Towards precision medicine for phenylketonuria: The effect of restoring a strict metabolic control in adult patients with early-treated phenylketonuria.

BACKGROUND AND OBJECTIVE: Neonatal screening and early treatment have changed the natural history of PKU, preventing severe neurological and intellectual disability. Nevertheless, the outcome of the disease in early-treated adult patients (ETPKU) is less than optimal, the predictive value of metabolic biomarkers is feeble, and the recommended levels of blood phenylalanine (Phe) for adulthood are controversial. A crucial question whose answer will improve our understanding and treatment of PKU is whether cognitive outcomes can be modulated by levels of Phe even in early-treated adults. To address this question, we carried out an interventional study in seven ETPKU women planning a pregnancy. METHODS: They underwent an extensive neurocognitive assessment at baseline, and 3 and 6 months after having attained the blood Phe concentration recommended to prevent PKU fetopathy, but before pregnancy. RESULTS: After 3 and 6 months with a stable blood Phe level of about 240 µmol/L, all participants experienced significant improvements in almost all neurocognitive domains and tasks. IQ also increased of 11 to 21 points from the last assessment before enrolment. This pattern remained strong and consistent after correction for multiple comparisons. CONCLUSION: Our results indicate that a) strong cognitive improvement is possible even in adulthood and may be demonstrated by lowering Phe near normal levels; b) testing cognition under different metabolic conditions may unveil an individual vulnerability to Phe. These results pave the way for personalised treatment of the disease in adults with ETPKU.

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.

Congenital lack and extraordinary ability in object and spatial imagery: An investigation on sub-types of aphantasia and hyperphantasia.

Studies that have shown a distinction between object and spatial imagery suggest more than one type of aphantasia and hyperphantasia, yet this has not been systematically investigated in studies on imagery ability extremes. Also, if the involuntary imagery is preserved in aphantasia and how this condition affects other skills is not fully clear. We collected data on spatial and object imagery, retrospective, and prospective memory, face recognition, and sense of direction (SOD), suggesting a distinction between two subtypes of aphantasia/hyperphantasia. Spatial aphantasia is associated with difficulties in visuo-spatial mental imagery and SOD. Instead, in object aphantasia there are difficulties in imaging single items and events - with no mental visualization of objects, out-of-focus, and black-and-white mental images more frequent than expected - in SOD and face recognition. Furthermore, associative involuntary imagery can be spared in aphantasia. The opposite pattern of performance was found in spatial and object hyperphantasia.

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.

Language processing and executive functions in early treated adults with phenylketonuria (PKU).

We provide an in-depth analysis of language functions in early-treated adults with phenylketonuria (AwPKUs, N = 15-33), as compared to age- and education-matched controls (N = 24-32; N varying across tasks), through: a. narrative production (the Cinderella story), b. language pragmatics comprehension (humour, metaphors, inferred meaning), c. prosody discrimination d. lexical inhibitory control and planning (Blocked Cyclic Naming; Hayling Sentence Completion Test, Burgess & Shallice, 1997). AwPKUs exhibited intact basic language processing (lexical retrieval, phonology/articulation, sentence construction). Instead, deficits emerged in planning and reasoning abilities. Compared to controls, AwPKUs were: less informative in narrative production (lower rate of Correct Information Units); slower in metaphorical understanding and inferred meaning; less accurate in focused lexical-search (Hayling test). These results suggest that i) executive deficits in PKU cannot be explained by an accumulation of lower-order deficits and/or general speed impairments, ii) executive functions engage dedicated neurophysiological resources, rather than simply being an emergent property of lower-level systems.

Speed of processing and executive functions in adults with phenylketonuria: Quick in finding the word, but not the ladybird.

