited by vowels was recorded while the vowels were spoken by seven patients with schizophrenia and seven healthy comparison subjects and while the same vowels were played back. RESULTS: In the healthy subjects, the N1 elicited by spoken vowels was smaller than the N1 elicited by played-back vowels. This reduction in N1 elicited by spoken vowels was not observed in the patients with schizophrenia. CONCLUSIONS: These findings provide direct neurophysiological evidence for a corollary discharge that dampens sensory responses to self-generated, relative to externally presented, percepts in healthy comparison subjects and its failure in patients with schizophrenia.

Cortical responsiveness during inner speech in schizophrenia: an event-related potential study.

OBJECTIVE: The study assessed the effects of inner speech on auditory cortical responsiveness in schizophrenia. METHOD: Comparison subjects (N=15) and patients with schizophrenia (N=15) were presented with acoustic and visual stimuli during three conditions: while subjects were silent, when spontaneous inner speech might occur; during directed inner speech, while subjects repeated a statement silently to themselves; and while subjects listened to recorded speech. N1 event-related potentials were recorded during the three conditions. RESULTS: N1 event-related potentials elicited by acoustic stimuli, but not by visual stimuli, were lower during directed inner speech than during the silent baseline condition in the comparison subjects but not in the patients. CONCLUSIONS: Abnormal auditory cortical responsiveness to inner speech in patients with schizophrenia may be a sign of corollary discharge dysfunction, which may potentially cause misattribution of inner speech to external voices.

Social anxiety and response to touch: incongruence between self-evaluative and physiological reactions.

Touch is an important form of social interaction, and one that can have powerful emotional consequences. Appropriate touch can be calming, while inappropriate touch can be anxiety provoking. To examine the impact of social touching, this study compared socially high-anxious (N=48) and low-anxious (N=47) women's attitudes concerning social touch, as well as their affective and physiological responses to a wrist touch by a male experimenter. Compared to low-anxious participants, high-anxious participants reported greater anxiety to a variety of social situations involving touch. Consistent with these reports, socially anxious participants reacted to the experimenter's touch with markedly greater increases in self-reported anxiety, self-consciousness, and embarrassment. Physiologically, low-anxious and high-anxious participants showed a distinct pattern of sympathetic-parasympathetic coactivation, as reflected by decreased heart rate and tidal volume, and increased respiratory sinus arrhythmia, skin conductance, systolic/diastolic blood pressure, stroke volume, and respiratory rate. Interestingly, physiological responses were comparable in low and high-anxious groups. These findings indicate that social anxiety is accompanied by heightened aversion towards social situations that involve touch, but this enhanced aversion and negative-emotion report is not reflected in differential physiological responding.

Cortical responsiveness during talking and listening in schizophrenia: an event-related brain potential study.

BACKGROUND: Failures to recognize inner speech as self-generated may underlie positive symptoms of schizophrenia-like auditory hallucinations. This could result from a faulty comparison in auditory cortex between speech-related corollary discharge and reafferent discharges from thinking or speaking, with misattribution of internal thoughts to external sources. Although compelling, failures to monitor covert speech (thoughts) are not as amenable to investigation as failures to monitor overt speech (talking). METHODS: Effects of talking on auditory cortex responsiveness were assessed in 10 healthy adults and 12 patients with schizophrenia (DSM-IV) using N1 event-related potentials (ERPs) to acoustic and visual probes during talking aloud, listening to one's speech played back, and silent baseline. Trials contaminated by muscle artifact while talking were excluded. RESULTS: Talking and listening affected N1 to acoustic but not to visual probes, reflecting modality specificity of effects. Patterns of responses to acoustic probes differed between control subjects and patients. N1 to acoustic probes was reduced during talking compared with baseline in control subjects, but not in patients. Listening reduced N1 equivalently in both groups. CONCLUSIONS: Although the failure of N1 to be reduced during talking was not related to current hallucinations in patients, it may be related to the potential to hallucinate.

Respiratory dysregulation in anxiety, functional cardiac, and pain disorders. Assessment, phenomenology, and treatment.

