Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Exploring the relationship between perceived loneliness and subjective cognitive decline in older individuals.

OBJECTIVE: Loneliness has been associated to a greater risk of cognitive decline and dementia in older individuals. However, evidence on whether this association also exists for older individuals who complain of cognitive problems is limited. We conducted a survey to examine the association between subjective cognitive decline in the working memory domain, perceived loneliness, depression, anxiety, and stress in older individuals with different profiles. METHODS: A total of 302 healthy, old individuals completed 3 questionnaires to assess subjective cognitive problems in attention, executive functions, storage, depression, anxiety, stress, and perceived loneliness. RESULTS: We conducted a cluster analysis and 3 clusters of individuals with different profiles emerged. Individuals with greater subjective cognitive problems (cluster 1) in the attention and storage domains, reported higher perceived loneliness and stress but not depression. In contrast, individuals with the least subjective cognitive problems (cluster 3) in the storage domain, reported lower perceived loneliness. CONCLUSIONS: Individuals with higher subjective cognitive decline also report higher levels of perceived loneliness but not more depression than their peers. However, this correlation is present only for individuals with mild subjective cognitive decline (cluster 2). The implications for future research and interventions are discussed.

Temporal learning in the suprasecond range: insights from cognitive style.

The acquisition of information on the timing of events or actions (temporal learning) occurs in both the subsecond and suprasecond range. However, although relevant differences between participants have been reported in temporal learning, the role of dimensions of individual variability in affecting performance in such tasks is still unclear. Here we investigated this issue, assessing the effect of field-dependent/independent cognitive style on temporal learning in the suprasecond range. Since different mechanisms mediate timing when a temporal representation is self-generated, and when it depends on an external referent, temporal learning was assessed in two conditions. Participants observed a stimulus across six repetitions and reproduced it. Unbeknownst to them, in an internally-based learning (IBL) condition, the stimulus duration was fixed within a trial, although the number of events defining it varied; in an externally-cued learning (ECL) condition, the stimulus was defined by the same number of events within each trial, although its duration varied. The effect of the reproduction modality was also assessed (motor vs. perceptual). Error scores were higher in IBL compared to ECL; the reverse was true for variability. Field-independent individuals performed better than field-dependent ones only in IBL, as further confirmed by correlation analyses. Findings provide evidence that differences in dimensions of variability in high-level cognitive functioning, such as field dependence/independence, significantly affect temporal learning in the suprasecond range, and that this effect depends on the type of temporal representation fostered by the specific task demands.

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO).

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.

Body Representation Alterations in Patients with Unilateral Brain Damage.

OBJECTIVE: Systematic studies about the impact of unilateral brain damage on the different body representations (body schema, body structural representation, and body semantics) are still rare. Aim of this study was to evaluate body representation deficits in a relatively large sample of patients with unilateral brain damage and to investigate the impact of right or left brain damage on body representations (BRs), independently from deficits in other cognitive processes. METHOD: Sixty-four patients with unilateral stroke (22 with left brain damage, LBD; 31 with right brain damage without neglect, RBD-N; 11 with right brain damage with neglect, RBD+N) and 41 healthy individuals underwent a specific battery including BR as well as control tasks. RESULTS: In more than a third of the sample, selective (37.5%) and pure (31%) deficits of BR were presented and equally distributed among the different BRs (˜10% for each representation), with selective (27.2%) and pure (22.7%) body schema deficit mainly presented after left brain damage. As a group, patients with unilateral brain damage, independently of the side of lesion (LBD, RBD-N, RBD+N), had significantly worse performance on body structural representation with respect to healthy individuals, whereas LBD had numerically worse performance on body schema with respect to healthy individuals and RBD-N. No significant differences among groups were found on body semantics. CONCLUSION: BR deficits are not a rare consequence of unilateral brain damage and are independent of a more general cognitive dysfunction. Accordingly, the need for an accurate assessment and specific neuropsychological training in clinical settings is discussed.

Neural underpinnings of the slowness of information processing in patients with traumatic brain injury: insights from tract-based spatial statistics.