A reduction in processing speed is widely reported in phenylketonuria (PKU), possibly due to white matter pathology. We investigated possible deficits and their relationships with executive functions in a sample of 37 early-treated adults with PKU (AwPKUs). AwPKUs were not characterized by a generalized speed deficit, but instead their performance could be explained by two more specific impairments: (a) a deficit in the allocation of visuo-spatial attention that reduced speed in visual search tasks, in some reading conditions and visuo-motor coordination tasks; and (b) a more conservative decision mechanism that slowed down returning an answer across domains. These results suggest that the impairments in executive functions seen in AwPKUs are not the consequence of a generalized speed deficit. They also suggest that processing speed is linked to the efficiency of a particular cognitive component and cannot be considered a general function spanning domains. Similarities with patterns in ageing are discussed.

Neuropsychological profile of mild temporal lobe epilepsy.

OBJECTIVE: In the current literature, whether patients with mild mesial temporal lobe epilepsy (mMTLE) have typical neurocognitive profile similar to patients with treatment-refractory seizures still remains unknown. The purpose of the present work was to analyze the neuropsychological profile in a group of consecutive patients with mMTLE. METHODS: Forty consecutive patients whose conditions were diagnosed with mMTLE and 30 healthy controls (HC) were evaluated with an extensive neuropsychological battery. In addition, self-report questionnaires were also administered to evaluate the subjective impairments in prospective and retrospective memories. Finally, the levels of depression and anxiety were evaluated using the Beck Depression Inventory II (BDI-II) and the State-Trait Anxiety Inventory - Form Y1 (STAI-YI e 2). RESULTS: Patients with mMTLE patients showed higher BDI-II scores (15.9 ±â€¯13.9 vs 7.2 ±â€¯6.7; p =, 002), and higher STAI-Y1 (41.2 ±â€¯14.6 vs 32.6 ± 9.8; p =, 005) together with both objective and subjective memory deficits. Although BDI-II and STAI scores strongly correlated to the outcome in Rey Auditory Verbal Learning Test (RAVLT) and prospective and retrospective memory questionnaire (PRMQ) (p < 0.0021), these results did not change without depression scores. CONCLUSION: We showed that a specific neurocognitive profile in patients with mMTLE exists. The neuropsychological features are mood depression, verbal memory immediate and delayed deficits, and subjective prospective and retrospective memory deficits.

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.

A penny for your thoughts! patterns of fMRI activity reveal the content and the spatial topography of visual mental images.

Visual mental imagery is a complex process that may be influenced by the content of mental images. Neuropsychological evidence from patients with hemineglect suggests that in the imagery domain environments and objects may be represented separately and may be selectively affected by brain lesions. In the present study, we used functional magnetic resonance imaging (fMRI) to assess the possibility of neural segregation among mental images depicting parts of an object, of an environment (imagined from a first-person perspective), and of a geographical map, using both a mass univariate and a multivariate approach. Data show that different brain areas are involved in different types of mental images. Imagining an environment relies mainly on regions known to be involved in navigational skills, such as the retrosplenial complex and parahippocampal gyrus, whereas imagining a geographical map mainly requires activation of the left angular gyrus, known to be involved in the representation of categorical relations. Imagining a familiar object mainly requires activation of parietal areas involved in visual space analysis in both the imagery and the perceptual domain. We also found that the pattern of activity in most of these areas specifically codes for the spatial arrangement of the parts of the mental image. Our results clearly demonstrate a functional neural segregation for different contents of mental images and suggest that visuospatial information is coded by different patterns of activity in brain areas involved in visual mental imagery.

Finding my own way: an fMRI single case study of a subject with developmental topographical disorientation.

Developmental topographical disorientation (DTD) causes impaired spatial orientation and navigation from early childhood with no evidence of cerebral damage. Using fMRI and a landmark sequencing task, we investigated the hypothesis that Dr Wai's abnormal cerebral activation pattern was related to his peculiar behavioral profile. Although Dr Wai was able to correctly perform landmark sequencing, he showed a lack of activity in regions activated in all control subjects and activity in areas that were not activated in any control subject. These results are discussed in light of cognitive and functional model of navigation, with relevant implications for DTD physiology.

The multidimensional assessment of body representation and interoception in multiple sclerosis.

