Psychiatric comorbidities in temporal lobe epilepsy: possible relationships between psychotic disorders and involvement of limbic circuits

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis

Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

Diskriminationsleistungen des Schmerzsinnes und deren Korrelate in Laser-evozierten Potenzialen

In der vorliegenden Arbeit sollte die Fähigkeit untersucht werden, Schmerzreize auf der Haut zu lokalisieren und deren Intensität zu differenzieren. Während dieser Diskriminationsaufgaben wurde die elektrische Aktivität des Gehirns gemessen.Traditionell werden dem nozizeptiven System nur geringe Diskriminationsleistungen zugeschrieben. In einer ersten Versuchsreihe sollten daher die räumlichen Diskriminationsleistungen für nozizeptive und taktile Reize verglichen werden. Auf dem Handrücken konnten schmerzhaft Laserhitzereize genauso gut lokalisiert werden wie taktile Reize (von-Frey-Haar). Nur ein mechanischer Nadelreiz, der taktiles und nozizeptives System koaktivierte, konnte noch besser lokalisiert werden. In der zweiten Versuchsreihe wurden während verschiedener Diskriminationsaufgaben (räumliche Diskrimination, Intensitätsdiskrimination) und einer Ablenkungsaufgabe (mentale Arithmetik) Laser-evozierte Potenziale von der Kopfhaut abgeleitet. Eine Dipolquellenanalyse zeigte als erstes eine Aktivierung des frontalen Operculums, entsprechend einem zur Zeit noch umstrittenen Projektionsgebiet eines nozizeptiven Thalamuskerns (VMpo), gefolgt vom primären somatosensorische Kortex (SI) und dem Gyrus cinguli. Im Gegensatz zum taktilen System wurde SI signifikant später aktiviert als SII (bzw. das Operculum). Die Diskriminationsaufgaben erhöhten die Aktivität aller Quellen im Vergleich zu der Ablenkungsbedingung. Dies konnte sogar für die früheste Quelle im Operculum gezeigt werden.Die frühe sensorisch-diskriminative Komponente der Schmerzverarbeitung im Operculum zeigte eine Hemisphärenasymmetrie, mit stärkerer Aktivierung der linken Hemisphäre unabhängig von der Stimulationsseite.

Studio neuroradiologico (morfologico e funzionale) nei pazienti con Epilessia Frontale Notturna

L'epilessia frontale notturna (EFN) è caratterizzata da crisi motorie che insorgono durante il sonno. Scopo del progetto è studiare le cause fisiopatologiche e morfo-funzionali che sottendono ai fenomeni motori nei pazienti con EFN e identificare alterazioni strutturali e/o metaboliche mediante tecniche avanzate di Risonanza Magnetica (RM). Abbiamo raccolto una casistica di pazienti con EFN afferenti al Centro Epilessia e dei Disturbi del Sonno del Dipartimento di Scienze Neurologiche, Università di Bologna. Ad ogni paziente è stato associato un controllo sano di età (± 5 anni) e sesso corrispondente. Tutti sono stati studiati mediante tecniche avanzate di RM comprendenti Spettroscopia del protone (1H-MRS), Tensore di diffusione ed imaging 3D ad alta risoluzione per analisi morfometriche. In particolare, la 1H-MRS è stata effettuata su due volumi di interesse localizzati nei talami e nel giro del cingolo anteriore. Sono stati inclusi nell’analisi finale 19 pazienti (7 M), età media 34 anni (range 19-50) e 14 controlli (6 M) età media 30 anni (range 19-40). A livello del cingolo anteriore il rapporto della concentrazione di N-Acetil-Aspartato rispetto alla Creatina (NAA/Cr) è risultato significativamente ridotto nei pazienti rispetto ai controlli (p=0,021). Relativamente all’analisi di correlazione, l'analisi tramite modelli di regressione multipla ha evidenziato che il rapporto NAA/Cr nel cingolo anteriore nei pazienti correlava con la frequenza delle crisi (p=0,048), essendo minore nei pazienti con crisi plurisettimanali/plurigiornaliere. Per interpretare il dato ottenuto è possibile solo fare delle ipotesi. L’NAA è un marker di integrità, densità e funzionalità neuronale. E’ possibile che alla base della EFN ci siano alterazioni metaboliche tessutali in precise strutture come il giro del cingolo anteriore. Questo apre nuove possibilità sull’utilizzo di strumenti di indagine basati sull’analisi di biosegnali, per caratterizzare aree coinvolte nella genesi della EFN ancora largamente sconosciute e chiarire ulteriormente l’eziologia di questo tipo di epilessia.

[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.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

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.

