Hyperreactivity and Impaired Habituation of Startle Amplitude During Unpleasant Pictures in Borderline but Not Schizotypal Personality Disorder: Quantifying Emotion Dysregulation.

BACKGROUND: Borderline personality disorder (BPD) is characterized by greater intensity of reactions to unpleasant emotional cues and a slower-than-normal return of these responses to baseline. Habituation is defined as decreased response to repeated stimulation. Affect-modulated startle (AMS), a translational psychophysiological approach, is mediated by the amygdala and used to study emotion processing in both humans and animals. This is the first study to examine the specificity of habituation anomalies in BPD during passive emotional and neutral picture processing. METHODS: A total of 90 participants were studied: patients with BPD (n = 35), patients with schizotypal personality disorder (n = 26; included as a psychopathological comparison group), and healthy control subjects (n = 29). Participants received rigorous clinical assessments, and patients were unmedicated. AMS was examined during a series of intermixed unpleasant, neutral, and pleasant pictures. RESULTS: Compared with the other groups, patients with BPD showed greater overall AMS during unpleasant pictures and prolonged habituation of startle amplitude during unpleasant pictures from early to later trials. The groups did not differ in AMS during neutral or pleasant pictures or self-reported picture valence. Among the patients with BPD, prolonged habituation to unpleasant pictures was associated with greater symptom severity and suicidal/self-harming behavior. CONCLUSIONS: These findings 1) indicate that abnormal processing of and habituation to unpleasant pictures is observed in BPD but not schizotypal personality disorder, suggesting that these deficits are not simply characteristics of personality disorders in general; 2) are consistent with studies showing deficient amygdala habituation to unpleasant pictures in BPD; and 3) have significant implications for clinical assessment and treatment of BPD, e.g., alternative therapies for BPD such as gradual exposure to unpleasant emotional stimuli or amygdala neurofeedback may aid habituation deficits.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Sensory gating disturbances in the spectrum: similarities and differences in schizotypal personality disorder and schizophrenia.

BACKGROUND: DSM-5 places schizophrenia on a continuum from severe, chronic schizophrenia to the attenuated schizophrenia-like traits of schizotypal personality disorder (SPD), the prototypic schizophrenia-related personality disorder. SPD shares common genetic and neurobiological substrates with schizophrenia, including information processing abnormalities, although they are less marked. This is the first study to directly compare the P50 evoked electroencephalographic response-a measure of sensory gating and a neurophysiological endophenotype-between schizophrenia-spectrum groups. Two hypotheses were tested: (1) Compared with healthy controls (HCs), schizophrenia patients show reduced P50 suppression and SPD patients resemble schizophrenia but exhibit less marked deficits; and (2) Deficient P50 suppression in SPD is associated with greater clinical symptom severity. METHODS: P50 was assessed in 32 schizophrenia-spectrum disorder patients (12 SPD, 20 schizophrenia patients) and 25 demographically-matched HCs. The standard conditioning (C)-testing (T) paradigm was used and P50 suppression was quantified using the T-C difference and the T/C ratio. RESULTS: All P50 measures showed a linear, stepwise pattern with the SPD group intermediate between the HC and schizophrenia groups. Compared with HCs, both patient groups had lower conditioning and T-C difference values. Among the SPD group, greater clinical symptom severity was associated with greater conditioning-response amplitude deficits. CONCLUSION: These findings: (1) are novel in showing that P50 deficits in SPD resemble those observed in schizophrenia, albeit less marked; (2) support the concept that the phenomenological link between SPD and schizophrenia lies in shared neurocognitive/neurophysiological pathologies; and (3) provide evidence that P50 is a neurophysiological endophenotype for schizophrenia-spectrum disorders.

Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia.

Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI ( patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule.

Statistical parametric mapping and cluster counting analysis of [18F] FDG-PET imaging in traumatic brain injury.

In this study we investigated regional cerebral glucose metabolism abnormalities of [(18)F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in traumatic brain injury (TBI). PET images of 81 TBI patients and 68 normal controls were acquired and a word list learning task was administered during the uptake period. The TBI group included 35 patients with positive structural imaging (CT or MRI) findings soon after injury, 40 patients with negative findings, and 6 cases without structural imaging. Statistical parametric mapping (SPM) analysis was applied with several levels of spatial smoothing. Cluster counting analysis was performed for each subject to identify abnormal clusters with contiguous voxel values that deviated by two standard deviations or more from the mean of the normal controls, and to count the number of clusters in 10 size categories. SPM maps demonstrated that the 81 patients had significantly lower FDG uptake than normal controls, widely across the cortex (including bilateral frontal and temporal regions), and in the thalamus. Cluster counting results indicated that TBI patients had a higher proportion of larger clusters than controls. These large low-FDG-uptake clusters of the TBI patients were closer to the brain edge than those of controls. These results suggest that deficits of cerebral metabolism in TBI are spread over multiple brain areas, that they are closer to the cortical surface than clusters in controls, and that group spatial patterns of abnormal cerebral metabolism may be similar in TBI patients with cognitive deficits with and without obvious acute abnormalities identified on structural imaging.

