Neuroleptic effects on autonomic activity in schizophrenia: between-group and within-subject paradigms and comparisons with controls

Effects of fluphenazine on electrodermal activity (EDA) and heart rate (HR) were studied in patients with schizophrenia and normal control subjects during rest periods, presentation of innocuous tones, and a reaction time (RT) task. Two types of analyses were used: (1) between-group analyses-patients taking placebo were compared with patients taking fluphenazine and with control subjects using only data from the first test session; and (2) within-subject analyses-the same patients were tested when taking fluphenazine and when taking placebo. Results showed higher resting EDA and HR and smaller increments to task performance in placebo patients than in control subjects. Fluphenazine attenuated EDA levels but not the tonic response. Fluphenazine attenuated the HR response but did not affect HR level. Placebo patients were electrodermally hyporesponsive to the RT stimuli but not to simple tones. Fluphenazine markedly attenuated responsivity to simple tones but it attenuated responsivity less for RT stimuli. Testing medicated patients may thus produce misleading results with respect to many, but not all, purported autonomic markers of diagnosis in schizophrenia studies.     

The effects of frontal cortex lesions on event-related potentials during auditory selective attention

We compared electrophysiological indices of auditory selective attention in control subjects and in patients with unilateral lesions of the dorsolateral frontal lobes. In control subjects, ERPs following attended tones showed an enhanced negativity from 80 to 500 msec post-stimulus which had a different topographic distribution than the N120. Lesions of the frontal lobes reduced the attention-related negativity and impaired behavioral performance. The ERP reductions were equivalent in recordings obtained from electrodes placed over the damaged and intact cortex. A difference was noted between left and right frontal groups as a function of ear of delivery of the stimuli. Patients with left frontal lesions showed reduced attention effects following tones presented to either ear. Patients with right frontal lesions showed intact attention effects to right ear tones, but no attention-related negativity to left ear tones. When the left and right frontal groups were considered together, tones in ignored channels produced larger responses when presented to the ear contralateral to damaged cortex. These results underline the important role of the frontal lobes in processes of selective attention. Although the endogenous negativity produced in selective attention tasks does not appear to originate in dorsolateral frontal cortex, the frontal lobes exhibit a modulating influence upon it. In addition, the endogenous attention related negativity and exogenous N120 components apparently arise from different neural generators.     

Mapping frontal-limbic correlates of orienting to change detection

Orienting responses are elicited by salient stimuli, and may be indexed by skin conductance responses. Concurrent functional magnetic resonance imaging and skin conductance response recording was used to identify neural correlates of orienting to abrupt sensory change (infrequent high pitch oddball 'target' tones embedded in frequent lower pitch 'standard' tones) in 16 healthy participants. 'With skin conductance response' responses to targets were distinguished by preferentially greater activity in the amygdala and ventral medial and lateral frontal cortical regions. By contrast, 'without skin conductance response' responses elicited distinctive activity in the dorsal lateral frontal cortex and supramarginal gyrus. These findings suggest that orienting to unexpected sensory change elicits a network for appraising salience and novelty, whereas, in the absence of orienting, a parallel network for sensory and context evaluation is preferentially engaged.     

"Missing links" in borderline personality disorder: loss of neural synchrony relates to lack of emotion regulation and impulse control

OBJECTIVE: Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD. METHODS: Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0-150 ms post stimulus) and late (250-500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance. RESULTS: Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity. CONCLUSIONS: These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.     

Go - no go learning after frontal lobe lesions in humans.

48 patients with unilateral frontal or non-frontal cortical lesions were given a go - no go learning task. Patients with frontal lesions in either hemisphere took longer to learn the task and made more false "go" responses than control patients. They also, unlike controls, took longer to make in correct positive responses than correct positive ones. Medial frontal lesions were found to be particularly important in giving rise to poor performance on this task. It is suggested that this task is non-unitary in nature and that the medial area may be important for more than one ability.     

