John F. Smiley

Anatomical mechanisms and functional implications of multisensory convergence in early cortical processing.

Recent findings in both monkeys and humans indicate that multisensory convergence occurs in low-level cortical structures generally believed to be unisensory in function. In an in-depth treatment of this theme, this paper reviews anatomical and physiological findings relating to the convergence of visual, somatosensory and auditory signals at early stages of auditory cortical processing. We discuss the potential anatomical sources of the input, and the types of known projections, and attempt to integrate this information with the current hierarchical model of auditory processing. Finally, we consider the functional implications of multisensory integration in early sensory processing.

Multisensory convergence in auditory cortex, I. Cortical connections of the caudal superior temporal plane in macaque monkeys

The caudal medial auditory area (CM) has anatomical and physiological features consistent with its role as a first‐stage (or “belt”) auditory association cortex. It is also a site of multisensory convergence, with robust somatosensory and auditory responses. In this study, we investigated the cerebral cortical sources of somatosensory and auditory inputs to CM by injecting retrograde tracers in macaque monkeys. A companion paper describes the thalamic connections of CM (Hackett et al., J. Comp. Neurol. [this issue]). The likely cortical sources of somatosensory input to CM were the adjacent retroinsular cortex (area Ri) and granular insula (Ig). In addition, CM had reliable connections with areas Tpt and TPO, which are sites of multisensory integration. CM also had topographic connections with other auditory areas. As expected, connections with adjacent caudal auditory areas were stronger than connections with rostral areas. Surprisingly, the connections with the core were concentrated along its medial side, suggesting that there may be a medial‐lateral division of function within the core. Additional injections into caudal lateral auditory area (CL) and Tpt showed similar connections with Ri, Ig, and TPO. In contrast to CM injections, these lateral injections had inputs from parietal area 7a and had a preferential connection with the lateral (gyral) part of Tpt. Taken together, the findings indicate that CM may receive somatosensory input from nearby areas along the fundus of the lateral sulcus. The differential connections of CM compared with adjacent areas provide additional evidence for the functional specialization of the individual auditory belt areas. J. Comp. Neurol. 502:894–923, 2007.

Multisensory convergence in auditory cortex, II. Thalamocortical connections of the caudal superior temporal plane.

Recent studies of macaque monkey auditory cortex have revealed convergent auditory and somatosensory activity in the caudomedial area (CM) of the belt region. In the present study and its companion (Smiley et al., J. Comp. Neurol. [this issue]), neuroanatomical tracers were injected into CM and adjacent areas of the superior temporal plane to identify sources of auditory and somatosensory input to this region. Other than CM, target areas included: A1, caudolateral belt (CL), retroinsular (Ri), and temporal parietotemporal (Tpt). Cells labeled by injections of these areas were distributed mainly among the ventral (MGv), posterodorsal (MGpd), anterodorsal (MGad), and magnocellular (MGm) divisions of the medial geniculate complex (MGC) and several nuclei with established multisensory features: posterior (Po), suprageniculate (Sg), limitans (Lim), and medial pulvinar (PM). The principal inputs of CM were MGad, MGv, and MGm, with secondary inputs from multisensory nuclei. The main inputs of CL were Po and MGpd, with secondary inputs from MGad, MGm, and multisensory nuclei. A1 was dominated by inputs from MGv and MGad, with light multisensory inputs. The input profile of Tpt closely resembled that of CL, but with reduced MGC inputs. Injections of Ri also involved CM but strongly favored MGm and multisensory nuclei, with secondary inputs from MGC and the inferior division (VPI) of the ventroposterior complex (VP). The results indicate that the thalamic inputs of areas in the caudal superior temporal plane arise mainly from the same nuclei, but in different proportions. Somatosensory inputs may reach CM and CL through MGm or the multisensory nuclei but not VP. J. Comp. Neurol. 502:924–952, 2007.

