Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

     

A multivariate analysis of PET activation studies

In this paper we present a general multivariate approach to the analysis of functional imaging studies. This analysis uses standard multivariate techniques to make statistical inferences about activation effects and to describe the important features of these effects. More specifically, the proposed analysis uses multivariate analysis of covariance (ManCova) with Wilk's lambda to test for specific effects of interest (e.g., differences among activation conditions), and canonical variates analysis (CVA) to characterize differential responses in terms of distributed brain systems. The data are subject to ManCova after transformation using their principal components or eigenimages. After significance of the activation effect has been assessed, underlying changes are described in terms of canonical images. Canonical images are like eigenimages but take explicit account of the effects of error or noise. The generality of this approach is assured by the general linear model used in the ManCova. The design and inferences sought are embodied in the design matrix and can, in principle, accommodate most parametric statistical analyses. This multivariate analysis may provide a statistical approach to PET activation studies that 1) complements univariate approaches like statistical parametric mapping, and 2) may facilitate the extension of existing multivariate techniques, like the scaled subprofile model and eigenimage analysis, to include hypothesis testing and statistical inference. © 1996 Wiley-Liss, Inc.     

Top‐down versus bottom‐up attention differentially modulate frontal–parietal connectivity

The moment‐to‐moment focus of our mind's eye results from a complex interplay of voluntary and involuntary influences on attention. Previous neuroimaging studies suggest that the brain networks of voluntary versus involuntary attention can be segregated into a frontal‐versus‐parietal or a dorsal‐versus‐ventral partition—although recent work suggests that the dorsal network may be involved in both bottom‐up and top‐down attention. Research with nonhuman primates has provided evidence that a key distinction between top‐down and bottom‐up attention may be the direction of connectivity between frontal and parietal areas. Whereas typical fMRI connectivity analyses cannot disambiguate the direction of connections, dynamic causal modeling (DCM) can model directionality. Using DCM, we provide new evidence that directed connections within the dorsal attention network are differentially modulated for voluntary versus involuntary attention. These results suggest that the intraparietal sulcus exerts a baseline inhibitory effect on the frontal eye fields that is strengthened during exogenous orienting and attenuated during endogenous orienting. Furthermore, the attenuation from endogenous attention occurs even with salient peripheral cues when those cues are known to be counter predictive. Thus, directed connectivity between frontal and parietal regions of the dorsal attention network is highly influenced by the type of attention that is engaged.     

Functional reorganization of the brain in recovery from striatocapsular infarction in man.

We used positron emission tomography (PET) to study organizational changes in the functional anatomy of the brain in 10 patients following recovery from striatocapsular motor strokes. Comparisons of regional cerebral blood flow maps at rest between the patients and 10 normal subjects revealed significantly lower regional cerebral blood flow in the basal ganglia, thalamus, sensorimotor, insular, and dorsolateral prefrontal cortices, in the brainstem, and in the ipsilateral cerebellum in patients, contralateral to the side of the recovered hand. These deficits reflect the distribution of dysfunction caused by the ischemic lesion. Regional cerebral blood flow was significantly increased in the contralateral posterior cingulate and premotor cortices, and in the caudate nucleus ipsilateral to the recovered hand. During the performance of a motor task by the recovered hand, patients activated the contralateral cortical motor areas and ipsilateral cerebellum to the same extent as did normal subjects. However, activation was greater than in normal subjects in both insulae; in the inferior parietal (area 40), prefrontal and anterior cingulate cortices; in the ipsilateral premotor cortex and basal ganglia; and in the contralateral cerebellum. The pattern of cortical activation was also abnormal when the unaffected hand, contralateral to the hemiplegia, performed the task. We showed that bilateral activation of motor pathways and the recruitment of additional sensorimotor areas and of other specific cortical areas are associated with recovery from motor stroke due to striatocapsular infarction. Activation of anterior and posterior cingulate and prefrontal cortices suggests that selective attentional and intentional mechanisms may be important in the recovery process. Our findings suggest that there is considerable scope for functional plasticity in the adult human cerebral cortex.     

Regional cerebral activity associated with the incidental processing of pseudo-words

In order to study brain activity associated with “incidental” cognitive processing, regional cerebral blood flow (rCBF) was measured in six volunteers while they monitored a sequence of pseudo-words (e.g., FLOPE) for the rare occasions when the letters were displayed in blue rather than white. In the control condition, the same pseudo-word was presented repeatedly. In one experimental condition all 60 pseudo-words were different, while in the other there were 18 repetitions. Although it was not necessary to “read” the pseudo-words to perform the monitoring task, subsequent forced choice recognition memory for these stimuli was significantly greater than chance. Furthermore, there were significant differences in blood flow between the three conditions. When different pseudo-words were presented there was significantly greater activity in brain areas concerned with shape and object identity (extrastriate cortex bilaterally), with visual word form (left inferior temporal gyrus), and with articulatory word form (Broca's area) even though none of this information about the pseudo-words was needed for performance of the monitoring task. In the condition in which some of the words were repeated, there was significantly reduced activity in the right lingual gyrus. This area may therefore be a possible anatomical locus for repetition priming with verbal stimuli. These results indicate the importance of taking into account incidental processing when designing tasks for functional imaging experiments. © 1995 Wiley-Liss, Inc.     

Opponent appetitive-aversive neural processes underlie predictive learning of pain relief

Termination of a painful or unpleasant event can be rewarding. However, whether the brain treats relief in a similar way as it treats natural reward is unclear, and the neural processes that underlie its representation as a motivational goal remain poorly understood. We used fMRI (functional magnetic resonance imaging) to investigate how humans learn to generate expectations of pain relief. Using a pavlovian conditioning procedure, we show that subjects experiencing prolonged experimentally induced pain can be conditioned to predict pain relief. This proceeds in a manner consistent with contemporary reward-learning theory (average reward/loss reinforcement learning), reflected by neural activity in the amygdala and midbrain. Furthermore, these reward-like learning signals are mirrored by opposite aversion-like signals in lateral orbitofrontal cortex and anterior cingulate cortex. This dual coding has parallels to 'opponent process' theories in psychology and promotes a formal account of prediction and expectation during pain.