ERP Indices of Resource Allocation Difficulties in Mild Head Injury

This study examined the hypothesis that distractibility is a characteristic sequela of mild closed head injury (MHI). The Minnesota Multiphasic Personality Inventory (MMPI-2) was used to study whether comorbid stress-related symptoms are associated with behavioral and electrophysiological indexes of attention. Event-related potentials (ERPs) and performance (reaction time, accuracy) were studied in patients with MHI (n = 20), patients with frontal lesions (n = 14), and healthy controls (n = 20) during a three-tone oddball task. Participants were instructed to detect rare target (2000 Hz) tones, and to withhold responding to equally rare distractor (500 Hz) tones and frequently occurring standard (1000 Hz) tones. All groups distinguished the two classes of deviants as indicated by the larger P3 amplitude to target relative to distractor tones. This indicates that the group with MHI was capable of differential allocation of attentional resources to target and non-target events. However, impaired performance and attenuated ERP amplitudes to both classes of deviants relative to patients with frontal lesions and controls, suggest limited availability, or expenditure of the resources needed for adequate task performance. In the group with MHI, both P3 amplitude and reaction time (RT) were significantly related to subjectively reported distress. The difference in RT disappeared, whereas the P3 amplitude differences between the patient groups remained when adjusting for level of distress.     

ERP indices of resource allocation difficulties in mild head injury

This study examined the hypothesis that distractibility is a characteristic sequela of mild closed head injury (MHI). The Minnesota Multiphasic Personality Inventory (MMPI-2) was used to study whether comorbid stress-related symptoms are associated with behavioral and electrophysiological indexes of attention. Event-related potentials (ERPs) and performance (reaction time, accuracy) were studied in patients with MHI (n = 20), patients with frontal lesions (n = 14), and healthy controls (n = 20) during a three-tone oddball task. Participants were instructed to detect rare target (2000 Hz) tones, and to withhold responding to equally rare distractor (500 Hz) tones and frequently occurring standard (1000 Hz) tones. All groups distinguished the two classes of deviants as indicated by the larger P3 amplitude to target relative to distractor tones. This indicates that the group with MHI was capable of differential allocation of attentional resources to target and non-target events. However, impaired performance and attenuated ERP amplitudes to both classes of deviants relative to patients with frontal lesions and controls, suggest limited availability, or expenditure of the resources needed for adequate task performance. In the group with MHI, both P3 amplitude and reaction time (RT) were significantly related to subjectively reported distress. The difference in RT disappeared, whereas the P3 amplitude differences between the patient groups remained when adjusting for level of distress.     

Skin conductance orienting response in unmedicated RDC schizophrenic, schizoaffective, depressed, and control subjects.

In an evaluation of the skin conductance orienting response (SCOR) as a marker for schizophrenia, skin conductance (SC) activity was studied in 36 Research Diagnostic Criteria (RDC) schizophrenic (SCZ), 17 schizoaffective--mainly schizophrenic (SA), 24 depressed (DEP), and 25 psychiatrically well control (CONT) subjects. All subjects were unmedicated. Data are presented from four paradigms: a series of 1 s 70 dB tones in a no-task habituation paradigm; a similar series of 103 dB tones; a series of tones with a button-press (reaction time) task; and a loud white noise stimulus (without task). The proportion of SCOR nonresponse to the first 70 dB tone was 39% for SCZ, 82% for SA, 46% for DEP, and 36% for CONT subjects; the response rate for SA subjects was significantly lower than for all other groups. The CONT group was less responsive than in most previous studies. SCZ subjects did not show increased responsivity to more intense and to task-relevant stimuli, although SA subjects did show such increases. DEP subjects showed some evidence of autonomic hyperarousal (higher tonic SC level, trend toward more spontaneous SC responses). The overall pattern of results does not support SCOR to neutral, moderate-intensity tones as a specific marker for schizophrenia, although there was some evidence for a generalized decrease in autonomic responsivity to stimuli.     