BACKGROUND: The mental representation of the body (or body representation, BR) derives from the processing of multiple sensory and motor inputs and plays a crucial role in guiding our actions and in how we perceive our body. Fundamental inputs for BR construction come also from the interoceptive systems which refer to the whole bidirectional processes between the brain and the body. People with Multiple sclerosis (MS) show an abnormal multisensory integration which may compromise BR and interoception integrity. However, no study has evaluated possible deficits on distinct and dissociable dimensions of body representation (i.e., action-oriented, aBR; and a nonaction-oriented body representation, NaBR) and interoception (i.e., interoceptive accuracy, interoceptive sensibility, and interoceptive awareness) in MS. OBJECTIVE: In the present study, we aimed to determine whether participants with MS present changes in BR and interoceptive dimensions. METHODS: We performed comparison analyses on tasks and questionnaires tapping all BR and interoceptive dimensions between 36 people with relapsing-remitting MS (RRMS) and 42 healthy controls, and between 23 people with progressive MS (PMS) and 33 healthy controls. RESULTS: Overall, patients with MS exhibited lower interoceptive accuracy than matched controls. The RRMS group also showed higher visceral interoceptive sensibility levels. No differences were found in BR accuracy measures, but the PMS reported longer response times when performing the aBR task. CONCLUSION: These findings open a new issue on the role of inner-signal monitoring in the body symptomatology of MS and highlight the need for an accurate BR and interoceptive assessment in a clinical setting.

The Body in Neurosciences: Representation, Perception and Space Processing.

The Special Issue "The Body in Neurosciences: Representation, Perception and Space Processing" deals with the understanding of body processing in terms of the multisensorial perception of bodily related information, interoception, and mental representation, as well as its relationship with the peripersonal, interpersonal, and extrapersonal spaces, integrating findings from normal and pathological functioning [...].

Combining the Inner Self with the Map of the Body: Evidence for White Matter Contribution to the Relation Between Interoceptive Sensibility and Nonaction-oriented Body Representation.

Very recent studies on healthy individuals suggest that changes in the sensibility toward internal bodily sensations across the lifespan affect the ability to mentally represent one's body, in terms of action-oriented and nonaction-oriented body representation (BR). Little is known about the neural correlates of this relation. Here we fill this gap using the neuropsychological model provided by focal brain damage. Sixty-five patients with unilateral stroke (20 with left and 45 with right brain damage, LBD and RBD, respectively) participated in this study. Both action-oriented BR and nonaction-oriented BR were tested; interoceptive sensibility was assessed as well. First, we tested whether interoceptive sensibility predicted action-oriented BR and nonaction-oriented BR, in RBD and LBD separately. Then, a track-wise hodological lesion-deficit analysis was performed in a subsample of twenty-four patients to test the brain network supporting this relation. We found that interoceptive sensibility predicted the performances in the task tapping nonaction-oriented BR. The higher interoceptive sensibility was, the worse patients performed. This relation was associated with the disconnection probability of the corticospinal tract, the fronto-insular tract, and the pons. We expand over the previous findings on healthy individuals, supporting the idea that high levels of interoceptive sensibility negatively affect BR. Specific frontal projections and frontal u-shaped tracts may play a pivotal role in such an effect, likely affecting the development of a first-order representation of the self within the brainstem autoregulatory centers and posterior insula and of a second-order representation of the self within the anterior insula and higher-order prefrontal areas.

Neural substrates of interoceptive sensibility: An integrated study in normal and pathological functioning.