A New Molecular Link between the Fibrillar and Granulovacuolar Lesions of Alzheimer's Disease

Alzheimers Disease (AD) is a progressive neurodegenerative disorder involving select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumulate hyperphosphorylated tau protein polymerized into filaments, and granulovacuolar lesions, which appear primarily within the hippocampus. The mechanism by which only select populations of neurons develop these lesions as well as the relationship between them is unknown. To address these questions, we have turned to AD tissue to search for enzymes specifically involved in tau hyperphosphorylation. Recently, we showed that the principal phosphotransferases associated with AD brain-derived tau filaments are members of the casein kinase-1 (CK1) family of protein kinases. Here we report the distribution of three CK1 isoforms (Ckialpha, Ckidelta, and Ckiepsilon) in AD and control brains using immunohistochemistry and Western analysis. In addition to colocalizing with elements of the fibrillar pathology, CK1 is found within the matrix of granulovacuolar degeneration bodies. Furthermore, levels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Ckidelta, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key role in the hyperphosphorylation of tau and in the formation of AD-related pathology.

Microarray analysis of gene expression in rat hippocampus after chronic ethanol treatment.

It is thought that changes in gene expression in the brain mediate chronic ethanol-induced complex behaviors such as tolerance, dependence, and sensitization, and also relate to ethanol-induced brain toxicity. Using high-density filter-based cDNA microarrays (GeneFilters), we analyzed the expression of over 5000 genes in the dorsal hippocampus of rats treated with 12% ethanol or tap water for 15 months. Ethanol-induced changes in gene expression were particularly prominent in two groups of genes. One group consisted of oxidoreductases, including ceruloplasmin, uricase, branched-chain alpha-keto acid dehydrogenase, NADH ubiquinone oxidoreductase, P450, NAD+-isocitrate dehydrogenase, and cytochrome c oxidase, which may be related to ethanol-induced oxidative stress. The other group of genes included ADP-ribosylation factor, RAS related protein rab10, phosphatidylinositol 4-kinase, dynein-associated polypeptides, and dynamin-1, which seem to be involved in membrane trafficking. The results may reveal some of the pathways involved in ethanol-induced pathophysiological changes.

Sources of Somatosensory Input to the Caudal Belt Areas of Auditory Cortex

The auditory cortex of nonhuman primates is comprised of a constellation of at least twelve interconnected areas distributed across three major regions on the superior temporal gyrus: core, belt, and parabelt. Individual areas are distinguished on the basis of unique profiles comprising architectonic features, thalamic and cortical connections, and neuron response properties. Recent demonstrations of convergent auditory – somatosensory interactions in the caudomedial (CM) and caudolateral (CL) belt areas prompted us to pursue anatomical studies to identify the source(s) of somatic input to auditory cortex. Corticocortical and thalamocortical connections were revealed by injecting neuroanatomical tracers into CM, CL, and adjoining fields of marmoset (Callithrix jacchus jacchus) and macaque (Macaca mulatta) monkeys. In addition to auditory cortex, the cortical connections of CM and CL included somatosensory (retroinsular, Ri; granular insula, Ig) and multisensory areas (temporal parietal occipital, temporal parietal temporal). Thalamic inputs included the medial geniculate complex and several multisensory nuclei (supra- geniculate, posterior, limitans, medial pulvinar), but not the ventroposterior complex. Injections of the core (A1, R) and rostromedial areas of auditory cortex revealed sparse multisensory connections. The results suggest that areas Ri and Ig are the principle sources of somatosensory input to the caudal belt, while multisensory regions of cortex and thalamus may also contribute. The present data add to growing evidence of multisensory convergence in cortical areas previously considered to be ‘unimodal’, and also indicate that auditory cortical areas differ in this respect.