Slowness of information processing (SIP) is frequently reported after traumatic brain injury (TBI). Previous studies point toward a pivotal role of white matter damage on speed of information processing. However, little is known about the more comprehensive and ecological assessment of SIP in TBI. Here, we combined an ecological assessment of SIP with the use of tract-based spatial statistics (TBSS) on individuals' fractional anisotropy (FA) maps. Twenty-six moderate-to-severe patients with TBI (21 males and 5 females) participated in this study: 10 individuals were classified as not having SIP (SIP-) and 16 were classified as having SIP (SIP +). SIP + showed lower FA in bilateral anterior thalamic radiation, corticospinal tract, cingulum, and forceps, as well as in bilateral inferior fronto-occipital, inferior and superior longitudinal fasciculi and uncinate fasciculus. Overall, this result is consistent with and expands previous reports on information processing speed to a more comprehensive and ecological perspective on SIP in TBI.

Testing a Model of Human Spatial Navigation Attitudes towards Global Navigation Satellite Systems.

Global navigation satellite systems (GNSS) can provide better data quality for different purposes; however, some age groups might lie outside its use. Understanding the barriers to its adoption is of interest in different fields. This work aims at developing a measurement instrument of the adoption attitudes towards this technology and examining the relationship of variables such as age and gender. A UTAUT model was tested on 350 participants. The main results can be summarised as follows: (i) the proposed GNSS scale on human spatial navigation attitudes towards geopositioning technology showed optimal psychometric properties; (ii) although statistically significant differences were found in the Wayfinding Questionnaire (WQ) between men and women, these did not reach the level of statistical significance for the scores on attitudes towards GNSS; (iii) by testing a model on human spatial navigation attitudes towards geopositioning technology, it was possible to show a higher relationship with age in women.

Overcoming navigational challenges: A novel approach to the study and assessment of topographical orientation.

Several studies investigating environmental navigation require participants to navigate in virtual environments, in which the proprioceptive and vestibular components present during real environmental navigation are lost. Here, we aimed to provide a novel computerized ecological navigational battery, investigating whether the absence of proprioceptive and vestibular inputs yields a representation of the navigational space comparable to that acquired ecologically. In Study 1, 38 participants underwent two sets of tasks, one performed in a laboratory-based setting (LBS) and the other in an ecological environment (EE), with both including evaluation of route, landmark, and survey knowledge and a landmark ordering task. All tasks, except the route task, significantly correlated between EE and LBS. In LBS, performance in the landmark ordering task was predicted by that in the survey task, but not by those in the route and landmark tasks. Results of Study 1 were replicated in Study 2, in which 44 participants completed a modified and shorter online version of LBS tests. Reliability of the online LBS tests was also tested and showed a moderate-to-high internal consistency. Overall, results show that the conditions in which tasks are performed affect the acquisition of route knowledge, likely due to the lack of proprioceptive and vestibular information in LBS. However, LBS tasks presented here provide a standard battery of tests that can overcome the replicability problems encountered by ecological navigation tests, while taking into consideration all the complexities of navigational processes in terms of the use of landmark, route, and survey strategies.

Interoceptive awareness in focal brain-damaged patients.

BACKGROUND: Interoception is the basic process enabling evaluation of one's own internal state of body, but its alteration in brain-damaged patients has not been adequately investigated. Our study aimed to investigate awareness of visceral and somatosensorial sensations in brain-damaged patients with unilateral stroke. METHODS: Sixty patients (22 with left brain damage, LP; 25 with right brain damage without neglect, RPN-; and 13 with right brain-damage and extrapersonal and/or personal neglect, RPN+) and 45 healthy controls (HC) completed the Self-Awareness Questionnaire (SAQ), a self-report tool for assessing interoceptive awareness with two domains related to visceral (VD) and somatosensory feelings (SD), respectively. RESULTS: Comparing the SAQ subdomains scores between three groups of patients (LP, RPN-, and RPN+) and HC, we found that RPN+ had significantly lower scores on VD than HC and LP, whereas no significant difference was found on scores of SD between groups. CONCLUSION: Our results support the hypothesis of a right-hemispheric dominance for "interoceptive neural network" suggesting that processing of visceral sensations would be located mainly in the right hemisphere. Therefore, a careful assessment of interoceptive awareness in clinical practice would be useful to improve rehabilitation and to engage patients with deficit of interoceptive awareness in developing greater accuracy of body signals.

The dynamic contribution of the high-level visual cortex to imagery and perception.

