Age-dependent increase of perineuronal nets in the human hippocampus and precocious aging in epilepsy.

OBJECTIVE: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. METHODS: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. RESULTS: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). SIGNIFICANCE: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. PLAIN LANGUAGE SUMMARY: "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.

Face processing and efficient recognition of facial expressions are impaired following right but not left anteromedial temporal lobe resections: Behavioral and fMRI evidence.

Anteromedial temporal lobe structures seem to support processing of faces and facial expressions. However, differential effects of unilateral left or right temporal lobe resections (TLR) on face processing, recognition of facial expressions, and on BOLD response to faces in intact brain areas are not yet fully understood. Therefore, we compared 39 patients with unilateral TLR (18 left, 21 right) and 20 healthy controls regarding recognition of facial identity and emotional facial expressions as well as BOLD response to fearful and neutral faces. We found impaired recognition of facial identity following right TLR, which was paralleled by reduced BOLD response to faces irrespective of expression in the right fusiform and lingual gyrus in postsurgical fMRI. Right TLR patients also exhibited subtle impairments of emotion recognition as they needed higher intensity of facial expressions for correct responses in a morphing task. Accuracy of emotion recognition and subjective appraisals of facial expressions did not differ between groups. There was no specific reduction of BOLD response to fearful versus neutral faces in either patient group. Our results underline the specific role of the right anteromedial temporal lobe in processing of faces and facial expressions by showing changes in face processing following right TLR in behavioral as well as imaging data.

Effects of left and right medial temporal lobe resections on hemodynamic correlates of negative and neutral scene processing.

Enhanced visual cortex activation by negative compared to neutral stimuli is often attributed to modulating feedback from the amygdala, but evidence from lesion studies is scarce, particularly regarding differential effects of left and right amygdala lesions. Therefore, we compared visual cortex activation by negative and neutral complex scenes in an event-related fMRI study between 40 patients with unilateral temporal lobe resection (TLR; 19 left [lTLR], 21 right [rTLR]), including the amygdala, and 20 healthy controls. We found preserved hemodynamic emotion modulation of visual cortex in rTLR patients and only subtle reductions in lTLR patients. In contrast, rTLR patients showed a significant decrease in visual cortex activation irrespective of picture content. In line with this, healthy controls showed small emotional modulation of the left amygdala only, while their right amygdala was activated equally by negative and neutral pictures. Correlations of activation in amygdala and visual cortex were observed for both negative and neutral pictures in the controls. In both patient groups, this relationship was attenuated ipsilateral to the TLR. Our results support the notion of reentrant mechanisms between amygdala and visual cortex and suggest laterality differences in their emotion-specificity. While right medial temporal lobe structures including the amygdala seem to influence visual processing in general, the left medial temporal lobe appears to contribute specifically to emotion processing. Still, effects of left TLR on visual emotion processing were relatively subtle. Therefore, hemodynamic correlates of visual emotion processing are likely supported by a distributed cerebral network, challenging an amygdalocentric view of emotion processing.

Right medial temporal lobe structures particularly impact early stages of affective picture processing.

Human vision prioritizes emotional stimuli. This is reflected in stronger electrocortical activation in response to emotional than neutral stimuli, measurable on the surface of the head. Feedback projections from brain structures deep within the medial temporal lobes (mTLs), in particular the amygdala, are thought to give rise to this phenomenon, although causal evidence is rare. Given the many pathways involved in visual processing, the influence of mTL structures could be restricted to specific time windows. Therefore, we delineate the temporal dynamics of the impact of right mTL structures on affective picture processing, investigating event-related potentials (ERPs) in 19 patients (10 female) with right mTL resections and 19 individually matched healthy participants, while they viewed negative and neutral scenes. Groups differed significantly at early- and mid-latency processing stages. Patients with right mTL resection, unlike controls, showed no (P1: 90-140 ms) or marginal (N1: 170-220 ms) emotion modulation. At mid-latency (early posterior negativity: 220-370 ms), emotion modulation over the ipsi-resectional right hemisphere was smaller in patients than in controls, but groups did not differ over the left hemisphere. During late parietal positivities (400-650 ms and 650-900 ms), both groups had similar emotion modulation. Our results demonstrate that right mTL structures attenuate particularly early processing of affectively negative scenes. This is theoretically consistent with an initial amygdala-dependent feedforward sweep in visual emotion processing whose absence is successively compensated. Findings specify the impact of right mTL structures on emotional picture processing and highlight the value of time-resolved measures in affective neuroscience.

Negative content enhances stimulus-specific cerebral activity during free viewing of pictures, faces, and words.

Negative visual stimuli have been found to elicit stronger brain activation than do neutral stimuli. Such emotion effects have been shown for pictures, faces, and words alike, but the literature suggests stimulus-specific differences regarding locus and lateralization of the activity. In the current functional magnetic resonance imaging study, we directly compared brain responses to passively viewed negative and neutral pictures of complex scenes, faces, and words (nouns) in 43 healthy participants (21 males) varying in age and demographic background. Both negative pictures and faces activated the extrastriate visual cortices of both hemispheres more strongly than neutral ones, but effects were larger and extended more dorsally for pictures, whereas negative faces additionally activated the superior temporal sulci. Negative words differentially activated typical higher-level language processing areas such as the left inferior frontal and angular gyrus. There were small emotion effects in the amygdala for faces and words, which were both lateralized to the left hemisphere. Although pictures elicited overall the strongest amygdala activity, amygdala response to negative pictures was not significantly stronger than to neutral ones. Across stimulus types, emotion effects converged in the left anterior insula. No gender effects were apparent, but age had a small, stimulus-specific impact on emotion processing. Our study specifies similarities and differences in effects of negative emotional content on the processing of different types of stimuli, indicating that brain response to negative stimuli is specifically enhanced in areas involved in processing of the respective stimulus type in general and converges across stimuli in the left anterior insula.