Continuous Phencyclidine Treatment Induces Schizophrenia-Like Hyperreactivity of Striatal Dopamine Release

Functional dopaminergic hyperactivity is a key feature of schizophrenia. Recent in vivo imaging studies have demonstrated greater striatal dopamine release in response to amphetamine challenge in schizophrenia subjects than in normal controls. N-methyl-D-aspartate (NMDA) receptors are known to play a prominent role in regulation of striatal dopamine release. In humans, NMDA antagonists induce a psychotic state that closely resembles schizophrenia. The present study investigates the degree to which chronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyperreactivity of striatal dopamine release to amphetamine in rodents. Rats were treated with 10 or 15 mg/kg/d PCP for two weeks by osmotic minipump, and striatal dopamine release to amphetamine challenge (1 mg/kg) was monitored by microdialysis. PCP-treated rats showed significant enhancement in amphetamine-induced dopamine release, along with significantly enhanced locomotor activity. These findings support the concept that NMDA receptor dysfunction may contribute to dopaminergic dysfunction in schizophrenia.

Multisensory connections of monkey auditory cerebral cortex.

Functional studies have demonstrated multisensory responses in auditory cortex, even in the primary and early auditory association areas. The features of somatosensory and visual responses in auditory cortex suggest that they are involved in multiple processes including spatial, temporal and object-related perception. Tract tracing studies in monkeys have demonstrated several potential sources of somatosensory and visual inputs to auditory cortex. These include potential somatosensory inputs from the retroinsular (RI) and granular insula (Ig) cortical areas, and from the thalamic posterior (PO) nucleus. Potential sources of visual responses include peripheral field representations of areas V2 and prostriata, as well as the superior temporal polysensory area (STP) in the superior temporal sulcus, and the magnocellular medial geniculate thalamic nucleus (MGm). Besides these sources, there are several other thalamic, limbic and cortical association structures that have multisensory responses and may contribute cross-modal inputs to auditory cortex. These connections demonstrated by tract tracing provide a list of potential inputs, but in most cases their significance has not been confirmed by functional experiments. It is possible that the somatosensory and visual modulation of auditory cortex are each mediated by multiple extrinsic sources.

Nitric oxide synthase interneurons in the monkey cerebral cortex are subsets of the somatostatin, neuropeptide Y, and calbindin cells

99%) immunoreactive for somatostatin and neuropeptide Y, but did not express calbindin. The LNOS cells comprised about 30% of the somatostatin cells and about 60% of the neuropeptide Y cells. The SNOS cells were nearly always (87-98%) calbindin-immunoreactive, and were rarely or never labeled with antibodies to somatostatin or neuropeptide Y. The SNOS cells accounted for about 20% of all of the calbindin cells. The findings demonstrate that the two types of nNOS cells can be distinguished by antibodies to calbindin, somatostatin and neuropeptide Y, but none of these markers is found exclusively in nNOS cells. Nevertheless, neuropeptide Y-immunoreactivity provides a useful marker for LNOS cells, because it is very dense in these cells and only light in the interneurons that lack nNOS.

Changing plans : neural correlates of executive control in monkey and human frontal cortex

Changing plans depends on executive control, the orchestration of behavior based on knowledge of both goal and context. Dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) cortices are clearly involved in these processes. Intracranial recordings in these regions were obtained from a monkey performing an executive control-challenging task that is widely used in clinic and laboratory to assess the integrity of cognitive function, the AX version of the continuous performance task (AX-CPT), and directly compared to scalp-recorded evoked potentials in humans. In this task the subject presses a button when detecting a frequent cue–target probe sequence in a stream of letters presented on a computer screen, and withholds response following incorrect sequences. Thus correct performance requires correct encoding of cue and probe instruction and inhibitory control. Intracranial recordings showed that DLPFC in the monkey was primarily activated by conditions that required inhibition of imminent action, as had been shown in human event-related potential (ERP) recordings. Different subregions of monkey ACC were activated primarily by either initiating or inhibiting action, whereas human ERP had shown ACC activation in both situations. We suggest that simultaneous activation of both types of subregions in conflict conditions may account the ubiquitous ACC activation observed with fMRI and ERP in those conditions.