Respiration is a complex physiological system affecting a variety of physical processes that can act as a critical link between mind and body. This review discusses the evidence for dysregulated breathing playing a role in three clinical syndromes: panic disorder, functional cardiac disorder, and chronic pain. Recent technological advances allowing the ambulatory assessment of endtidal partial pressure of CO2 (PCO2) and respiratory patterns have opened up new avenues for investigation and treatment of these disorders. The latest evidence from laboratories indicates that subtle disturbances of breathing, such as tidal volume instability and sighing, contribute to the chronic hypocapnia often found in panic patients. Hypocapnia is also common in functional cardiac and chronic pain disorders, and studies indicate that it mediates some of their symptomatology. Consistent with the role of respiratory dysregulation in these disorders, initial evidence indicates efficacy of respiration-focused treatment.

Respiratory biofeedback-assisted therapy in panic disorder.

The authors describe a new methodologically improved behavioral treatment for panic patients using respiratory biofeedback from a handheld capnometry device. The treatment rationale is based on the assumption that sustained hypocapnia resulting from hyperventilation is a key mechanism in the production and maintenance of panic. The brief 4-week biofeedback therapy is aimed at voluntarily increasing self-monitored end-tidal partial pressure of carbon dioxide (PCO2) and reducing respiratory rate and instability through breathing exercises in patients' environment. Preliminary results from 4 patients indicate that the therapy was successful in reducing panic symptoms and other psychological characteristics associated with panic disorder. Physiological data obtained from home training, 24-hour ambulatory monitoring pretherapy and posttherapy, and laboratory assessment at follow-up indicate that patients started out with low resting PCO2 levels, increased those levels during therapy, and maintained those levels at posttherapy and/or follow-up. Partial dissociation between PCO2 and respiratory rate questions whether respiratory rate should be the main focus of breathing training in panic disorder.

Slow recovery from voluntary hyperventilation in panic disorder.

OBJECTIVE: Because hyperventilation has figured prominently in theories of panic disorder (PD) but not of social phobia (SP), we compared predictions regarding diagnosis-specific differences in psychological and physiological measures before, during, and after voluntary hyperventilation. METHOD: Physiological responses were recorded in 14 patients with PD, 24 patients with SP, and 24 controls during six cycles of 1-minute of fast breathing alternating with 1 minute of recovery, followed by 3 minutes of fast breathing and 10 minutes of recovery. Speed of fast breathing was paced by a tone modulated at 18 cycles/minute, and depth by feedback aimed at achieving an end-tidal pCO2 of 20 mm Hg. These values were reached equally by all groups. RESULTS: During fast breathing, PD and SP patients reported more anxiety than controls, and their feelings of dyspnea and suffocation increased more from baseline. Skin conductance declined more slowly in PD over the six 1-minute fast breathing periods. At the end of the final 10-minute recovery, PD patients reported more awareness of breathing, dyspnea, and fear of being short of breath, and their pCO2s, heart rates, and skin conductance levels had returned less toward normal levels than in other groups. Their lower pCO2s were associated with a higher frequency of sigh breaths. CONCLUSIONS: PD and SP patients report more distress than controls to equal amounts of hypocapnia, but PD differ from SP patients and controls in having slower symptomatic and physiological recovery. This finding was not specifically predicted by hyperventilation, cognitive-behavioral, or suffocation alarm theories of PD.

The emotional Stroop effect in anxiety disorders: general emotional or disorder specificity?

Selective attentional biases, often documented with a modified Stroop task, are considered to play an important role in the etiology and maintenance of anxiety. Two competing explanations for these effects are selectivity for highly emotional words in general vs. selectivity for disorder-specific words. We tested these explanations in 32 patients with generalized anxiety disorder (GAD), 29 patients with social phobia (SP), and 31 non-anxious controls. Stimuli were of four kinds: GAD-related words, SP-related words, words with a neutral valence, and words with a positive valence. Different attentional biases were observed: GAD patients were slowed by all types of emotional words, while SP patients were distracted specifically by speech-related words.