Mental imagery and visual perception rely on the same content-dependent brain areas in the high-level visual cortex (HVC). However, little is known about dynamic mechanisms in these areas during imagery and perception. Here we disentangled local and inter-regional dynamic mechanisms underlying imagery and perception in the HVC and the hippocampus (HC), a key region for memory retrieval during imagery. Nineteen healthy participants watched or imagined a familiar scene or face during fMRI acquisition. The neural code for familiar landmarks and faces was distributed across the HVC and the HC, although with a different representational structure, and generalized across imagery and perception. However, different regional adaptation effects and inter-regional functional couplings were detected for faces and landmarks during imagery and perception. The left PPA showed opposite adaptation effects, with activity suppression following repeated observation of landmarks, but enhancement following repeated imagery of landmarks. Also, functional coupling between content-dependent brain areas of the HVC and HC changed as a function of task and content. These findings provide important information about the dynamic networks underlying imagery and perception in the HVC and shed some light upon the thin line between imagery and perception which has characterized the neuropsychological debates on mental imagery.

Field dependence-independence differently affects retrospective time estimation and flicker-induced time dilation.

Field dependence-independence (FDI) is a stable dimension of individual functioning, transversal to different cognitive domains. While the role of some individual variables in time perception has received considerable attention, it is not clear whether and how FDI influences timing abilities. In this study, we tested the hypothesis that FDI differently affects timing performance depending on whether the task requires cognitive restructuring. Participants were assessed for FDI using the embedded figures test (EFT). They performed a prospective timing task, reproducing the duration of a flickering stimulus, and a retrospective timing task, estimating the duration of the task. We expected performance of field-dependent (FD) and field-independent (FI) individuals not to differ in the prospective task, since restructuring of task material is not needed to reproduce the stimulus duration. Conversely, we predicted that FI individuals should be more accurate than FD ones in the retrospective condition, involving restructuring skills. Results show that while both FD and FI individuals under-reproduced the stimulus duration in the prospective task, only FD participants significantly underestimated the duration of the timing task in the retrospective condition. These results suggest that differences across FD and FI individuals are apparent in timing only when the task requires high-level cognitive processing; conversely, these differences do not affect basic sensory processing.

How does environmental knowledge allow us to come back home?

Herein, we investigate how the three types of mental spatial representation (landmark, route and survey) are reorganized to perform wayfinding and homing behaviour. We also investigate the contribution of visuo-spatial working memory in reaching and in vista space in performing the retracing of the path. For this purpose, we asked 68 healthy college students to learn and come back along an unknown path in a real environment and to perform two different forward and backward working memory tasks, one in the reaching space (Corsi Block-Tapping Test) and the other in a vista space (Walking Corsi Test). The results show that participants performed better when travelling the route forward (which corresponds to the originally learned direction) than when travelling the route backward (return path) and that working memory in vista space is crucial for both wayfinding and homing behaviour, while the working memory for reaching space contributes only to homing behaviour. Although homing behaviour is an early mechanism in navigation shared among many species, it represents a very complex behaviour that requires both topographic and visuo-spatial memory as well as the first two levels of environmental knowledge.

Psychosis of Alzheimer's disease: Neuropsychological and neuroimaging longitudinal study.

OBJECTIVES: Psychosis of Alzheimer's disease (AD) may represent a distinct disease phenotype; however, neuropsychological profile and neural basis linked to this phenotype have not yet been clarified. In this study, we aimed at detecting whether impairment in specific cognitive domains predicts the onset of psychosis in AD patients and what grey matter alterations, their location, and the rate of atrophy are associated with psychosis of AD. METHODS: Longitudinal neuropsychological data from AD patients with and without psychosis were analysed to determine whether the neuropsychological profile can predict the onset of psychosis. A voxel-based morphometry (VBM) on longitudinal T1-weighted images was used to explore differences in grey matter volume and in the rate of atrophy between groups. RESULTS: Noncognitive domain predicted the psychosis onset. However, AD patients with psychosis exhibited greater atrophy in the right anterior-inferior temporal lobe, including the fusiform gyrus (cluster-p-family-wise error [pfwe] < 0.05; peak-p uncorrected [pUNC] < 0.001) as well as greater rate of atrophy in the right insula than nonpsychotic patients (cluster-pFWE = 0.075; peak-pUNC < 0.001). The anterior-inferior temporal lobe is part of the ventral visual stream, and the insula plays a key role in the salience network. CONCLUSIONS: This finding suggests that damage in these areas underpins an impairment in the visual processing of the objects and an impairment in the attribution of salience to the misperceived stimuli, which in turn leads to the onset of psychosis. These findings tie in well with the neuropsychological model of psychosis, according to which the simultaneous presence of two factors, namely misperception and misattribution, underlies psychosis in dementia.