The thalamus and schizophrenia: current status of research.

The thalamus provides a nodal link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed.

Deficient attentional modulation of startle eyeblink is associated with symptom severity in the schizophrenia spectrum.

Patients with schizophrenia-spectrum disorders show deficient prepulse inhibition (PPI) of the startle eyeblink reflex which is thought to reflect an early stage of information processing called automatic sensorimotor gating. They also exhibit deficient attentional modulation of PPI and prepulse facilitation (PPF) of startle which is thought to reflect deficient early and later controlled attentional processing. This is the first study to assess attentional modulation of PPI and PPF in a 3-group schizophrenia-spectrum sample of age- and sex-matched unmedicated schizotypal personality disorder (SPD) and schizophrenia patients, and healthy controls. Participants performed a tone-length judgment task involving attended, ignored, and novel tone prepulses while the acoustic startle eyeblink reflex was measured. Healthy controls showed greater PPI and PPF during the attended prepulses compared with the ignored prepulses. In contrast, both the SPD and schizophrenia patient groups failed to show this pattern, indicating deficient early and later controlled attentional processing. These findings suggest abnormal attentional modulation of PPI and PPF may be a trait-like feature found in patients with schizophrenia-spectrum disorders. Among the schizophrenia-spectrum sample, more deficient PPI during the attended prepulses was associated with greater symptom severity as measured by the total 18-item Brief Psychiatric Rating Scale score.

Exaggerated affect-modulated startle during unpleasant stimuli in borderline personality disorder.

BACKGROUND: Excessive emotional responding is considered to be a hallmark of borderline personality disorder (BPD). The affect-modulated startle response is a reliable indicator of emotional processing of stimuli. The aim of this study was to examine emotional processing in BPD patients (n = 27) and healthy control subjects (n = 21). METHODS: Participants viewed an intermixed series of unpleasant, borderline-salient (e.g., "hate"), and neutral (e.g., "view") words and were instructed to think about the meaning of the word for them personally while eyeblink responses were assessed. RESULTS: The BPD patients exhibited larger startle eyeblink during unpleasant but not neutral words, indicating exaggerated physiological affect. This finding remained significant when we controlled for comorbid diagnoses, including generalized anxiety disorder and post-traumatic stress disorder. Greater symptom severity was associated with greater affective-startle difference scores (unpleasant-neutral). CONCLUSIONS: Consistent with the symptom of affective dysregulation, these results suggest an abnormality in the processing of unpleasant emotional stimuli by BPD patients.

Metabolic thalamocortical correlations during a verbal learning task and their comparison with correlations among regional volumes.

Methods based on the analysis of metabolic and volumetric interregional correlations have been used in neuroimaging research, yet metabolic and volumetric interregional correlations for identical regions of interest have never been compared in the same group of subjects. Magnetic resonance and [18F]-fluorodeoxyglucose positron emission tomography brain images were acquired in 59 healthy subject. Correlation matrices for relative glucose metabolic rates during a verbal learning task and for relative gray matter volumes were compiled between the manually traced mediodorsal, centromedian, and pulvinar nuclei of the thalamus and 39 cortical Brodmann's areas. Metabolic correlations between the cortex and these thalamic nuclei followed the known patterns of anatomical connectivity in non-human primates. Intercorrelations of the mediodorsal nucleus were widespread with the prefrontal cortex (9 out of 10 Brodmann's areas in the left hemisphere) and temporal lobe (10 out of 11 Brodmann's areas in the left hemisphere) while the pulvinar correlated only with the parietal and occipital cortical areas. Different correlation patterns were observed for the regional gray matter volumes whereby only the pulvinar yielded extensive cortical intercorrelations, primarily with the occipital, parietal, anterior cingulate, and orbitofrontal areas in the right hemisphere. Metabolic thalamocortical correlations were much more extensive for the mediodorsal and centromedian nuclei whereas structural correlations were more extensive for the pulvinar. Therefore, metabolic and volumetric correlational methods are sensitive to different aspects of interregional relations in the brain and their comparison in the same group of subjects may render complementary and only partially overlapping connectivity information.

Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders.