In early studies interoception strictly referred to the awareness of visceral sensations, but recent theories have expanded this concept to denote the ongoing status of the body, including somatosensory feelings. Here, we integrated data from normal and pathological functioning to disclose neural underpinnings of interoceptive sensibility, taking into account the crucial distinction between visceral and somatosensory feelings. Twenty-seven healthy young individuals underwent structural MRI (including T1w images and DTI). Voxel-wise analyses of the gyrification index (GI) and fractional anisotropy (FA) data were performed to assess the relation between interoceptive sensibility and surface morphometry and anatomical connectivity. Thirty-three unilateral brain-damaged patients took part in this study for Voxel-Based Lesion-Symptom Mapping (VLSM) and track-wise hodological lesion-deficit analysis (TWH). All participants completed the Self-Awareness Questionnaire (SAQ), a self-report tool assessing interoceptive sensibility of visceral (F1) and somatosensory feelings (F2). Tract-Based Spatial Statistics showed that F2 was positively associated with FA in the bilateral anterior thalamic radiation, corticospinal tract, cingulum, forceps, inferior longitudinal, fronto-occipital, superior longitudinal, and uncinate fasciculi; no significant association was detected for F1. However, F1 was positively associated with GI in the left anterior cingulate cortex. VLSM showed that F1 mainly relies on the right posterior insula, whereas F2 is related mostly to subcortical nuclei and surrounding white matter in the right hemisphere. Accordingly, patients with disconnection of the anterior thalamic projection, corticospinal tract, inferior fronto-occipital, inferior longitudinal, uncinate and superior longitudinal fasciculus III showed lower scores on F2. Overall, results support the dissociation between interoceptive sensibility of visceral and somatosensory feelings.

The bodily fundament of empathy: The role of action, nonaction-oriented, and interoceptive body representations.

Mental representations with bodily contents or in various bodily formats have been suggested to play a pivotal role in social cognition, including empathy. However, there is a lack of systematic studies investigating, in the same sample of participants and using an individual differences approach, whether and to what extent the sensorimotor, perceptual, and interoceptive representations of the body could fulfill an explanatory role in the empathic abilities.To address this goal, we carried out two studies in which healthy adults were given measures of interoceptive sensibility (IS), action (aBR), and nonaction-oriented body representations (NaBR), and affective, cognitive, and motor empathy. A higher tendency to be self-focused on interoceptive signals predicted higher affective, cognitive, and motor empathy levels. A better performance in tasks probing aBR and NaBR predicted, respectively, higher motor and cognitive empathy levels.These findings support the view that the various facets of the empathic response are differently grounded in the body since they diversely involve representations with a different bodily format.Individual differences in the focus on one's internal body state representation can directly modulate all the components of the empathic experience. Instead, a body representation used interpersonally to represent both one's own body and others' bodies, in particular in its spatial specificity, could be necessary to accurately understand other people's minds (cognitive empathy), while a sensorimotor body representation used to represent both one's own body and others' bodies actions, could be fundamental for the self-awareness of feelings expressed in actions (motor empathy).

Sensitivity of conventional cognitive tests in multiple sclerosis: Application of item response theory.

BACKGROUND: Cognitive impairment (CI) is common in Multiple Sclerosis (MS), and its prevalence rate ranges between 22% and 70%. Because CI significantly impacts vocational status, caregiver burden, and quality of life, an accurate neuropsychological assessment is required. Three widely used and validated batteries for MS-associated CI are the Brief Repeatable Neuropsychological Battery (BRN-B), the Minimal Assessment of Cognitive Function (MACFIMS), and the Brief International Cognitive Assessment (BICAMS). Although similar, these batteries differ in time-consuming and in specific tests employed. This study aims to assess the sensitivity of cognitive tests included in these batteries through an Item Response Theory approach. METHODS: Ninety-seven patients with MS and 91 demographically matched controls (HC) were consecutively assessed using the three neuropsychological batteries (i.e., BRN-B, MACFIMS, and BICAMS). Continuous Response Model (CRM) was used to identify the cognitive test(s) that best discriminate patients with MS from HC. Receiver Operating Characteristic (ROC) curve analysis was used to determine the accuracy of the CRM results. RESULTS: Cognitive tests loaded on two different latent variables: the 'higher-order executive functioning,' consisting of tests assessing concept formation, problem-solving, and inhibitory control, and the 'memory and information processing speed,' comprising tests assessing long-term, working memory, and information processing speed. The Delis Kaplan Executive Functioning System-Sorting Test and the Stroop Test were the most sensitive tests in differentiating cognitive functioning between MS and HC. CONCLUSIONS: This study confirms the importance of including a more extensive executive assessment in MS clinical practice since higher-order executive functions (e.g., abstraction and inhibitory control) significantly impact patients' quality of life and functional autonomy. Clinical implications of careful dissection of executive functioning in MS neuropsychological assessment are discussed.