The somatic symptom paradox in DSM-IV anxiety disorders: suggestions for a clinical focus in psychophysiology.

Although DSM-IV criteria for anxiety disorders include physiological symptoms, these symptoms are evaluated exclusively by verbal report. The current review explores the background for this paradox and tries to demonstrate on theoretical and empirical grounds how it could be resolved, providing new insights about the role of psychophysiological measures in the clinic. The three-systems approach to evaluating anxiety argues that somatic measures as well as verbal and behavioral ones are indispensable. However, the low concordance between these domains of measurement impugns their reliability and validity. We argue that concordance can be improved by examining the relationship of variables less global than anxiety and by restriction to specific anxiety disorders. For example, recent evidence from our and other laboratories indicate a prominent role of self-reported and physiologically measured breathing irregularities in panic disorder. Nonetheless, even within a diagnosis, anxiety patients vary radically in which somatic variables are deviant. Thus, in clinical practice, individual profiles of psychological and physiological anxiety responses may be essential to indicate distinct therapeutic approaches and ways of tracking improvement. Laboratory provocations specific to certain anxiety disorders and advances in ambulatory monitoring vastly expand the scope of self-report and physiological measurement and will likely contribute to a refined assessment of anxiety disorders.

Blushing and physiological arousability in social phobia.

Blushing is the most prominent symptom of social phobia, and fear perception of visible anxiety symptoms is an important component of cognitive behavioral models of social phobia. However, it is not clear how physiological and psychological aspects of blushing and other somatic symptoms are linked in this disorder. The authors tested whether social situations trigger different facial blood volume changes (blushing) between social phobic persons with and without primary complaint of blushing and control participants. Thirty social phobic persons. 15 of whom were especially concerned about blushing, and 14 control participants were assessed while watching an embarrassing videotape, holding a conversation, and giving a talk. Only when watching the video did the social phobic persons blush more than controls blushed. Social phobic persons who complained of blushing did not blush more intensely than did social phobic persons without blushing complaints but had higher heart rates, possibly reflecting higher arousability of this subgroup.

Physiologic instability in panic disorder and generalized anxiety disorder.

BACKGROUND: Because panic attacks can be accompanied by surges in physiologic activation, we tested the hypothesis that panic disorder is characterized by fluctuations of physiologic variables in the absence of external triggers. METHODS: Sixteen patients with panic disorder, 15 with generalized anxiety disorder, and 19 normal control subjects were asked to sit quietly for 30 min. Electrodermal, cardiovascular, and respiratory measures were analyzed using complex demodulation to quantify variability in physiologic indices. RESULTS: Both patient groups reported equally more anxiety and cardiac symptoms than control subjects, but certain other somatic symptoms, including breathlessness, were elevated only in panic disorder patients. Mean end-tidal pCO(2) and respiratory rates were lower, and tidal volume and the number of sighs were higher in panic disorder patients than control subjects. Neither cardiovascular (heart rate, arterial pressure, cardiac output), nor electrodermal instability including sighs distinguished the groups; however, tidal volume instability was greater in panic disorder than generalized anxiety disorder patients or control subjects. Several other respiratory measures (pCO(2), respiratory rate, minute volume, duty cycle) showed greater instability in both patient groups than in control subjects. CONCLUSIONS: Respiration is particularly unstable in panic disorder, underlining the importance of respiratory physiology in understanding this disorder. Whether our findings represent state or trait characteristics is discussed.

Characteristics of sighing in panic disorder.