Effect of Cognitive Style on Topographical Learning Across Life Span: Insights From Normal Development.

Notwithstanding its well-established role on high-demanding spatial navigation tasks during adulthood, the effect of field dependence-independence during the acquisition of spatial navigation skills is almost unknown. This study assessed for the first time the effect of field dependence-independence on topographical learning (TL) across the life span: 195 individuals, including 54 healthy young-adults (age-range = 20-30), 46 teenagers (age-range = 11-14), and 95 children (age-range = 6-9) participated in this study. Field dependence-independence interacted with age in predicting TL. Also during childhood higher field independence was associated with better performances but not later in the life, that is, during adolescence and adulthood. This result suggests that field dependence-independence may have a role in fostering the acquisition of TL.

Effects of oral contraceptives and natural menstrual cycling on environmental learning.

BACKGROUND: Endogenous ovarian hormones as well as exogenous oestradiol and progesterone play an important role in cognitive processing. Specifically, these hormones play a role in different aspects of memory, both in terms of storage capacity and temporal duration of the mnemonic track. These hormones also have various effects on different types of memory (i.e., verbal, visuo-spatial, prospective). This study investigated the effects of hormones on topographic memory, a type of memory specifically needed to recall a pathway and to acquire spatial information about locations, distances, and directions. METHODS: We compared 25 naturally cycling women (NCW) in two different cycling phases, the early follicular phase (4th - 5th days) and the mid-luteal phase (20th-21st days), with 26 women taking oral contraceptives (OC) tested in the active pill phase (20th to 21st day of OC cycle) and the inactive pill phase (2nd to 4th day of OC cycle). Both groups performed the Walking Corsi Test to assess topographic memory in their respective cycling phases. Women were instructed to learn an eight-step sequence path and recall the path five minutes later. RESULTS: We found that the two groups differed in terms of learning the 8-step sequence path; OC users were always better (4-5 days vs. 20-21 days) than NCW. No differences emerged in the delayed recall of the same path. CONCLUSIONS: As already observed in other memory domains (i.e., verbal memory, emotional memory), OC users showed an advantage in terms of topographic learning. Our results might be explained by hormonal mechanisms and may suggest the future application of OC in women with topographic disorders or visuo-spatial difficulties.

I can see where you would be: Patterns of fMRI activity reveal imagined landmarks.

Visual mental imagery arises when perceptual information is accessed from memory, originating the experience of "seeing with the mind's eye". Different content-dependent brain areas in the human ventral visual stream are activated during visual mental imagery, similarly to what happens during visual perception. The neural patterns within these regions, but not in the early visual cortex, are similar during imagery and perception, suggesting that, in the absence of perceptual stimulation, content-dependent brain areas are able to re-instantiate specific neural patterns allowing for mental imagery. However, it remains unknown whether these areas contain adequate neural representations that create mental images or need to interact with other regions in the brain, such as the hippocampus (HC), to access the necessary information from memory. To test this hypothesis, we used functional magnetic resonance imaging and both multivoxel pattern classification and psychophysiological interaction analyses. Participants were scanned while viewing or imagining scenes of familiar environments. We found that the identity of familiar places can be decoded from the neural patterns in the parahippocampal place area (PPA), retrosplenial complex/parieto-occipital sulcus (RSC/POS) and HC, during both imagery and perception, and that item-specific information from perceived places was re-instantiated during mental imagery of the same places and vice versa. Furthermore, the right PPA significantly interacted with the right HC and RSC/POS according to the performed task. Specifically, the functional coupling between PPA and HC was higher during mental imagery, whereas the functional coupling between PPA and RSC/POS was higher during perception. Our investigation provides an important contribution to the understanding of how the brain uses previously acquired knowledge to build a mental representation of the world.

