Chronic Pelvic Pain Syndrome in Men is Associated with Reduction of Relative Gray Matter Volume in the Anterior Cingulate Cortex Compared to Healthy Controls

Although chronic pelvic pain syndrome impairs the life of millions of people worldwide, the exact pathomechanisms involved remain to be elucidated. As with other chronic pain syndromes, the central nervous system may have an important role in chronic pelvic pain syndrome. Thus, we assessed brain alterations associated with abnormal pain processing in patients with chronic pelvic pain syndrome.

Altered response control and anterior cingulate function in attention-deficit/hyperactivity disorder boys

To investigate mechanisms and structures underlying prefrontal response control and inhibition in boys suffering from attention-deficit/hyperactivity disorder (ADHD).

Nerve Injury-Induced Neuropathic Pain Causes Disinhibition of the Anterior Cingulate Cortex

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

Prefrontal Thinning Affects Functional Connectivity and Regional Homogeneity of the Anterior Cingulate Cortex in Depression

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

Functional lateralization of the anterior insula during feedback processing

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.

[Chronic right-sided pain-associated nondermatomal somatosensory deficit following an accident]

We present the case of a 48-year old man who, eight years after an industrial accident, presents with chronic right-sided nondermatomal pain and hypaesthesia to heat and touch. During symmetric peripheral touch functional magnetic resonance imaging revealed hypometabolism in the left thalamus, somatosensory cortex, and anterior cingulate cortex. Pain-associated nondermatomal somatosensory deficits (NDSDs) localizing to one side of the body are a frequent clinical entity, which are often triggered by an accident. The tendency of NDSDs to extend to adjunct ipsilateral body parts and to become chronic points to maladaptive adjustment of pain-processing areas in the central nervous system. Psychological stress prior to or around the triggering event seems an important risk factor for NDSDs.

Semantic memory involvement in the default mode network: a functional neuroimaging study using independent component analysis

The Default Mode Network (DMN) is a higher order functional neural network that displays activation during passive rest and deactivation during many types of cognitive tasks. Accordingly, the DMN is viewed to represent the neural correlate of internally-generated self-referential cognition. This hypothesis implies that the DMN requires the involvement of cognitive processes, like declarative memory. The present study thus examines the spatial and functional convergence of the DMN and the semantic memory system. Using an active block-design functional Magnetic Resonance Imaging (fMRI) paradigm and Independent Component Analysis (ICA), we trace the DMN and fMRI signal changes evoked by semantic, phonological and perceptual decision tasks upon visually-presented words. Our findings show less deactivation during semantic compared to the two non-semantic tasks for the entire DMN unit and within left-hemispheric DMN regions, i.e., the dorsal medial prefrontal cortex, the anterior cingulate cortex, the retrosplenial cortex, the angular gyrus, the middle temporal gyrus and the anterior temporal region, as well as the right cerebellum. These results demonstrate that well-known semantic regions are spatially and functionally involved in the DMN. The present study further supports the hypothesis of the DMN as an internal mentation system that involves declarative memory functions.

Cortico-cortical white matter motor pathway microstructure is related to psychomotor retardation in major depressive disorder

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.

Altered cortico-basal ganglia motor pathways reflect reduced volitional motor activity in schizophrenia

