While much evidence indicates that reaction time increases as a function of computational load in many cognitive tasks, quantification of changes in neural activity related to increasing demand of cognitive control has rarely been attempted. In this functional magnetic resonance imaging study, we used a majority function task to quantify the effect of computational load on brain activation, reflecting the mental processes instantiated by cognitive control under conditions of uncertainty. We found that the activation of the fronto-parieto-cingulate (FPC) system as well as the deactivation of the anticorrelated default mode network varied parametrically as a function of information entropy, estimated with an information theoretic model. The current findings suggest that activity changes in the dynamic networks of the brain (especially the FPC system) track with information entropy or uncertainty, rather than only conflict or other commonly proposed targets of cognitive control.
Cognitive control; computational load; entropy; fMRI; information theory
The corpus callosum has been implicated as a region of dysfunctional connectivity in schizophrenia, but the association between age and callosal pathology is unclear. Magnetic resonance imaging (MRI) and diffusion-tensor imaging (DTI) were performed on adults (n=34) and adolescents (n=17) with schizophrenia and adult (n=33) and adolescent (n=15) age- and sex-matched healthy controls. The corpus callosum was manually traced on each participant’s MRI, and the DTI scan was co-registered to the MRI. The corpus callosum was divided into five anteroposterior segments. Area and anisotropy were calculated for each segment. Both patient groups demonstrated reduced callosal anisotropy; however, the adolescents exhibited reductions mostly in anterior regions while the reductions were more prominent in posterior regions of the adults. The adolescent patients showed greater decreases in absolute area as compared with the adult patients, particularly in the anterior segments. However, the adults showed greater reductions when area was considered relative to whole brain white matter volume. Our results suggest that the initial stages of the illness are characterized by deficiencies in frontal connections, and the chronic phase is characterized by deficits in the posterior corpus callosum; or, alternatively, adolescent-onset schizophrenia may represent a different or more severe form of the illness.
diffusion tensor imaging; white matter; schizophrenia spectrum; MRI; magnetic resonance imaging
Prior diffusion tensor imaging (DTI) studies examining schizotypal personality disorder (SPD) and schizophrenia, separately have shown that compared with healthy controls (HCs), patients show frontotemporal white matter (WM) abnormalities. This is the first DTI study to directly compare WM tract coherence with tractography and fractional anisotropy (FA) across the schizophrenia spectrum in a large sample of demographically matched HCs (n = 55), medication-naive SPD patients (n = 49), and unmedicated/never-medicated schizophrenia patients (n = 22) to determine whether (a) frontal-striatal-temporal WM tract abnormalities in schizophrenia are similar to, or distinct from those observed in SPD; and (b) WM tract abnormalities are associated with clinical symptom severity indicating a common underlying pathology across the spectrum. Compared with both the HC and SPD groups, schizophrenia patients showed WM abnormalities, as indexed by lower FA in the temporal lobe (inferior longitudinal fasciculus) and cingulum regions. SPD patients showed lower FA in the corpus callosum genu compared with the HC group, but this regional abnormality was more widespread in schizophrenia patients. Across the schizophrenia spectrum, greater WM disruptions were associated with greater symptom severity. Overall, frontal-striatal-temporal WM dysconnectivity is attenuated in SPD compared with schizophrenia patients and may mitigate the emergence of psychosis.
DTI; MRI; schizotypal personality disorder; schizophrenia; psychosis; white matter; genu; cingulum; inferior longitudinal fasciculus
Siever and Davis’ (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT.
Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale.
fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale).
These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity—part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation.
Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI
Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer’s disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer’s disease.
Alzheimer’s disease; biomarker; long-term clinical TBI phenotypes; mild cognitive impairment; monocyte chemotactic protein-1; plasma; traumatic brain injury
Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women between the ages of 18 and 79 (mean = 39.83, SD = 15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range = 13–38, SD = 6). Patients were divided into an acute subgroup (duration ≤ 3 years, n = 25), and a chronic subgroup (duration > 3 years, n = 64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean = 35.77, SD = 18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness.