Comparing phoneme frequency, age of acquisition, and loss in aphasia: Implications for phonological universals.

Phonological complexity may be central to the nature of human language. It may shape the distribution of phonemes and phoneme sequences within languages, but also determine age of acquisition and susceptibility to loss in aphasia. We evaluated this claim using frequency statistics derived from a corpus of phonologically transcribed Italian words (phonitalia, available at phonitalia,org), rankings of phoneme age of acquisition (AoA) and rate of phoneme errors in patients with apraxia of speech (AoS) as an indication of articulatory complexity. These measures were related to cross-linguistically derived markedness rankings. We found strong correspondences. AoA, however, was predicted by both apraxic errors and frequency, suggesting independent contributions of these variables. Our results support the reality of universal principles of complexity. In addition they suggest that these complexity principles have articulatory underpinnings since they modulate the production of patients with AoS, but not the production of patients with more central phonological difficulties.

Restructuring the navigational field: individual predisposition towards field independence predicts preferred navigational strategy.

To successfully navigate within an environment, individuals have to organize the spatial information in terms of salient landmarks, paths and general layout of the navigational environment. They may differ in the strategy they adopt to orientate themselves, with some individuals preferring to use salient landmarks (landmark spatial style, L-SS), others preferring to plan routes or paths through an egocentric strategy in which landmarks are connected with each other (route spatial style, R-SS) and others still create a global map-like configuration of the environment regardless of their own position in the environment (survey spatial style, S-SS). Here, we assessed whether Field independence (FI), that is the extent to which the individual perceives part of a field as discrete from the surrounding field rather than embedded in the field, predicted the individual's spatial style. We assessed the individual's spatial style using the spatial cognitive style test (SCST) and measured FI using the group embedded figure test (GEFT). We found that FI predicted general spatial ability, with a higher level of FI being associated with better performances on the SCST. Also, Field-independent individuals showed a marked preference for an S-SS. These results suggest that a higher level of FI is associated with better performance on higher level spatial tasks (i.e. R-SS and S-SS) that is tasks requiring individuals to restructure the "navigational field" according to the navigational goal. The results also suggest that a higher level of FI makes individuals more prone to use a global and complex map-like representation of the environment.

The Tower of London (ToL) in Italy: standardization of the ToL test in an Italian population.

Deficit in planning and problem-solving, affecting a wide range of neuropsychological patients, has been widely investigated using the Tower of London (ToL) test, as developed by Shallice (Philos Trans R Soc Lond Ser B Biol Sci 298:199-209, 1). The ToL taps on several executive functions (EF), such as planning, time for planning or rule breaks, which may be usefully indexed by different ToL measurements. However, in its original version, the different aspects involved in ToL are not evaluated in a specific way.Here, we report the standardization of the ToL, on 896 individuals aged 15-86 years, taking in account individual factors (i.e. gender, age, years of education) which may affect performances on ToL. We computed several indexes on the ToL including score, planning and execution times, perseverations, rule breaks and self-monitoring. We found that these indexes were affected by individual factors such as gender, age and education. Present results not only provide extensive normative data according to gender, as well as different age and education ranges, but also represent a very useful instrument for a more fine-grained diagnosis of EF deficits in a wide range of neuropsychological patients, including traumatic brain injury and brain-damaged patients, as well as Alzheimer's disease and Parkinson's disease patients.

Functional connectivity between posterior hippocampus and retrosplenial complex predicts individual differences in navigational ability.

Individuals vary widely in their ability to orient and navigate within the environment. Previous neuroimaging research has shown that hippocampus (HC) and scene-responsive regions (retrosplenial complex [RSC] and parahippocampal gyrus/parahippocampal place area [PPA]) were crucial for spatial orienting and navigation. Resting-state functional connectivity and a self-reported questionnaire of navigational ability were used to examine the hypothesis that the pattern of reciprocal connections between these regions reflects individual differences in spatial navigation. It was found that the functional connectivity between the posterior HC and RSC was significantly higher in good than in poor navigators. These results confirmed the crucial role of hippocampal and extra-hippocampal regions in spatial navigation and provided new insight into how spontaneous brain activity may account for individual differences in spatial ability. © 2016 Wiley Periodicals, Inc.