Temporal and spatial context memory in patients with focal frontal, temporal lobe, and diencephalic lesions

Patients with focal frontal, temporal lobe, or diencephalic lesions were investigated on measures of temporal (recency) and spatial (position) context memory, after manipulating exposure times to match recognition memory for targets (pictorial stimuli) as closely as possible. Patients with diencephalic lesions from an alcoholic Korsak off syndrome showed significant impairment on the temporal context (recency) task, as did patients with frontal lesions penetrating the dorsolateral frontal cortex, according to MRI (and PET) evidence. Patients with temporal lobe lesions showed only a moderate (non-significant) impairment on this task, and patients with medial frontal lesions, or large frontal lesions not penetrating the dorsolateral cortical margins, performed as well as healthy controls at this task. On the spatial context memory task, patients with lesions in the temporal lobes showed significant impairment, and patients with right temporal lesions performed significantly worse than patients with left temporal lesions. Patients with diencephalic lesions showed only a modest (non-significant) impairment on this task, and the frontal lobe group performed normally. When a group of patients with temporal lobe lesions resulting from herpes encephalitis were examined separately, an identical pattern of results was obtained, the herpes group being significantly impaired on spatial memory and showing a trend towards impairment for temporal context memory. There were strong correlations between anterograde memory quotients and context memory performance (despite the use of an exposure time titration procedure) and a weak association with one frontal/executive task (card-sorting perseverations). It is predicted that correlations between temporal context memory and frontal/executive tasks will be greater in samples of patients all of whom have frontal lesions invading the dorsolateral cortical margin.     

Prefrontal mechanisms for executive control over emotional distraction are altered in major depression

A dysfunction in the interaction between executive function and mood regulation has been proposed as the pathophysiology of depression. However, few studies have investigated the alteration in brain systems related to executive control over emotional distraction in depression. To address this issue, 19 patients with major depressive disorder (MDD) and 20 healthy controls were scanned using functional magnetic resonance imaging. Participants performed an emotional oddball task in which infrequently presented circle targets required detection while sad and neutral pictures were irrelevant novel distractors. Hemodynamic responses were compared for targets, sad distractors, and for targets that followed sad or neutral distractors (Target-after-Sad and Target-after-Neutral). Patients with MDD revealed attenuated activation overall to targets in executive brain regions. Behaviorally, MDD patients were slower in response to Target-after-Sad than Target-after-Neutra stimuli. Patients also revealed a reversed activation pattern from controls in response to this contrast in the left anterior cingulate, insula, right inferior frontal gyrus (IFG), and bilateral middle frontal gyrus. Those patients who engaged the right IFG more during Target-after-Neutral stimuli responded faster to targets, confirming a role of this region in coping with emotional distraction. The results provide direct evidence of an alteration in the neural systems that interplay cognition with mood in MDD.     

Bilateral electrodermal asymmetry in euthymic patients with unipolar and bipolar affective disorders

Bilateral electrodermal activity (EDA) was examined in depressed patients in remission. In Study 1, 26 unipolar and 24 bipolar patients were compared to 46 psychiatrically healthy controls. Subjects were exposed to 17 86-dB pure tones while skin conductance was recorded from both hands. In Study 2, which was conducted 1 year later, many of these same subjects were recalled to form euthymic groups containing 22 unipolar, 22 bipolar, and 26 controls subjects. EDA was monitored bilaterally while subjects heard 8 86-dB tones and 12 105-dB tones followed by 8 familiar sounds that had a peak intensity of 105-dB. No consistent bilateral asymmetries in EDA were observed. Retest reliability coefficients indicating the stability of lateral differences over the 1-year period were close to zero. The results indicate that bilateral electrodermal asymmetry is not a trait characteristic of individuals prone to major affective disorder.     