Schizophrenia; White Matter; Diffusion Tensor Imaging; Anisotropy; Brodmann Areas; Age
Schizotypal personality disorder (SPD) individuals and borderline personality disorder (BPD) individuals have been reported to show neuropsychological impairments and abnormalities in brain structure. However, relationships between neuropsychological function and brain structure in these groups are not well understood. This study compared visual-spatial working memory (SWM) and its associations with dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) gray matter volume in 18 unmedicated SPD patients with no BPD traits, 18 unmedicated BPD patients with no SPD traits, and 16 healthy controls (HC). Results showed impaired SWM in SPD but not BPD, compared with HC. Moreover, among the HC group, but not SPD patients, better SWM performance was associated with larger VLPFC (BA44/45) gray matter volume (Fisher's Z p-values<0.05). Findings suggest spatial working memory impairments may be a core neuropsychological deficit specific to SPD patients and highlight the role of VLPFC subcomponents in normal and dysfunctional memory performance.
working memory; borderline personality disorder; schizotypal personality disorder; dorsolateral prefrontal cortex; ventrolateral prefrontal cortex; MRI
The anterior cingulate cortex (ACC) and frontoinsular cortex (FI) have been implicated in processing information across a variety of domains, including those related to attention and emotion. However, their role in rapid information processing, for example, as required for timely processing of salient stimuli, is not well understood. Here, we designed an emotional face priming paradigm and employed functional magnetic resonance imaging to elucidate their role in these mechanisms. Target faces with either neutral or fearful emotion were briefly primed by either neutral or fearful faces, or by blank ovals. Activation in the pregenual ACC and the FI, together with other regions, such as the amygdala, were preferentially activated in response to fearful face priming, suggesting that these regions are involved in the rapid processing of salient facial emotional information.
anterior cingulate cortex; emotion; fMRI; frontoinsular cortex; priming
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
The role of the prefrontal cortex as an executive oversight of posterior brain regions raises the question of the extent to which the anterior regions of the brain interconnect with the posterior regions. The aim of this study is to test the complexity of rostral white matter tracts, which connect anterior and posterior brain regions, in comparison to caudal white matter tracts and the corpus callosum. Diffusion tensor imaging (DTI) is a modality that measures fractional anisotropy (FA). Higher white matter complexity could result in a decrease of FA, possibly through denser intersection of fiber tracts. DTI was used to determine regional FA in 9 healthy bonnet macaques (Macaca radiata). Four regions of interest were included: anterior and posterior limbs of the internal capsule, the occipital lobe white matter, and the corpus callosum. FA of the anterior limbs of the internal capsule was lowest compared to all other regions of interest (Newman-Keuls (N-K); p < 0.0001), whereas FA of the corpus callosum was highest (N-K; p < 0.0001). The posterior limbs of the internal capsule and the occipital white matter were not distinguishable but exhibited intermediate FA in comparison to the former (N-K; p < 0.0001) and the latter (N-K; p < 0.0001). The current study demonstrates that FA, a measure of white matter complexity, can vary markedly as a function of region of interest. Moreover, validation of these findings using neurohistological studies and replication in human samples appears warranted.
Diffusion tensor imaging; fractional anisotropy; white matter; gap junctions; nonhuman primates; neuroimaging; neurodevelopment
Persistent depressive symptoms after acute coronary syndrome (ACS) are common and increase the risk of recurrent cardiac events and mortality. However, the neurobiological correlates of post-ACS depressive symptoms have not yet been studied.
Three months after ACS, 22 patients were scanned for the presence of cerebral deep white matter changes and microstructural abnormalities in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. We used the Coffey Rating Scale of deep white matter changes and measures of fractional anisotropy derived from diffusion tensor imaging. Patients also completed the Beck Depression Inventory, and the number of cardiovascular comorbidities as well as modifiable cardiovascular risk factors were assessed.