BACKGROUND: Sighs, breaths with larger tidal volumes than surrounding breaths, have been reported as being more frequent in patients with anxiety disorders. METHODS: Sixteen patients with panic disorder, 15 with generalized anxiety disorder, and 19 normal control subjects were asked to sit quietly for 30 min. Respiratory volumes and timing were recorded with inductive plethysmography and expired pCO(2), from nasal prongs. RESULTS: Panic disorder patients sighed more and had tonically lower end-tidal pCO(2)s than control subjects, whereas generalized anxiety disorder patients were intermediate. Sighs defined as >2.0 times the subject mean discriminated groups best. Sigh frequency was more predictive of individual pCO(2) levels than was minute volume. Ensemble averaging of respiratory variables for sequences of breaths surrounding sighs showed no evidence that sighs were triggered by increased pCO(2) or reduced tidal volume in any group. Sigh breaths were larger in panic disorder patients than in control subjects. After sighs, pCO(2) and tidal volume did not return to baseline levels as quickly in panic disorder patients as in control subjects. CONCLUSIONS: Hypocapnia in panic disorder patients is related to sigh frequency. In none of the groups was sighing a homeostatic response. Panic disorder patients show less peripheral chemoreflex gain than control subjects, which would maintain low pCO(2) levels after sighing.

Characteristics of worry in GAD patients, social phobics, and controls.

Phenomenological features of worry such as thought content, subjective experience of worry, and efforts to control were investigated in the present interview study, as well as retrospective information about possible origins. To examine the clinical specificity of worrying in Generalized Anxiety Disorder (GAD), 36 GAD patients were compared to a normal control group (N = 30) and to a clinical control group (N = 22 social phobics). GAD patients differed from both groups in having higher frequency of worry, higher number of different worry topics, lower subjective controllability, more accompanying bodily symptoms, and more distress during worry. Thus, in general, our data confirm the central and specific role of worrying in GAD. Furthermore, in contrast to other topics, worrying about daily hassles was specific to GAD patients, which represents a lower threshold for starting to worry.

Psychophysiological assessment: clinical applications for PTSD.

Descriptions of anxiety disorders clearly recognize the physiological features of anxiety, yet in most clinical practice and research there is little actual use of physiological measurement. This is unfortunate because a potentially important source of information is thereby unavailable and is likely to result in judgements about emotional experience that are less accurate, complete, and reliable than those that include physiological information. The neglect of physiological measures may result from a variety of concerns regarding test attributes such as reliability, validity, utility, and complexity. Promising results from studies of posttraumatic stress disorder (PTSD) demonstrate that physiological assessment can provide valuable clinical and theoretical insight. Numerous studies have now shown that heightened physiological reactivity to trauma-related cues is highly indicative of a diagnosis of PTSD. Physiological tests have achieved some success in predicting the development and persistence of PTSD, and in predicting and assessing treatment response. Studies of the startle response, aversive conditioning, and brain potentials during cognitive processing have identified several potentially important differences between PTSD patients and controls. This paper provides an overview of psychophysiological findings in PTSD and considers potential clinical applications of psychophysiological assessment for this disorder.

Failures of automatic and strategic processing in schizophrenia: comparisons of event-related brain potential and startle blink modification.

Noises elicit startle blinks that are inhibited when immediately (approximately 100 ms) preceded by non-startling prepulses, perhaps reflecting automatic sensory gating. Startle blinks are facilitated when preceded by prepulses at longer lead intervals, perhaps reflecting strategic processes. Event-related brain potentials (ERPs) and startle blinks were used to investigate the well-documented prepulse inhibition failure in schizophrenia. Blinks and ERPs were recorded from 15 schizophrenic men and 20 age-matched controls to noises alone and to noises preceded by prepulses at 120 (PP120), 500 (PP500) and 4000 ms (PP4000) lead intervals. Neither blinks nor any of the ERP components elicited by the noise alone differentiated schizophrenics from controls, although responses to noises were modified by prepulses differently in the two groups. With the N1 component of the ERP, patients showed normal inhibition but lacked facilitation, and with P2, patients lacked inhibition, but showed normal facilitation. With reflex blinks and P300, inhibition was seen in both groups, but no facilitation. These results suggest that different neural circuits are involved in blink and cortical reflections of startle modification in schizophrenics and controls, with both automatic and strategic processes being impaired in schizophrenia.

Explicit memory in anxiety disorders.