Assessing topographical orientation skills in cannabis users.

The long-term effects of cannabis on human cognition are still unclear, but, considering that cannabis is a widely used substance and, overall, its potential use in therapeutic interventions, it is important to evaluate them. We hypothesize that the discrepancies among studies could be attributed to the specific cognitive function investigated and that skills subserved by the hippocampus, such as the spatial orientation abilities and, specifically, the ability to form and use cognitive maps, should be more compromised than others. Indeed it has been showed that cannabis users have a reduced hippocampus and that the hippocampus is the brain region in which cannabis has the greatest effect since it contains the highest concentration of cannabinoid receptors. To test this hypothesis we asked 15 heavy cannabis users and 19 nonusers to perform a virtual navigational test, the CMT, that assesses the ability to form and use cognitive maps. We found that using cannabis has no effect on these hippocampus-dependent orientation skills. We discuss the implications of our findings and how they relate to evidence reported in the literature that the intervention of functional reorganization mechanisms in cannabis user allows them to cope with the cognitive demands of navigational tasks.

On the Embodiment of Social Cognition Skills: The Inner and Outer Body Processing Differently Contributes to the Affective and Cognitive Theory of Mind.

A specific interpretation of embodiment assigns a central role to the body representations (BR) in cognition. In the social cognition domain, BR could be pivotal in representing others' actions and states. However, empirical evidence on the relationship between different BR and social cognition, in terms of Theory of Mind (ToM), in the same sample of participants is missing. Here, this relationship was explored considering individual differences in the action-oriented BR (aBR), nonaction-oriented BR (NaBR), and subjective predisposition toward internal bodily sensations (interoceptive sensibility, ISe). Eighty-two healthy adults were given behavioral measures probing aBR, NaBR, ISe, and affective/cognitive ToM. The results suggest that NaBR, which mainly relies on exteroceptive signals, predicts individual differences in cognitive ToM, possibly because it can allow differentiating between the self and others. Instead, the negative association between affective ToM and ISe suggests that an alteration of the internal body state representation (i.e., over-reporting interoceptive sensations) can affect emotional processing in social contexts. The finding that distinct aspects of the body processing from within (ISe) and from the outside (NaBR) differently contribute to ToM provides empirical support to the BR role in social cognition and can be relevant for developing interventions in clinical settings.

"Where am I?" A snapshot of the developmental topographical disorientation among young Italian adults.

In the last decade, several cases affected by Developmental Topographical Disorientation (DTD) have been described. DTD consists of a neurodevelopmental disorder affecting the ability to orient in the environment despite well-preserved cognitive functions, and in the absence of a brain lesion or other neurological or psychiatric conditions. Described cases showed different impairments in navigational skills ranging from topographic memory deficits to landmark agnosia. All cases lacked a mental representation of the environment that would allow them to use high-order spatial orientation strategies. In addition to the single case studies, a group study performed in Canada showed that the disorder is more widespread than imagined. The present work intends to investigate the occurrence of the disorder in 1,698 young Italian participants. The sample is deliberately composed of individuals aged between 18 and 35 years to exclude people who could manifest the loss of the ability to navigate as a result of an onset of cognitive decline. The sample was collected between 2016 and 2019 using the Qualtrics platform, by which the Familiarity and Spatial Cognitive Style Scale and anamnestic interview were administered. The data showed that the disorder is present in 3% of the sample and that the sense of direction is closely related to town knowledge, navigational strategies adopted, and gender. In general, males use more complex navigational strategies than females, although DTD is more prevalent in males than in females, in line with the already described cases. Finally, the paper discusses which protective factors can reduce DTD onset and which intervention measures should be implemented to prevent the spread of navigational disorders, which severely impact individuals' autonomy and social relationships.