OBJECTIVE: In patients with autism, behavioral deficits as well as neuroimaging studies of the anterior cingulate cortex suggest ventral rather than dorsal striatal and thalamic abnormalities in structure and function. The authors used imaging studies to map volumetric and metabolic differences within the entire dorsoventral extent of the striatum and thalamus. METHOD: Magnetic resonance imaging (MRI) and positron emission tomography (PET) were used to measure volumes and metabolic activity in the thalamus, caudate, and putamen in 17 patients with autism or Asperger's disorder and 17 age- and sex-matched comparison subjects. Subjects performed a serial verbal learning test during the [(18)F]-fluorodeoxyglucose uptake period. The regions of interest were outlined on contiguous axial MRI slices. After PET/MRI coregistration, region-of-interest coordinates were applied to the PET scan for each individual. Between-group differences in metabolism were assessed by three-dimensional statistical probability mapping. RESULTS: The patients with autism spectrum disorders had greater volumes of the right caudate nucleus than comparison subjects as well as a reversal of the expected left-greater-than-right hemispheric asymmetry. Patients also had lower relative glucose metabolic rates bilaterally in the ventral caudate, putamen, and thalamus. Patients with autism had lower metabolic activity in the ventral thalamus than those with Asperger's disorder, but they did not differ from comparison subjects in metabolic activity in the caudate nucleus. CONCLUSIONS: These results are consistent with a deficit in the anterior cingulate-ventral striatum-anterior thalamic pathway in patients with autism spectrum disorders. The results also suggest an important role for the caudate in helping support working-memory demands.

Thalamus size and outcome in schizophrenia.

The size of the thalamus was assessed in 106 patients with schizophrenia and 42 normal controls using high-resolution magnetic resonance imaging. The thalamus was traced at five axial levels proportionately spaced from dorsal to ventral directions. Patients with schizophrenia had significantly smaller thalamic areas at more ventral levels. Thalamic size was positively associated with frontal lobe and temporal lobe size. The effects were most marked in the patients with poorer clinical outcome (i.e., "Kraepelinian" patients). These findings are consistent with post-mortem and MRI measurement suggesting reduction in volume of the pulvinar, which occupies a large proportion of the ventral thalamus and which has prominent connections to the temporal lobe.

Ventricular enlargement in schizophrenia related to volume reduction of the thalamus, striatum, and superior temporal cortex.

OBJECTIVE: Enlargement of the lateral ventricles is among the most frequently reported macroscopic brain structural changes in schizophrenia, although variable in extent and localization. The authors investigated whether ventricular enlargement is related to regionally specific volume loss. METHOD: High-resolution magnetic resonance imaging scans from 39 patients with schizophrenia were analyzed with deformation-based morphometry, a voxel-wise whole brain morphometric technique. RESULTS: Significant negative correlations with the ventricle-brain ratio were found for voxels in the left and right thalamus and posterior putamen and in the left superior temporal gyrus and insula. CONCLUSIONS: Thalamic shrinkage, especially of medial nuclei and the adjacent striatum and insular cortex, appear to be important contributors to ventricular enlargement in schizophrenia.

Magnetic resonance imaging of mediodorsal, pulvinar, and centromedian nuclei of the thalamus in patients with schizophrenia.

BACKGROUND: Postmortem and magnetic resonance imaging (MRI) data have suggested volume reductions in the mediodorsal (MDN) and pulvinar nuclei (PUL) of the thalamus. The centromedian nucleus (CMN), important in attention and arousal, has not been previously studied with MRI. METHODS: A sample of 41 patients with schizophrenia (32 men and 9 women) and 60 healthy volunteers (45 men and 15 women) underwent assessment with high-resolution 1.2-mm thick anatomical MRI. Images were differentiated to enhance the edges and outline of the whole thalamus, and the MDN, PUL, and CMN were outlined on all slices by a tracer masked to diagnostic status. RESULTS: Significantly smaller volumes of the MDN and PUL were found in patients with schizophrenia compared with controls. Volume relative to brain size was reduced in all 3 nuclei; differences in relative reduction did not differ among the nuclei. The remainder of the thalamic volume (whole thalamus minus the volume of the 3 delineated nuclei) was not different between schizophrenic patients and controls, indicating that the volume reduction was specific to these nuclei. Volume relative to brain size was reduced in all 3 nuclei and remained significant when only patients who had never been exposed to neuroleptic medication (n = 15) were considered. For the MDN, women had larger relative volumes than men among controls, but men had larger volumes than women among schizophrenic patients. CONCLUSIONS: Three association regions of the thalamus that have reciprocal connectivity to schizophrenia-associated regions of the cortex have significantly smaller volumes on MRI in patients with schizophrenia.

Deficient attentional modulation of the startle response in patients with schizotypal personality disorder.

OBJECTIVE: Attentional deficits have been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. The purpose of this study was to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated subjects with schizotypal personality disorder. METHOD: Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed in an acoustic attention-to-prepulse paradigm. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval. RESULTS: The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response. In contrast, the subjects with schizotypal personality disorder failed to show this pattern. CONCLUSIONS: Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.