Controlling for cardiovascular comorbidity, depressive symptom severity at 3 months was negatively related to fractional anisotropy in the ACC (r = −0.72, p < 0.001), but this association disappeared when controlling for cardiovascular risk factors (p = 0.21). In comparison to patients who were non-depressed at 3 months after hospitalization (n = 14), patients with persistent depressive symptoms (n = 8) exhibited more advanced deep white matter changes overall (p < 0.02), but not when controlling for cardiovascular comorbidity. Persistently depressed patients also had lower fractional anisotropy in the ACC (p < 0.05), but this effect disappeared when controlling for modifiable cardiovascular risk factors.
This study provides the first evidence that persistent depressive symptoms after ACS are associated with vascular brain changes. Longitudinal studies are needed to determine whether depressive symptoms precede these changes or vice versa.
Depression; Acute coronary syndrome; White matter lesions; Diffusion tensor imaging
Background and Purpose
To examine the neurophysiological basis for the pronounced differences in hyperactivity and impulsiveness that distinguish the Predominantly Inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD-PI) from the combined type of the disorder (ADHD-C).
Event-related brain responses to a go/no-go test of inhibitory control were measured with functional magnetic resonance imaging (fMRI) in 11 children with ADHD-C and nine children with ADHD-PI, aged 7 to 13 years, who were matched for age, sex, and intelligence.
There were no significant group differences in task performance. Children with ADHD-C and ADHD-PI activated overlapping regions of right inferior frontal gyrus, right superior temporal lobe, and left inferior parietal lobe during inhibitory control. However, the magnitude of the activation in the temporal and parietal regions, as well as in the bilateral middle frontal gyrus, was greater in children with ADHD-PI than those with ADHD-C. Conversely, children with ADHD-C activated bilateral medial occipital lobe to a greater extent than children with ADHD-PI.
The results provide preliminary evidence that phenotypic differences between the ADHD-C and ADHD-PI subtypes are associated with differential activation of regions that have previously been implicated in the pathophysiology of ADHD and are thought to mediate executive and attentional processes.
Superior temporal gyrus (STG/BA22) volume is reduced in schizophrenia and to a milder degree in schizotypal personality disorder (SPD), representing a less severe disorder in the schizophrenia-spectrum. SPD and Borderline personality disorder (BPD) are severe personality disorders characterized by social and cognitive dysfunction. However, while SPD is characterized by social withdrawal/anhedonia, BPD is marked by hyper-reactivity to interpersonal stimuli and hyper-emotionality. This is the first morphometric study to directly compare SPD and BPD patients in temporal volume.
We compared three age-gender- and education-matched groups: 27 unmedicated SPD individuals with no BPD traits, 52 unmedicated BPD individuals with no SPD traits, and 45 healthy controls. We examined gray matter volume of frontal and temporal lobe Brodmann areas (BAs), and dorsal/ventral amygdala from 3T magnetic resonance imaging.
In the STG, an auditory association area reported to be dysfunctional in SPD and BPD, the SPD patients had significantly smaller volume than healthy controls and BPD patients. No group differences were found between BPD patients and controls. Smaller BA22 volume was associated with greater symptom severity in SPD patients. Reduced STG volume may be an important endophenotype for schizophrenia-spectrum disorders. SPD is distinct from BPD in terms of STG volume abnormalities which may reflect different underlying pathophysiological mechanisms and could help discriminate between them.
Schizotypal personality disorder; Borderline personality disorder; Schizophrenia; MRI; Brodmann area 22; Auditory cortex
Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self-regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either process alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event-related functional magnetic resonance imaging (fMRI) and a go/no-go task that independently manipulated the context preceding no-go trials (i.e., number of go trials) and the valence (i.e., happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no-go trials preceded by increasing numbers of go trials and associated activation for correct no-go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence-dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence-dependent variations in the quadratic trend in no-go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively.
fMRI; motor inhibition; emotion; response context; prefrontal cortex; amygdala
White matter abnormalities have been detected using diffusion tensor imaging (DTI) in a variety of locations in the brains of patients with schizophrenia. Studies that included first-episode patients report less severe or no abnormalities but more pronounced deficits in chronic patients. Here we investigated these abnormalities in a very large group of schizophrenia that had both large ranges in age and in duration of illness. A highly reproducible DTI-tractography technique was used to quantify the fractional anisotropy of the genu and splenium of the corpus callosum as well as the bilateral pyramidal tracts. We found a decline in fractional anisotropy that correlated with the duration of illness in the genu and splenium of the corpus callosum but not in the pyramidal tracts. The findings suggest that there are white matter tract-specific degenerative mechanisms that may be present at the point of illness onset and that progress throughout the illness.