Two experiments were conducted to study selective memory bias favoring anxiety-relevant materials in patients with anxiety disorders. In the 1st experiment, 32 patients with generalized anxiety disorder (GAD), 30 with social phobia (speaking anxiety), and 31 control participants incidentally learned GAD-relevant words, speech anxiety-relevant words, strongly pleasant words, and words with a neutral valence. Participants did not show any explicit memory bias for threatening materials. Thirty patients suffering from panic disorder (PD) with agoraphobia and 30 controls took part in the 2nd experiment. The design was similar to the 1st experiment. This time a highly specific selective memory bias for threatening words was found. Words describing symptoms of anxiety were better recalled by PD patients. Results are consistent with previous findings but are inexplicable by existing theories.

Analysis of cardiovascular regulation.

Adequate characterization of hemodynamic and autonomic responses to physical and mental stress can elucidate underlying mechanisms of cardiovascular disease or anxiety disorders. We developed a physiological signal processing system for analysis of continuously recorded ECG, arterial blood pressure (BP), and respiratory signals using the programming language Matlab. Data collection devices are a 16-channel digital, physiological recorder (Vitaport), a finger arterial pressure transducer (Finapres), and a respiratory inductance plethysmograph (Respitrace). Besides the conventional analysis of the physiological channels, power spectral density and transfer functions of respiration, heart rate, and blood pressure variability are used to characterize respiratory sinus arrhythmia (RSA), 0.10-Hz BP oscillatory activity (Mayer-waves), and baroreflex sensitivity. The arterial pressure transducer waveforms permit noninvasive estimation of stroke volume, cardiac output, and systemic vascular resistance. Time trends in spectral composition of indices are assessed using complex demodulation. Transient dynamic changes of cardiovascular parameters at the onset of stress and recovery periods are quantified using a regression breakpoint model that optimizes piecewise linear curve fitting. Approximate entropy (ApEn) is computed to quantify the degree of chaos in heartbeat dynamics. Using our signal processing system we found distinct response patterns in subgroups of patients with coronary artery disease or anxiety disorders, which were related to specific pharmacological and behavioral factors.

Voluntary breath holding in panic and generalized anxiety disorders.

OBJECTIVE: Because breath holding causes arterial pCO2 to increase, we used it to test the hypothesis that in panic disorder (PD) a biological suffocation monitor is pathologically sensitive. METHOD: Nineteen patients with PD, 17 with generalized anxiety disorder (GAD), and 22 normal controls took deep breaths on signal and held them until a release signal was given 30 seconds later. This was repeated 12 times separated by 60-second normal breathing periods. RESULTS: PD patients reported having had in the past more symptoms of shortness of breath when anxious, and more frequent frightening suffocation experiences than the other groups. However, increases in self-rated anxiety between periods of normal breathing and periods of breath holding were similar in all three groups. Skin conductance, blood pressure, and T-wave amplitude reactions to breath holdings were also similar, but heart rate acceleration upon taking a deep breath was greater in GAD patients. Before and after individual breath holdings, end-tidal pCO2 was lower in PD patients than in normal controls; GAD patients were intermediate. Inspiratory flow rate did not differ between groups. CONCLUSIONS: Our physiological results provide no direct support for an overly sensitive suffocation alarm system in PD. Lower pCO2 may be due to anxiety causing hyperventilation in patients prone to panic.

Using minute ventilation for ambulatory estimation of additional heart rate.

Both physical activity and emotion produce physiological activation. The emotional component of heart rate (HR) can be estimated as the additional HR (aHR) above that predicted by O2 consumption. Our innovation was to substitute minute ventilation (V) for O2 consumption, calculating aHR from individual relations between V and HR during an exercise test. We physiologically monitored 28 flight phobics and 15 non-anxious controls while walking (leaving the hospital, entering a plane), and during a commercial flight. Raw HR did not differ between phobics and controls when leaving the hospital (118/114 bpm) or entering the plane (117/110 bpm). However, although aHR was not different when leaving the hospital (7.0/8.6 bpm), it was significantly greater when entering the plane (17.5/9.9 bpm), accurately reflecting the increased subjective anxiety of the phobics. V was not higher in phobics than controls during any condition, suggesting an absence of hyperventilation in the phobics. The results demonstrate the utility of our method for analyzing HR in people whose stress occurs when they are physically active.