Lateralization of the frontal lobe functions elicited by a cognitive bias task is a fundamental process. Lesion study

Cognitive neuroscience researchers have hypothesized that context-dependent and context-independent response selection is associated with the left and right frontal lobe, respectively, in right-handed adult males. Patients with left frontal lobe lesions show context-independent reasoning in a cognitive bias task (CBT), while those with right frontal lesions show context-dependent reasoning. Young children show more context-independent responses in a modified CBT (mCBT), while adolescents and adults show more context-dependent responses. We investigated the cognitive bias of right-handed children with unilateral frontal lobe lesions/epileptic foci to explore the plasticity of lateralization in the frontal lobes. The study included eight children with left frontal lobe lesions/epileptic foci (LLF) and four children with right frontal lobe lesions/epileptic foci (RLF). Twenty-three right-handed age-matched males served as controls. A computer presented version of the original card-choice task that was simplified and modified for children was used (mCBT). Simple visual stimuli differed dichotomously in shape, color, number, and shading. A target object presented alone was followed by two choices from which subjects made selection based on preference. Considering all four characteristics, the degree of similarity between the target and the subjects' choice was scored for 30 trials. A high score indicated a context-dependent response selection bias and a low score indicated a context-independent bias. The RLF subjects had a higher converted score (mean: 26.8+/-2.2), while LLF subjects showed a lower converted score (mean: 7.75+/-6.3). There were highly significant differences between LLF subjects and the other groups (P<0.001 vs. controls or RLF subjects). No significant correlations were observed between the converted scores and the age at onset, time since insult, or IQ in either LLF or RLF subjects. These findings suggest that the lateralization of frontal lobe function elicited by mCBT is fundamental and independent of language lateralization, rather than secondary to it. Furthermore, these findings also indicate that the timetable for the development of lateralized frontal lobe functions depends upon biologic factors.     

Discrimination and evocation of affectively intoned speech in patients with right parietal disease

Patients with right parietal disease have disturbed comprehension of affective speech. Ability to discriminate affective speech (make same/different discriminations) and ability to repeat emotionally bland sentences with affective tones were tested in three groups of subjects--patients with right parietal dysfunction and neglect, conduction aphasics with left hemispheric lesions, and patients without intracranial disease. Patients with right parietal dysfunction performed significantly poorer than did aphasic controls on both a recognition and discrimination task. Patients with right parietal dysfunction also scored poorer on the evocative task than the nonaphasic controls.     

Skin conductance responses to tones with and without attentional significance in schizophrenic and nonschizophrenic psychiatric patients

The skin conductance responses of schizophrenics with and without orienting responses to tones without attentional significance, were examined to the same tones with signal value, and randomly presented with non-signal or neutral tones. Most schizophrenics without orienting responses exhibited responses to signal tones and remained non-responders to neutral tones. Schizophrenics with orienting responses responded to both tones and their response rates were higher to neutral tones than non-schizophrenic patients. This is interpreted as evidence that schizophrenic responding and non-responding is not a function of frontal lobe involvement. Lateral asymmetry and group differences in response characteristics are reported.     

Autonomic response in the perception of disgust and happiness in depersonalization disorder

Patients with depersonalization disorder have shown attenuated responses to emotional unpleasant stimuli, hence supporting the view that depersonalization is characterised by a selective inhibition on the processing of unpleasant emotions. It was the purpose of this study to establish if autonomic responses to facial emotional expressions also show the same blunting effect. The skin conductance responses (SCRs) of 16 patients with chronic DSM-IV depersonalization disorder, 15 normal controls and 15 clinical controls with DSM-IV anxiety disorders were recorded in response to facial expressions of happiness and disgust. Patients with anxiety disorders were found to have greater autonomic responses than patients with depersonalization, in spite of the fact that both groups had similarly high levels of subjective anxiety as measured by anxiety scales. SCR to happy faces did not vary across groups. The findings of this study provide further support to the idea that patients with depersonalization have a selective impairment in the processing of threatening or unpleasant emotional stimuli.     