Electroencephalographic topography measures of experienced utility

Economic theory distinguishes two concepts of utility: decision utility, objectively quantifiable by choices, and experienced utility, referring to the satisfaction by an obtainment. To date, experienced utility is typically measured with subjective ratings. This study intended to quantify experienced utility by global levels of neuronal activity. Neuronal activity was measured by means of electroencephalographic (EEG) responses to gain and omission of graded monetary rewards at the level of the EEG topography in human subjects. A novel analysis approach allowed approximating psychophysiological value functions for the experienced utility of monetary rewards. In addition, we identified the time windows of the event-related potentials (ERP) and the respective intracortical sources, in which variations in neuronal activity were significantly related to the value or valence of outcomes. Results indicate that value functions of experienced utility and regret disproportionally increase with monetary value, and thus contradict the compressing value functions of decision utility. The temporal pattern of outcome evaluation suggests an initial (∼250 ms) coarse evaluation regarding the valence, concurrent with a finer-grained evaluation of the value of gained rewards, whereas the evaluation of the value of omitted rewards emerges later. We hypothesize that this temporal double dissociation is explained by reward prediction errors. Finally, a late, yet unreported, reward-sensitive ERP topography (∼500 ms) was identified. The sources of these topographical covariations are estimated in the ventromedial prefrontal cortex, the medial frontal gyrus, the anterior and posterior cingulate cortex and the hippocampus/amygdala. The results provide important new evidence regarding “how,” “when,” and “where” the brain evaluates outcomes with different hedonic impact.

Neural correlates of sleepiness induced by catecholamine depletion

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

Dopaminergic modulation of the human reward system: a placebo-controlled dopamine depletion fMRI study

Reward related behaviour is linked to dopaminergic neurotransmission. Our aim was to gain insight into dopaminergic involvement in the human reward system. Combining functional magnetic resonance imaging with dopaminergic depletion by α-methylparatyrosine we measured dopamine-related brain activity in 10 healthy volunteers. In addition to blood-oxygen-level-dependent (BOLD) contrast we assessed the effect of dopaminergic depletion on prolactin response, peripheral markers for dopamine and norepinephrine. In the placebo condition we found increased activation in the left caudate and left cingulate gyrus during anticipation of reward. In the α-methylparatyrosine condition there was no significant brain activation during anticipation of reward or loss. In α-methylparatyrosine, anticipation of reward vs. loss increased activation in the right insula, left frontal, right parietal cortices and right cingulate gyrus. Comparing placebo versus α-methylparatyrosine showed increased activation in the left cingulate gyrus during anticipation of reward and the left medial frontal gyrus during anticipation of loss. α-methylparatyrosine reduced levels of dopamine in urine and homovanillic acid in plasma and increased prolactin. No significant effect of α-methylparatyrosine was found on norepinephrine markers. Our findings implicate distinct patterns of BOLD underlying reward processing following dopamine depletion, suggesting a role of dopaminergic neurotransmission for anticipation of monetary reward.

Serotonin transporter genotype differentially modulates neural responses to emotional words following tryptophan depletion in patients recovered from depression and healthy volunteers

Previous studies have suggested that polymorphism in the serotonin transporter gene (5-HTTLPR) influences responses to serotonergic manipulation, with opposite effects in patients recovered from depression (rMDD) and controls. Here we sought to clarify the neurocognitive mechanisms underpinning these surprising results. Twenty controls and 23 rMDD subjects completed the study; functional magnetic resonance imaging (fMRI) and genotype data were available for 17 rMDD subjects and 16 controls. Following tryptophan or sham depletion, subjects performed an emotional-processing task during fMRI. Although no genotype effects on mood were identified, significant genotype(∗)diagnosis(∗)depletion interactions were observed in the hippocampus and subgenual cingulate in response to emotionally valenced words. In both regions, tryptophan depletion increased responses to negative words, relative to positive words, in high-expression controls, previously identified as being at low-risk for mood change following this procedure. By contrast, in higher-risk low-expression controls and high-expression rMDD subjects, tryptophan depletion had the opposite effect. Increased neural responses to negative words following tryptophan depletion may reflect an adaptive mechanism promoting resilience to mood change following perturbation of the serotonin system, which is reversed in sub-groups vulnerable to developing depressive symptoms. However, this interpretation is complicated by our failure to replicate previous findings of increased negative mood following tryptophan depletion.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

Widespread grey matter changes and hemodynamic correlates to interictal epileptiform discharges in pharmacoresistant mesial temporal epilepsy

Focal onset epilepsies most often occur in the temporal lobes. To improve diagnosis and therapy of patients suffering from pharmacoresistant temporal lobe epilepsy it is highly important to better understand the underlying functional and structural networks. In mesial temporal lobe epilepsy (MTLE) widespread functional networks are involved in seizure generation and propagation. In this study we have analyzed the spatial distribution of hemodynamic correlates (HC) to interictal epileptiform discharges on simultaneous EEG/fMRI recordings and relative grey matter volume (rGMV) reductions in 10 patients with MTLE. HC occurred beyond the seizure onset zone in the hippocampus, in the ipsilateral insular/operculum, temporo-polar and lateral neocortex, cerebellum, along the central sulcus and bilaterally in the cingulate gyrus. rGMV reductions were detected in the middle temporal gyrus, inferior temporal gyrus and uncus to the hippocampus, the insula, the posterior cingulate and the anterior lobe of the cerebellum. Overlaps between HC and decreased rGMV were detected along the mesolimbic network ipsilateral to the seizure onset zone. We conclude that interictal epileptic activity in MTLE induces widespread metabolic changes in functional networks involved in MTLE seizure activity. These functional networks are spatially overlapping with areas that show a reduction in relative grey matter volumes.

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.