Little is known about the neurobiology of hypokinesia in schizophrenia. Therefore, the aim of this study was to investigate alterations of white matter motor pathways in schizophrenia and to relate our findings to objectively measured motor activity. We examined 21 schizophrenia patients and 21 healthy controls using diffusion tensor imaging and actigraphy. We applied a probabilistic fibre tracking approach to investigate pathways connecting the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the supplementary motor area proper (SMA-proper), the primary motor cortex (M1), the caudate nucleus, the striatum, the pallidum and the thalamus. Schizophrenia patients had lower activity levels than controls. In schizophrenia we found higher probability indices forming part of a bundle of interest (PIBI) in pathways connecting rACC, pre-SMA and SMA-proper as well as in pathways connecting M1 and pre-SMA with caudate nucleus, putamen, pallidum and thalamus and a reduced spatial extension of motor pathways in schizophrenia. There was a positive correlation between PIBI and activity level in the right pre-SMA-pallidum and the left M1-thalamus connection in healthy controls, and in the left pre-SMA-SMA-proper pathway in schizophrenia. Our results point to reduced volitional motor activity and altered motor pathway organisation in schizophrenia. The identified associations between the amount of movement and structural connectivity of motor pathways suggest dysfunction of cortico-basal ganglia pathways in the pathophysiology of hypokinesia in schizophrenia. Schizophrenia patients may use cortical pathways involving the supplementary motor area to compensate for basal ganglia dysfunction.

Neural correlates of antinociception in borderline personality disorder

CONTEXT: A characteristic feature of borderline personality disorder (BPD) is self-injurious behavior in conjunction with stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with BPD, but the neural correlates of antinociceptive mechanisms in BPD are unknown. We predicted that heat stimuli in patients with BPD would activate brain areas concerned with cognitive and emotional evaluation of pain. OBJECTIVE: To assess the psychophysical properties and neural correlates of altered pain processing in patients with BPD. DESIGN: Case-control study. SETTING: A university hospital. PARTICIPANTS: Twelve women with BPD and self-injurious behavior and 12 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and blood oxygen level-dependent functional magnetic resonance imaging during heat stimulation with fixed-temperature heat stimuli and individual-temperature stimuli adjusted for equal subjective pain in all the participants. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes during heat pain stimulation. RESULTS: Patients with BPD had higher pain thresholds and smaller overall volumes of activity than controls in response to identical heat stimuli. When the stimulus temperature was individually adjusted for equal subjective pain level, overall volumes of activity were similar, although regional patterns differed significantly. Patient response was greater in the dorsolateral prefrontal cortex and smaller in the posterior parietal cortex. Pain also produced neural deactivation in the perigenual anterior cingulate gyrus and the amygdala in patients with BPD. CONCLUSION: The interaction between increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala is associated with an antinociceptive mechanism in patients with BPD.

Cell-type specific alterations of cortical interneurons in schizophrenic patients

In the human brain, cortical GABAergic interneurons represent an important population of local circuit neurons responsible for the intrinsic modulation of neuronal information and have been supposed to be involved in the pathophysiology of schizophrenia. We conducted a quantitative study on the differentiated three-dimensional morphological structure of two types of parvalbumin-immunoreactive interneurons in the anterior cingulate cortex (ACC) of schizophrenic patients versus controls. While type A interneurons ('small bipolar cells') showed a significant reduction of their soma size in schizophrenics, type B interneurons ('small multipolar cells') of schizophrenic patients exhibited a marked decrease in the extent of their dendritic system. These results further support the assumption of a considerable significance of the ACC, an important limbic relay centre, for the etiopathogenesis of schizophrenic psychoses.

Increased NoGo-anteriorisation in first-episode schizophrenia patients during Continuous Performance Test