Impairments in proverb interpretation following focal frontal lobe lesions

The proverb interpretation task (PIT) is often used in clinical settings to evaluate frontal “executive” dysfunction. However, only a relatively small number of studies have investigated the relationship between frontal lobe lesions and performance on the PIT. We compared 52 patients with unselected focal frontal lobe lesions with 52 closely matched healthy controls on a proverb interpretation task. Participants also completed a battery of neuropsychological tests, including a fluid intelligence task (Raven’s Advanced Progressive Matrices). Lesions were firstly analysed according to a standard left/right sub-division. Secondly, a finer-grained analysis compared the performance of patients with medial, left lateral and right lateral lesions with healthy controls. Thirdly, a contrast of specific frontal subgroups compared the performance of patients with medial lesions with patients with lateral frontal lesions. The results showed that patients with left frontal lesions were significantly impaired on the PIT, while in patients with right frontal lesions the impairments approached significance. Medial frontal patients were the only frontal subgroup impaired on the PIT, relative to healthy controls and lateral frontal patients. Interestingly, an error analysis indicated that a significantly higher number of concrete responses were found in the left lateral subgroup compared to healthy controls. We found no correlation between scores on the PIT and on the fluid intelligence task. Overall our results suggest that specific regions of the frontal lobes contribute to the performance on the PIT.     

Attentional inhibition in patients with focal frontal lobe lesions

Patients with unilateral, frontal lobe damage and matched controls performed an identity negative priming task as a measure of inhibition in selective attention. Control participants demonstrated a normal negative priming effect, as evidenced by slower reaction times when a previously to-be-ignored item became the target on a subsequent trial (distractor suppression). On the other hand, patients with left medial frontal lobe damage showed positive priming in the distractor suppression condition suggesting facilitation of distractor information. Patients with right frontal lobe damage showed an unreliable pattern of negative priming, some demonstrating an absence of negative priming and others demonstrating enhanced negative priming in the distractor suppression condition. Neither patient group nor controls demonstrated slower responses on a target-to-distractor condition included to evaluate a noninhibitory (i.e., episodic retrieval) account of negative priming. Taken together, our results suggest that (a) the negative priming effect represents active inhibition of a distractor representation, rather than a noninhibitory mismatch between retrieval episodes, and (b) that the frontal lobes, especially the left frontal lobes, contribute to this active inhibition.     

Semantic priming in patients with right frontal lobe lesions.

Patients with unilateral, right frontal lobe damage (N=13) and matched controls (N=20) performed a task of lexical ambiguity resolution in order to explore the contribution of right frontal regions to lexical-semantic priming. Word triplets consisting of balanced homographs were presented to participants in four conditions: concordant, discordant, neutral, and unrelated. Controls demonstrated facilitation for concordant meanings of homographs, as evidenced by their faster reaction times in the concordant relative to the unrelated (baseline) condition, as well as a lack of facilitation for the discordant meaning relative to the neutral and concordant conditions. Results in patients with right frontal lobe damage differed depending on the site of the lesion. Patients with lesions restricted to the right medial frontal lobe only showed facilitation in the neutral condition, while those with lesions encroaching upon the right dorsolateral region demonstrated facilitation of both discordant and concordant meanings relative to the baseline condition. These results support a role for the right frontal lobe in semantic priming and suggest possible specialization within the right prefrontal cortex for the processing of lexical-semantic information.     

Auditory micropattern discrimination in brain damaged subjects

Patients with cerebral lesions were given two tests of pitch discrimination. The first was a pure tone discrimination test; in the second, complex tones were employed in which the pitch difference between the test tones was a consequence of the temporal microstructure of the stimuli. In contrast to non-fluent aphasics whose performance was normal for both tests, six of the seven patients having a fluent aphasia performed normally on the first test but revealed a significant deficit in the second. Patients with right temporal lesions also had the same pattern of deficit. The results suggest that the temporal lobes play a special role in the processing of auditory information in which the temporal structure of the stimuli is a critical feature.