Diffusion Tensor Imaging; Schizophrenia; Fiber Tracking
Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eye-blink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrate frontal-striatal-thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST-circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD-response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions--dorsolateral prefrontal cortex (Brodmann areas 46,9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus (MDN). In contrast, schizophrenia patients failed to show differential BOLD responses in FST-circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST-circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST-circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.
dorsolateral prefrontal cortex; caudate nucleus; putamen; thalamus; mediodorsal nucleus; fMRI; schizophrenia; schizotypal personality disorder; startle; prepulse inhibition; attention; sensorimotor gating
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation.
12 unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC.
The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC.
This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).
borderline personality disorder; frontolimbic; amygdala; anterior cingulate cortex; gray matter; voxel-based morphometry
Clinical hallmarks of borderline personality disorder (BPD) include social and emotional dysregulation. We tested a model of frontolimbic dysfunction in facial emotion processing in BPD. Groups of 12 unmedicated adults with BPD by DSM-IV and 12 demographically-matched healthy controls (HC) viewed facial expressions (Conditions) of neutral emotion, fear and anger, and made gender discriminations during rapid event-related functional magnetic resonance imaging (fMRI). Analysis of variance of Region of Interest signal change revealed a statistically significant effect of the Group-by-Region-by-Condition interaction. This was due to the BPD group exhibiting a significantly larger magnitude of deactivation (relative to HC) in the bilateral rostral/subgenual anterior cingulate cortex (ACC) to fear and in the left ACC to fear minus neutral; and significantly greater activation in the right amygdala to fear minus neutral. There were no significant between-group differences in ROI signal change in response to anger. In voxel-wise analyses constrained within these ROIs, the BPD group exhibited significant changes in the fear minus neutral contrast, with relatively less activation in the bilateral rostral/subgenual ACC, and greater activation in the right amygdala. In the anger minus neutral contrast this pattern was reversed, with the BPD group showing greater activation in the bilateral rostral/subgenual ACC and less activation in the bilateral amygdala. We conclude that adults with BPD exhibit changes in fronto-limbic activity in the processing of fear stimuli, with exaggerated amygdala response and impaired emotion-modulation of ACC activity. The neural substrates underlying processing of anger may also be altered. These changes may represent an expression of the volumetric and serotonergic deficits observed in these brain areas in BPD.
anterior cingulate cortex; amygdala; fear; anger; functional magnetic resonance imaging
Evidence suggests that white matter integrity may play an underlying pathophysiological role in schizophrenia. N-acetylaspartate (NAA), as measured by Magnetic Resonance Spectroscopy (MRS), is a neuronal marker and is decreased in white matter lesions and regions of axonal loss. It has also been found to be reduced in the prefrontal and temporal regions in patients with schizophrenia. Diffusion Tensor Imaging (DTI) allows one to measure the orientations of axonal tracts as well as the coherence of axonal bundles. DTI is thus sensitive to demyelination and other structural abnormalities. DTI has also shown abnormalities in these regions.
MRS and DTI were obtained on 42 healthy subjects and 40 subjects with schizophrenia. The data was analyzed using regions of interests in the Dorso-Lateral Prefrontal white matter, Medial Temporal white matter and Occipital white matter using both imaging modalities.
NAA was significantly reduced in the patient population in the Medial Temporal regions. DTI anisotropy indices were also reduced in the same Medial Temporal regions. NAA and DTI-anisotropy indices were also correlated in the left medial temporal region.
Our results implicate defects in the medial temporal white matter in patients with schizophrenia. Moreover, MRS and DTI are complementary modalities for the study of white matter disruptions in patients with schizophrenia.