OBJECTIVE: NoGo-stimuli during a Continuous Performance Test (CPT) activate prefrontal brain structures such as the anterior cingulate gyrus and lead to an anteriorisation of the positive electrical field of the NoGo-P300 relative to the Go-P300, so-called NoGo-anteriorisation (NGA). NGA during CPT is regarded as a neurophysiological standard index for cognitive response control. While it is known that patients with chronic schizophrenia exhibit a significant reduction in NGA, it is unclear whether this also occurs in patients undergoing their first-episode. Thus, the aim of the present study was to determine NGA in a group of patients with first-episode schizophrenia by utilizing a CPT paradigm. METHODS: Eighteen patients with first-episode schizophrenia and 18 matched healthy subjects were investigated electrophysiologically during a cued CPT, and the parameters of the Go- and NoGo-P300 were determined using microstate analysis. Low resolution tomography analysis (LORETA) was used for source determination. RESULTS: Due to a more posterior Go- and a more anterior NoGo-centroid, NGA was greater in patients than in healthy controls. LORETA indicated the same sources for both groups after Go-stimuli, but a more anterior source in patients after NoGo-stimuli. In patients P300-amplitude responses to both Go- and NoGo-stimuli were decreased, and P300-latency to NoGo-stimuli was increased. After the Go-stimuli false reactions and reaction times were increased in patients. CONCLUSIONS: Attention was reduced in patients with first-episode schizophrenia, as indicated by more false reactions, prolongation of reaction time, P300-latencies and by a decrease in P300-amplitude. Significantly however, the NGA and prefrontal LORETA-sources indicate intact prefrontal brain structures in first-episode schizophrenia patients. Previously described changes in this indicator of prefrontal function may be related to a progressive decay in chronic schizophrenia. SIGNIFICANCE: The results support the idea of a possible new biological marker of first episode psychosis, which may be a useful parameter for the longitudinal measurement of changing prefrontal brain function in a single schizophrenia patient.

Nondermatomal somatosensory deficits in patients with chronic pain disorder: clinical findings and hypometabolic pattern in FDG-PET

Patients with chronic pain disorders often show somatosensory disturbances that are considered to be functional. This paper aims at a more precise clinical description and at a documentation of functional neuroimaging correlates of this phenomenon. We examined 30 consecutive patients with unilaterally accentuated chronic pain not explained by persistent peripheral tissue damage and ipsilateral somatosensory disturbances including upper and lower extremities and trunk. The patients were assessed clinically and with conventional brain CT or MRI scan. In the last 11 patients functional neuroimaging was carried out (18-fluordeoxyglucose positron emission tomography=FDG-PET). Depressive symptoms were assessed with the Hamilton depression scale (HAMD-17) and pain intensity was rated with a visual analogue scale for pain (VAS). All patients suffered from mild to moderate depressive symptoms. All patients had experienced a prolonged antecedent phase of severe emotional distress; most of them remembered a "trigger episode of somatic pain" on the affected side. Somatosensory deficits were a replicable hyposensitivity to touch and heat perception of nondermatomal distribution. Conventional imaging procedures (brain CT or MRI scans) showed no structural changes. However, in 11 patients functional imaging with FDG-PET showed a significant hypometabolic pattern of changes in cortical and subcortical areas, mainly in the post-central gyrus, posterior insula, putamen, and anterior cingulate cortex. In summary, pain-related nondermatomal somatosensory deficits (NDSDs) are a phenomenon involving biological as well as psychosocial factors with replicable neuroperceptive clinical findings and a complex neurodysfunctional pattern in the FDG-PET.

Diminished prefrontal brain function in adults with psychopathology in childhood related to attention deficit hyperactivity disorder

The aim of the present study was to investigate prefrontal brain function and cognitive response control in patients with personality disorders who either suffered or did not suffer from psychopathology related to attention deficit hyperactivity disorder (ADHD) during childhood. For this purpose, 36 psychiatric out-patients with personality disorders--24 of whom showed ADHD-related psychopathology during childhood assessed by the German short form of the Wender Utah Rating Scale--and 24 healthy controls were investigated electrophysiologically by means of a cued Go-NoGo task (Continuous Performance Test). Topographical analyses were conducted to individually quantify the NoGo anteriorisation (NGA), a neurophysiological correlate of prefrontal response control that has been suggested to reflect activation of the anterior cingulate cortex. ADHD patients exhibited a significantly reduced mean NGA and diminished amplitudes of the Global Field Power, as well as a reduced increase of fronto-central P300 amplitudes, in NoGo-trials compared with the healthy controls, whereas patients with personality disorders alone did not differ from the control group in any of the electrophysiological parameters. The results indicate that ADHD-related psychopathology is associated with prefrontal brain dysfunction, probably related to processes of response inhibition and/or cognitive response control.